An Open-label, Phase II, Platform Trial Evaluating Safety and Efficacy of Multiple BI 754091 (Ezabenlimab) Anti-PD-1 Based Combination Regimens in PD-(L)1 naïve and PD-(L)1 Pretreated Patient Populations With Advanced and/or Metastatic Solid Tumours Who Have Had at Least One Line of Systemic Therapy
Phase: PHASE2
Conditions: Neoplasm Metastasis, Advanced Tumors, Metastatic Solid Tumors
Sponsor: Boehringer Ingelheim

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Clinical trial protocol Module C (ezabenlimab + BI 836880)
TITLE PAGE
Document Number:
c29377542-04
EudraCT No.
2018-002344-81
BI Trial No.
1381-0009
BI Investigational 
Medicinal Product(s)
Ezabenlimab (BI 754091 [anti-PD-1])
BI 836880 (anti-VEGF/Ang2)
Title
An open-label, Phase II trial evaluating the safety and efficacy of 
BI 836880 in combination with ezabenlimab in PD-(L)1 naïve 
and PD-(L)1 pretreated patient populations with advanced and/or 
metastatic solid tumours who have had at least one line of 
systemic therapy.
Lay Title
Platform trial module evaluating safety and efficacy of BI 836880
in combination with ezabenlimab in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced/metastatic solid 
tumours.
Clinical Phase
Phase II
Clinical Trial Leader
Phone: 
Coordinating 
Investigator
Phone: 
Status
Final Revised Protocol (based on Global Amendment 3)
Version and Date
Version: 4.0
13 JUN 2023
Page 1 of 83
Proprietary confidential information.
2023 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 MODULE C
(EZABENLIMAB + BI 836880)
Company name
Boehringer Ingelheim
Name of finished 
product :
N.A.
Name of active 
ingredient :
Ezabenlimab (BI 754091) and BI 836880
Protocol date
23 April 2020
Revision date
13 JUN 2023
BI trial number
1381-0009
Title of trial
An open-label, Phase II trial evaluating the safety and efficacy of 
BI 836880 in combination with ezabenlimab in PD-(L)1 naïve and 
PD-(L)1 pretreated patient populations with advanced and/or 
metastatic solid tumours who have had at least one line of systemic 
therapy.  
Coordinating 
Investigator
Phone: 
Trial site(s)
This multicentre trial will be conducted in North America and the 
United Kingdom.
Clinical phase
Phase II
Trial rationale
Refer to Master protocol.
Trial objective(s)
The main objective of this treatment-specific Module is to assess the 
antitumour response of ezabenlimab combined with BI 836880 in 
patients with advanced and/or metastatic solid tumours.
Trial endpoints
Refer to Master protocol.
Trial design
Open-label, multicentre, Phase II, Master design with treatment-
specific Modules. Both Module C and the Master protocol must be 
followed. Where there are differences in stringency or cut-off values 
between the Master protocol and specific module, the specific 
module takes precedence.
Total number of 
patients randomised 
Not applicable
Number of patients 
on each treatment
Approximately 150 patients are planned for Module C.

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Diagnosis
Cohort 1 GEC: Patients with locally advanced, unresectable or 
metastatic gastric adenocarcinoma or gastro-oesophageal 
adenocarcinoma with ≥1 prior systemic treatment, excluding prior 
anti-PD-1 or anti-PD-L1 based treatment.
Cohort 2: Patients with secondary resistance to anti-PD-1 or anti-
PD-L1 based therapy: Any advanced or metastatic solid tumour
(excluding non-squamous non-small cell lung cancer [NSCLC] and 
all melanoma) with previous anti-PD-1 or anti-PD-L1 based 
treatment which progressed after achieving benefit (at least stable 
disease [SD] with a minimum duration of benefit of 4 months and 
minimum treatment duration of 2 months on the previous anti-PD-1 
or anti-PD-L1 based treatment without experiencing disease 
progression during that period). 
Cohort 3: Patients with primary resistance to anti-PD-1 or anti-PD-
L1 based therapy: Select advanced or metastatic solid tumour types 
with previous anti-PD-1 or anti-PD-L1 based treatment without 
achieving benefit (RECIST v1.1 SD <4 months or progressive 
disease in <4 months while on previous anti-PD-1 or anti PD-L1 
based treatment).
Cohort 4 CRC: Locally advanced, unresectable or metastatic second 
line or greater, microsatellite stable (MSS) colorectal cancer with no 
prior anti-PD-1 or anti-PD-L1 based treatment.
Cohort 5 Endometrial: Patients with advanced endometrial
carcinoma that is not microsatellite instability-high (MSI-H) or 
mismatch repair deficient (dMMR) and who have documented 
disease progression following one line of chemotherapy and are not
candidates for curative surgery or radiation and have not been 
treated previously with anti-PD1 or anti-PDL1. Hormonal 
monotherapy does not count as a line of therapy. Patients may have 
received up to one additional line of chemotherapy if given in the 
neoadjuvant or adjuvant treatment setting. Patients who have just 
received one line of chemotherapy in the neoadjuvant or adjuvant 
treatment setting and progressed without subsequent treatment are 
also eligible.
Main in- and 
exclusion criteria
Abbreviated Inclusion Criteria 
1. At least one measurable lesion according to RECIST v1.1
2. Patient must agree to pre- and on-treatment tumour biopsies. If 
archived tumour tissue is available from the last treatment failure, 
sections may be supplied instead of a pre-treatment biopsy. 

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Abbreviated Exclusion Criteria 
1. Any exclusion criteria listed in the Master protocol.
2. Unresolved, Grade >1 toxicity before the start of treatment 
with the study drug except for hair loss (alopecia) and 
hypothyroidism that requires thyroid hormone supplements 
but is asymptomatic under therapy. 
3. Significant cardiovascular/cerebrovascular diseases (i.e. 
uncontrolled hypertension, unstable angina, history of 
infarction within past 6 months, congestive heart failure > 
New York Heart Association [NYHA] II).
4. Uncontrolled hypertension defined as: blood pressure in 
rested and relaxed condition ≥140 mmHg systolic or ≥90 
mmHg diastolic (with or without medication) measured in 
triplicate, taken 2-5 minutes apart and averaged. 
5. History of severe haemorrhagic or thromboembolic event in 
the past 12 months (excluding central venous catheter 
thrombosis and peripheral deep vein thrombosis).
6. Known inherited predisposition to bleeding or to thrombosis 
in the opinion of the Investigator.
Test product(s)
Ezabenlimab will be co-administered with BI 836880.
dose(s)
Ezabenlimab: a fixed dose of 240 mg once every 3 weeks
BI 836880: 720 mg once every 3 weeks 
method and route of 
administration
Ezabenlimab: by intravenous infusion
BI 836880: by intravenous infusion
Comparator 
product(s)
Not applicable.
dose
Not applicable.
method and route of 
administration
Not applicable.
Duration of 
treatment
Treatment may continue until progression of disease (PD), 
unacceptable toxicity, withdrawal of patient consent, or 53 cycles 
[approximately 3 years] from the start of first treatment 
administration, whichever occurs first. Patients will be allowed to 
stay on treatment in case of initial radiological PD, until progression 
is confirmed or 53 cycles from the start of first treatment 
administration if the Investigator considers that the treatment is 
beneficial for the patient
Statistical methods
Refer to Master Protocol

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FLOW CHART MODULE C BI 1381-0009
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Days
Informed consent, 
tumour 
assessment, and 
screening with 28-
day window
Screening 
with 14-day 
windowc
Cycle 1
Cycles 
2-4
Cycles 
5-11
Cycles 
12-53
End-of-
Treatment 
(EOT) Visit
30-Day
Safety 
Follow-
up
Assessments (Days)
-28 to -1
-14 to -1
1
2
8 (±1)
15 (±1)
1 (±2)
1 (±2)
1 (±2)
(within 7 days 
of EOT)
(+2)
Informed Consentb
X
Inclusion/Exclusion Criteria
X
Medical History and 
Demographicsd
X
Physical Examinationc, d, e
X
X
X
X
X
X
X
X
ECOG Performance Statusc, d, e
X
X
X (C2, 3)
X (C5, 7, 
9, 11)
X (C13, 15)
X
X
Vital Signsc, d, k
X
X
X
X
X
X
X
X
X
X
Triplicate BP and Pulse
X
X
X
X
X
X
X
X
X
X
12-Lead Digital 
Electrocardiogramc, d, f
X
X
X
X
X
X
(X)
Echocardiogram
Xm
If clinically indicated
X
Infectious Screeningl
If clinically indicated

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Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Days
Informed consent, 
tumour 
assessment, and 
screening with 28-
day window
Screening 
with 14-day 
windowc
Cycle 1
Cycles 
2-4
Cycles 
5-11
Cycles 
12-53
End-of-
Treatment 
(EOT) Visit
30-Day
Safety 
Follow-
up
Assessments (Days)
-28 to -1
-14 to -1
1
2
8 (±1)
15 (±1)
1 (±2)
1 (±2)
1 (±2)
(within 7 days 
of EOT)
(+2)
Haematology and Clinical 
Chemistry Labsc, d
X
X
X
X
X
X
X
X
X
Urinalysisc, d
X
X
X
X
X
X
X
Pregnancy Test for Women of 
Child-Bearing Potentialc, d, g
X
X
X
X
X
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
Adverse Eventsc
X
X
X
X
X
X
X
X
X
X
SAEs/AESIs considered 
related to study drug(s) and 
cancer of new histology
Tumour Assessmentsc, d, h
X
X
Can be performed according to institutional practices and SOC from the 
acknowledgement of the amendment
Patient status
X
Ezabenlimab Infusioni,j
X
X
X
X
BI 836880 Infusioni,j
X
X
X
X

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Flow Chart Footnotes:
a
All cycles are 3 weeks (21 days) in duration. Days are calculated as calendar days. The date of an assessment is considered Day 1 of the window. Patients will continue treatment with 
the study drugs until disease progression (PD) by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and/or immune-related RECIST (iRECIST), withdrawal of patient 
consent, an unacceptable toxicity occurs, or 1 year of treatment is completed, whichever occurs first. Patients will be allowed to stay on treatment in the case of initial radiological PD, if 
the Investigator feels that it is in the patient’s best interest. In addition, patients without PD may stay on trial beyond 1 year on a case-by-case basis after discussion with the Medical 
Monitor and the Sponsor. A new informed consent will be required if the patient remains on study with radiological PD. Day 1 of Cycle 1 is defined as the first day when the combination 
of BI 836880 and ezabenlimab is administered.
b
Informed consent for Module C must be obtained ≤28 days prior to the initiation of treatment. The date of the assessments is considered Day 1 of the window.
c
Screening assessments required in the Master protocol and the Module obtained ≤14 days prior to Cycle 1 Day 1 do not need to be repeated unless otherwise noted.
d
Safety laboratory assessments including haematology, serum biochemistry, and urinalysis will be performed locally. The screening medical history and demographics, physical 
examination and Eastern Cooperative Oncology Group (ECOG) performance status, vital signs (BP to be conducted in triplicate, taken 2-5 minutes apart and averaged), haematology
(including reticulocytes), clinical chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, albumin, total protein, aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, bilirubin [indirect and direct], lactate dehydrogenase, serum glucose, troponin [only at screening, C1D1, C1D8, C1D15, C2D1, C3D1, C4D1 and anytime creatine 
phosphokinase (CPK) is elevated], haptoglobin, CPK [if CPK is elevated, then CPK-muscle/brain (CPK-MB), troponin, and myoglobin should be reactively tested], serum urea nitrogen 
[or urea], serum uric acid, and thyroid panel [thyroid stimulating hormone (TSH), free T4, and free T3]), urinalysis, and screening pregnancy test should be done ≤14 days prior to 
initiation of treatment. The date of the assessments is considered Day 1 of the window. Additionally, amylase and lipase should be analysed in case of symptoms of pancreatitis. If these 
assessments are performed within 72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 Day 1 with the exception of the ECOG performance status, an abbreviated 
physical examination, vital signs (pre- and post-infusion), and a single ECG required prior to first trial dose. Baseline programmed cell death ligand 1 (PD-L1) expression level, 
microsatellite instability, and tumour mutation burden information will be collected in the electronic case report form (eCRF), if locally available. Refer to the Master protocol for 
additional details. Vital signs are checked at every visit.
e
Physical examinations will be done at screening, on Day 1 of each treatment cycle, at the end of treatment (EOT) visit, and at the 30-day safety follow-up visit. However, patients will 
have an additional abbreviated physical examination (focused on the specific disease, at the Investigator’s discretion) on Cycle 1 Day 15. ECOG performance status will be done at 
screening, on Day 1 of Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, and at the 30-day follow-up visit.
f
Single digitalised ECGs must be done. Pre ECGs are to be done before blood work or other procedures after 5 minutes of rest at screening, on Day 1 of every cycle, at the EOT visit, and 
whenever the Investigator deems it necessary. An ECG is optional at the 30-day safety follow-up visit if the EOT visit ECG was normal and no drug-related abnormalities were detected 
in on-trial ECGs (see Master protocol).
g
Women of child-bearing potential must have a  serum beta human chorionic gonadotropin (β-HCG) 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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. (see Master protocol).
h
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]). Tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment and copies may be collected by the Sponsor or designee. The same 
radiographic procedure must be used throughout the trial. Assessments will be performed by the Investigator at screening and afterwards can be performed according to institutional 
practices and standard of care (SOC) form the acknowledgement of this protocol forward every 2 cycles (6 weeks ±3 days) for the first 6 months of treatment, once every 3 cycles 
(9 weeks ±3 days) thereafter, at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator, and copies will be collected by the sponsor or 
designee.
i
Dosing of BI 836880 and ezabenlimab is described in Module C Section 4.1.
j
If the decision is made to permanently discontinue study treatments during a scheduled visit, both ezabenlimab and BI 836880 should be discontinued together and the EOT visit should be 
performed instead of the scheduled visit.

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k
See Appendix 10.7 for BP and HR management and see Appendix 10.6 for the BP monitoring and study drug administration guidelines. BP and HR should be measured before and after 
study drugs have been administered. BP and HR should be measured in triplicate, taken 2-5 minutes apart and averaged. 
l
Hepatitis B surface antigen (HBsAg; qualitative), hepatitis B core antibody (anti-HBc; qualitative), Hep B DNA, hepatitis C antibodies (Anti-HCV; qualitative), Hep C DNA, hepatitis D 
antibodies (Anti-HDV; qualitative), human immunodeficiency virus (HIV)-1 and HIV-2 antibody performed at the discretion of the Investigator where clinically indicated.
m
Echocardiogram must be collected ≤28 days prior to the initiation of treatment.
n
As of 01 June 2021, 
samples are no longer collected.  

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS MODULE C (EZABENLIMAB + BI 
836880) ...................................................................................................................2
FLOW CHART MODULE C BI 1381-0009 .........................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................15
1.2.1
BI 836880 .............................................................................................................15
1.2.2
Ezabenlimab (BI 754091) ...................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
COVID-19 Related Risks....................................................................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint................................................................................................22
2.1.3
Secondary endpoints...........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS.........................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................27
3.3.3.1
Withdrawal of patients from treatment or assessments ........................................28
4.
TREATMENTS...................................................................................................28
4.1
INVESTIGATIONAL TREATMENTS ...........................................................28
4.1.1
Identity of the Investigational Medicinal Products..........................................28
4.1.1.1
BI 836880..............................................................................................................28
4.1.1.2
Ezabenlimab..........................................................................................................28
4.2
SELECTION OF DOSES IN THE TRIAL......................................................29
4.2.1
BI 836880 .............................................................................................................29
4.2.2
Ezabenlimab ........................................................................................................30
4.2.3
Method of assigning patients to treatment groups...........................................30

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4.2.4
Blinding and procedures for unblinding...........................................................30
4.2.5
Packaging, labelling, and re-supply...................................................................30
4.2.6
Storage conditions...............................................................................................30
4.2.7
Drug accountability.............................................................................................30
4.2.8
Dose administration and modifications.............................................................30
4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................33
4.3.1
Other treatments and emergency procedures..................................................33
4.3.2
Restrictions ..........................................................................................................33
4.3.2.1
Restrictions regarding concomitant treatment ......................................................33
4.3.2.2
Permitted concomitant medications......................................................................34
4.3.2.3
Restricted concomitant medications .....................................................................34
4.3.2.4
Restrictions on diet and life style..........................................................................35
4.3.2.5
Contraception requirements..................................................................................35
4.4
TREATMENT COMPLIANCE........................................................................36
4.4.1
Ezabenlimab ........................................................................................................36
4.4.2
BI 836880 .............................................................................................................36
5.
ASSESSMENTS..................................................................................................36
5.1
ASSESSMENT OF EFFICACY........................................................................36
5.2
ASSESSMENT OF SAFETY.............................................................................37
5.2.1
Other safety parameters.....................................................................................37
5.2.2
Adverse events of special interest (AESI) .........................................................37
5.2.2.1
Persistent Hypertension Unresponsive to Treatment............................................38
5.2.3
All other AEs .......................................................................................................38
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................38
5.3.1
Assessment of pharmacokinetics .......................................................................38
5.3.2
Methods of sample collection .............................................................................38
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................39
5.5
BIOBANKING ....................................................................................................42
6.
INVESTIGATIONAL PLAN.............................................................................43
6.1
VISIT SCHEDULE.............................................................................................43
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................43

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6.2.1
Screening period..................................................................................................44
6.2.2
Treatment period ................................................................................................44
6.2.3
Follow-up period and trial completion..............................................................44
6.2.3.1
End-of-treatment visit ...........................................................................................44
6.2.3.2
30-day post-treatment safety visit.........................................................................44
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................45
7.1
STATISTICAL DESIGN – MODEL ................................................................45
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................45
7.3
PLANNED ANALYSES.....................................................................................45
7.3.1
Primary endpoint analyses.................................................................................45
7.3.2
Secondary endpoint analyses .............................................................................45
7.3.4
Safety analyses.....................................................................................................45
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................46
7.4
INTERIM ANALYSES ......................................................................................46
7.5
HANDLING OF MISSING DATA ...................................................................46
7.6
RANDOMISATION ...........................................................................................47
7.7
DETERMINATION OF SAMPLE SIZE .........................................................47
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........48
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................48
8.2
DATA QUALITY ASSURANCE ......................................................................49
8.3
RECORDS...........................................................................................................49
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................49
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........49
8.6
TRIAL MILESTONES.......................................................................................49
9.
REFERENCES....................................................................................................50
9.1
PUBLISHED REFERENCES............................................................................50
9.2
UNPUBLISHED REFERENCES......................................................................51
10.
APPENDICES.....................................................................................................52
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....52
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS..............52
10.3
PHARMACOKINETIC METHODS AND ANALYSES................................52
10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................53
10.4.1
Schedules for PK, 
 and biomarker blood sampling................................53
10.5
TRIAL BIOMARKER PLAN............................................................................56
10.6
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................56
10.7
BLOOD PRESSURE MANAGEMENT AND STUDY DRUG
ADMINISTRATION GUIDELINES................................................................57
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................58

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11.1
GLOBAL AMENDMENT 1 ..............................................................................58
11.2
GLOBAL AMENDMENT 2 ..............................................................................74
11.3
GLOBAL AMENDMENT 3 ..............................................................................82

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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANG2
Angiopoietin-2
AUC
Area under the Curve
BHM
Bayesian Hierarchical Model
BI
Boehringer Ingelheim
Cmax
Maximum Plasma Drug Concentration After a Single Dose
CRC
Colorectal Cancer
CRF
Case Report Form, paper or electronic 
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DBP
Diastolic Blood Pressure
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FFPE
Formalin Fixed and Paraffin Embedded
GEC
Gastro-oesophageal Adenocarcinoma
IB
Investigator’s Brochure
ICF
Informed Consent Form
IHC
Immunohistochemistry
irAE
Immune-Related Adverse Events
iRECIST
Immune-Related Response Evaluation Criteria in Solid Tumours
ISF
Investigator Site File
i.v.
Intravenous
LAG-3
Lymphocyte-Activation Gene 3
mAb
Monoclonal Antibody
MDSC
Myeloid-Derived Suppressor Cell

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MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
MSS
Microsatellite Stable
NSCLC
Non-Small-Cell Lung Cancer
ORR
Overall Response Rate
p.o.
per os (Orally)
PD
Progression of disease
PD-1
Programmed Cell Death 1 (receptor)
PD-L1
Programmed Cell Death Ligand 1
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PK
Pharmacokinetics
qw
Every Week
q3w
Every 3 Weeks
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SD
Stable Disease
SBP
Systolic Blood Pressure
SOC
Standard of Care
TNFα
Tumour Necrosis Factor-Alpha

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Refer to the Master protocol document to review the medical background information.  
1.2
DRUG PROFILE
1.2.1
BI 836880
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 vascular endothelial growth factor 
(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 VEGF expression levels have been correlated with poor survival 
(R15-1720). The VEGF neutralising monoclonal antibody bevacizumab has demonstrated 
anti-tumour activity in clinical trials and is currently approved for several indications and 
settings, mainly in combination with standard chemotherapy regimens (R15-1222).
Studies in mice have shown that Ang2, a ligand of the Tie2 receptor, controls vascular 
remodelling by enabling the functions of other angiogenic factors, such as VEGF (R12-
3593). Ang2 is primarily expressed by endothelial cells and 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).
VEGF-A induces accumulation of myeloid-derived suppressor cells (MDSCs), immature 
dendritic cells, Tregs and tumour-associated macrophages. MDSCs are able to control 
activation of T-cell and natural killer (NK) cells. Anti-VEGF treatment significantly enhances 
dendritic cell maturation (R17-4036, R17-4037), and decreases T-regs either by inhibiting the 
accumulation of MDSCs and immature dendritic cells in the tumour environment or directly 
through VEGF/VEGFR pathway inhibition of Tregs (R17-4038, R17-4039).
The Nanobody® technology was originally developed following the discovery that camelidae 
(camels and llamas) possess fully functional antibodies that lack light chains. These heavy 
chain antibodies contain a single variable domain (VHH) and two constant domains (CH3). 
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 antibody (VHH) and one 
Ang2-binding single domain antibody (Nanobody®). The two single domain antibody 
moieties are linked via a human serum albumin-binding Alb11 domain, serving as half-life 
extension, and glycine-serine linkers between the domains. The protein has a molecular mass 
of 40.7 kDa.
BI 836880 is highly selective for VEGF-A and Ang2, as the molecule did not bind to the
related growth factors VEGF-B, -C, -D, placental growth factor (PlGF), and angiopoietin 1

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(Ang1). BI 836880 is highly potent and showed in vivo monotherapy efficacy (tumour growth 
inhibition) in several tumour xenografts representing colon cancer (CXF 243), non-small-cell 
lung cancer (NSCLC; 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.
At the time of data cut off for the last IB version (17 Aug 2021), 421 patients had been 
treated with BI 836880 in 5 clinical trials, either as a monotherapy (n = 62) or in a 
combination therapy (n = 359). The combination therapy trials evaluate BI 836880 in 
combination with ezabenlimab, an anti-PD-1 monoclonal antibody, administered every 3 
weeks (1336-0011, 1336-0012 Part 2, 1381-0009 Module C). Of the 359 patients exposed to 
combination therapy so far, 347 patients have been treated with the recommended Phase II 
dose (RP2D).
The most frequent adverse events (AEs) in patients treated with BI 836880 monotherapy
were hypertension (54.8%), asthenia (48.4%), vomiting (29.0%), nausea (27.4%), diarrhoea
(25.8%), and constipation (25.8%). One patient (1.6%) was reported with an AE requiring
dose reduction and 13 patients (21.0%) with AEs leading to treatment discontinuation. There
were 43.5% of patients with on-treatment SAEs; hypertension and pleural effusion (3 patients
[4.8%] each) were the only SAEs reported for more than 2 patients.
After evaluating all available PK, PD, efficacy, and safety data, the dose of 720 mg
BI 836880 every 3 weeks (q3w) was determined as a RP2D. The most common AEs reported
for this dosing regimen were hypertension (73.9%), asthenia (43.5%), vomiting (34.8%), and
nausea (39.1%). Hypertension (34.8%) was also the most frequently reported Grade 3 event.
Two patients (8.7%) were reported with a Grade 4 AE; these AEs were neutropenia and
dyspnoea. One patient in this dose group was reported with fatal AEs resulting from disease
progression: metastases to liver and hepatic failure.
Data pooled from the combination trials showed that 326 patients (90.8%) treated so far have
been reported with at least 1 AE. The most common individual AE (by preferred term) has
been hypertension (20.3%), followed by asthenia (17.5%), diarrhoea (17.3%), nausea
(16.7%), fatigue (15.3%), decreased appetite (12.8%), peripheral oedema (12.3%), and
vomiting (10.3%). Six patients (1.7%) have been reported with AEs requiring dose changes;
25 patients (7.0%) had an AE leading to treatment discontinuation. Hypertension (8.4%) has
been the most frequently reported Grade 3 event. Adverse events of Grade 4 have been
reported for 13 patients (3.6%); each Grade 4 AE has been reported for a single patient. There
have been 22 patients (6.1%) with AEs resulting in death; sepsis and general physical health
deterioration (3 patients each, 0.8%) as well as respiratory failure (2 patients, 0.6%) have
been the only fatal AEs reported for more than 1 patient. Adverse events under the SMQ
haemorrhages occurred in 28 patients (7.8%), with 4 patients (1.1%) presenting AEs of

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Grade 3 and 3 patients (0.8%) presenting a Grade 5 AE. There have been 59 patients (16.4%)
reported with immune-related AEs according to investigators judgement; 7 patients (1.9%)
had Grade 3 AEs and 6 patients (1.7%) had Grade 4 AEs.
The pharmacokinetics, pharmacodynamics and immunogenicity of BI 836880 were
investigated based on data from the monotherapy Phase I studies. Maximum plasma 
concentrations were reached shortly after the end of infusion. BI 836880 plasma 
concentration remained around the maximum for up to 8 h and started to decline afterwards 
slowly. Cmax and AUC increased in a dose-proportional manner over the entire dose range. 
As expected for a nanobody, the clearance was low, resulting in a terminal half-life of ~275 h 
(~11 days). The volume of distribution was also low and in the range of the average blood 
volume. An accumulation ratio of 1.11 to 1.54 was observed, showing slight accumulation of 
BI 836880 after multiple dosing. A PopPK/PD model showed that the preliminary results of 
the combination of BI 836880 and ezabenlimab are consistent with PK results from the 
BI 836880 monotherapy studies.
Free Ang2 and free VEGF-A plasma concentrations were measured as target engagement
biomarkers. Free VEGF-A and free Ang2 were already depleted at the first post-dose
sampling point (8 h) and remained depleted over entire Cycle 1 and also over all subsequent
cycles. The depletion was independent of the dose administrated for free VEGF-A, and it was
observed for doses ≥360 mg for free Ang2.
Pre-existing anti-drug antibodies (ADAs) were detected in approximately half of patients, and
an additional 33.3% of the patients developed ADAs during treatment. There was no dose
dependency observed in the development of treatment-induced BI 836880 ADAs. The PK
was not influenced by the development of ADAs.
After evaluating all available PK, PD, efficacy, and safety data, a dose of 720 mg BI 836880
every 3 weeks in combination with 240 mg ezabenlimab was determined as the 
recommended Phase II dose (RP2D), and this was endorsed by the Safety Monitoring 
Committee.
The Residual Effect Period (REP) is the period after the last administration of study drug 
with measurable drug levels and/or pharmacodynamics effects still likely to be present. The 
REP of BI 836880 and ezabenlimab is up to 30 days.
For a more detailed description of the BI 836880 profile please refer to the current 
Investigator’s Brochures (IBs) (c02353883-09).
1.2.2
Ezabenlimab (BI 754091)
Ezabenlimab is a mouse derived; monoclonal IgG4Pro antibody (mAb) targeted to the human 
programmed cell death 1 (PD-1) immune checkpoint inhibitor. Ezabenlimab is extensively 
humanized and potently blocks PD-1/PD-L1 and PD-1/PD-L2 interactions in vitro. The mAb 
is devoid of Complement Dependent Cytotoxicity (CDC) and Antibody-Dependent Cell-
mediated Cytotoxicity (ADCC) activities.

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At the time of data cut off for the last IB version (01 Nov 2021), 117 patients with 
advanced/metastatic solid tumours have been treated with single agent ezabenlimab, 111 of 
these patients were treated with the 240 mg q3w recommended phase II dose (RP2D). 
Additionally, 881 patients have been treated with the RP2D of ezabenlimab in combination 
with other agents. Three hundred and ninety four patients treated in combination with 
BI 754111 (anti-LAG-3 mAb), 381 patients were treated in combination with BI 836880 
(VEGF/Ang-2 inhibitor), 37 patients were treated in combination with BI 891065 (SMAC 
mimetic) and 11 patients were treated in combination with BI 754111 and BI 907828 
(MDM2-p53 antagonist).Six patients were treated with the combination of ezabenlimab and 
BI 907828 (MDM2 inhibitor), 5 patients were treated with the combination of ezabenlimab 
and BI 1387446 (STING agonist), 20 patients were treated with the combination of 
ezabenlimab plus BI 765063 (SIRPαantagonist), and 27 patients were treated with the 
combination of ezabenlimab plus BI 3018078 (anti-tumour vaccine).
The currently available ezabenlimab clinical data demonstrate that it is well tolerated. The
most common AEs reported in patients treated with ezabenlimab monotherapy were fatigue
(39.3%), nausea (29.9%) and decreased appetite (21.4%). There were no Grade 5 or treatment
related Grade 4 events reported in patients treated with ezabenlimab monotherapy. 
Immune-related AEs (irAEs) were reported in 32 patients (27.4%) on ezabenlimab
monotherapy, the vast majority were Grade 1 and 2. There were no Grade 4 or Grade 5 irAEs 
and no infusion related reaction of any grade reported in patients treated with ezabenlimab
monotherapy.
Preliminary efficacy analysis shows overall objective response rate in 111 patients receiving 
240 mg ezabenlimab monotherapy to be 16.2% (15 patients with confirmed partial response 
[PR] and 3 patients with complete responses [CR]) (95% CI 9.4, 23.2). All 3 patients with 
CRs and 8 of the 15 patients with PR were still on treatment at the time of last data cut-off. 
Tumour responses were seen in diverse cancer types.
The available PK data show that ezabenlimab has a (at least) bi-phasic distribution. The
volume of distribution ranged between 4.63 L and 5.88 L. The systemic clearance of
ezabenlimab ranged between 0.00971 L/h (80mg dose) and 0.0119 L/h (400mg dose) (i.e.
approx. 0.0237 - 0.0286 L/day) resulting in gMean half-life estimates of 13.8 to 17.8 days.
Volume of distribution ranged from 4.63L to 5.88 L. The small total volume of distribution is 
consistent with a limited extravascular disposition as expected for a therapeutic antibody. 
For a more detailed description of the ezabenlimab profile please refer to the current 
Investigator’s Brochures (IBs) (c07895879-06) and the Master protocol.

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research efforts are now focusing on achieving clinical benefit using a combination therapy 
approach.
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 the antitumour 
effect of the combination of VEGF and PD-1 inhibition. Furthermore, internal Boehringer 
Ingelheim (BI) preclinical data showed an additive effect of angiopoietin inhibition to the 
dual VEGF and PD-1 inhibition (BI 836880 IB).
This scientific rationale and preclinical data support a combination trial of the triple 
inhibition of VEGF, Ang-2 and PD-1 inhibition. This trial will evaluate the tolerability of the 
combination of BI 836880 and ezabenlimab and the effect of triple inhibition in patients with 
advanced solid tumours including CRC and GEC. This will allow a decision on further 
development of this combination in these patients and the start of a dedicated Phase II
program. The therapeutic benefit or specific AEs in patients cannot always be anticipated 
during the trial setup. Later on, there may be new scientific knowledge about biomarkers and 
other factors contributing to diseases or the action of a drug. In order to be able to address 
future scientific questions, patients will be asked to voluntarily donate bio-specimens for 
banking. If the patient agrees, banked samples may be used for future drug development.
As of January 2022, a total of 134 patients have been treated in this ongoing Phase II trial. 
Clinical activity was observed across all cohorts.
DECISION TO TERMINATE THE TRIAL
Although a preliminary assessment of the available data from the ongoing clinical program 
for the ezabenlimab + BI 836880 combination exhibit signs of antitumour activity and a 
manageable safety profile for an overall positive benefit risk ratio, careful review of the full 
data set performed in the context of the current standards of care for the indications under 
study has led to the decision taken by the sponsor in December 2021 to discontinue 
recruitment in study 1381-0009, and terminate further expansion of the study. 
An important consideration in the review process was whether the investigational 
combination treatment under study, namely BI 836880 plus ezabenlimab, had demonstrated 
benefit that delivered clear improvement over the current standards of care, some of which 
had evolved over the course of the study. The measure used to evaluate efficacy was the 
Objective Response Rate (ORR) which was the primary efficacy endpoint of the trial. It is 
important to note that at the time of this evaluation all cohorts had completed planned 
enrolment, and sufficient data had been collected to support a well-informed decision. Based 
on this evaluation, the efficacy observed in the different indications did not show clear 
improvement over the standards of care relative to published efficacy results in the different 
indications, with the one possible promising result in the 2L Endometrial carcinoma cohort. 
Given the evolution of the standard of care for 2L Endometrial carcinoma to combination 
treatment with immune checkpoint inhibitor plus an tyrosine kinase inhibitor (KEYNOTE-
775), it was determined that this setting does no more present an opportunity for further 
development moving forward. Based on this evaluation, the decision was taken to terminate 
the trial.

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As a part of this decision, for patients still under active treatment, treatment with BI 836880 
plus ezabenlimab may continue until disease progression, undue toxicity, withdrawal of 
patient consent, or 53 cycles [approximately 3 years] from the start of first treatment 
administration, whichever occurs first (see Section 4.2.8, ‘Treatment duration’ for full 
details). 
1.4
BENEFIT - RISK ASSESSMENT
Both BI 836880 and ezabenlimab are currently being tested in early phase clinical trials.
As of 17 Aug 2021, 62 patients with solid tumours had been treated with BI 836880 
monotherapy in 3 Phase I clinical trials testing either an every-3-week schedule (1336-0001, 
1336-0012 Part 1) or a weekly schedule (1336-0006).
Overall, dose-limiting toxicities (DLTs) were reported for 6 patients: there was 1 patient with 
a DLT in Trial 1336-0001 and 5 patients with DLTs in Trial 1336-0006. Based on the safety 
profile and PK/PD data of these 2 trials, q3w dosing was chosen to be taken forward for the 
monotherapy and combination trials. The dose of 720 mg q3w was determined as the 
recommended Phase II dose (RP2D) for monotherapy and was later confirmed for the 
combination therapy with ezabenlimab.
Additional 359 patients with solid tumours received BI 836880 in combination with a 
checkpoint inhibitor ezabenlimab in Part 2 of a Phase I trial (1336-0012), in a 
Phase Ib trial (1336-0011), and in a Phase II trial (1381-0009, Module C); 347 of these 
patients have been treated at the recommended Phase II dose (RP2D) for the combination 
therapy.
After completing a dose escalation phase and determination of RP2D, ezabenlimab is 
currently used in an expansion phase evaluating the preliminary efficacy of the compound in 
several tumour types including NSCLC. Three doses of ezabenlimab (80, 240 and 400 mg) 
were tested in the dose escalation part of the phase I trial in 9 patients with solid tumours. No 
dose-limiting toxicities (DLTs) or drug-related serious AEs (SAEs) were observed during the 
maximum tolerated dose (MTD) evaluation period at any dose level. The most common 
reported AEs were nausea, fatigue, decreased appetite, constipation and arthralgia. Based on 
this dose escalation data, the dose of 240 mg is recommended for further development in 
monotherapy or as a starting dose in combination trials.
The combination of an immune checkpoint inhibitor with a 
 blocker has previously 
been tested in a phase I trial combining atezolizumab with bevacizumab in patients with renal 
cell carcinoma. This combination was well tolerated with most AEs reported as mild or 
moderate in severity. The only Grade 3-4 reported event was hypertension. Other reported 
AEs included check-point inhibitor related events such as fatigue, chills, diarrhoea, rash and 
pruritus and other AEs related to 
 blockade (fatigue, hypertension, andepistaxis).
Based on the mode of action of ezabenlimab and BI 836880, published and internal 
preclinical data and available clinical data, it is expected that the combination will increase 

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the anti- tumour efficacy resulting in an increase in response rate with prolonged duration of 
response as compared to each monotherapy.
Despite the positive safety profile reported for both drugs, patients should be advised of the 
potential risk of side effects from these investigational drugs. Furthermore, patients with 
uncontrolled hypertension or history of severe haemorrhage or thromboembolism are not 
allowed to participate to this study. Other side effects may be rare and unknown with 
irreversible and/or life-threatening effects.
Although rare, a potential for drug-induced liver injury (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 5.2.2, adverse events of special interest [AESIs]).
A Safety Review Committee will be responsible for the continuous assessment of the trial 
data to ensure the overall safety of the patients treated. They will also provide the 
Investigators and the Sponsor with advice about the conduct of the trial and the integrity of 
the data.
In summary, considering the unmet medical need for new treatment option in patients with 
advanced or metastatic cancer, the anti-tumour activity of a 
 blockade or PD-1 
inhibition, the safety profiles of BI 836880 and ezabenlimab monotherapy, and the existing 
data suggesting that a combination of PD-1 blockade with 
blockade is a promising 
therapeutic strategy, the benefit-risk assessment for patients enrolled into this trial is 
considered to be favourable.
Even so, patients should be advised of the potential risks of side effects from investigational 
trial treatments (e.g., relatlimab and nivolumab reports of a few cases of myocarditis). While 
some may be anticipated, others may be rare and unknown with irreversible and/or life-
threatening effects. Patients should also be advised that there are other unknown risks 
associated with participation in a clinical trial.
1.4.1
COVID-19 Related Risks
To date, there is no evidence suggesting a link between susceptibility to COVID-19 
infections and the inhibition of VEGF-A and Ang2 targeted by BI 836880. Also, there is no 
evidence suggesting a link between susceptibility to COVID-19 infections and the inhibition 
of PD-1/PDL-1 by ezabenlimab. Available non-clinical and clinical data from completed 
clinical trials have not shown an increased risk of infections with BI 836880 and 
ezabenlimab.
Considering the limited and sparse data on immune activation and the role of inflammation as 
well as other underlying factors that may increase the severity and mortality from COVID-19 
infection, there may be some factors representing the risk for using inhibitors of VEGF/Ang2 
or PD1 that are currently still unknown. The information about the risk factors, the severity
and the activity of immune response in patients with COVID-19 infections will be constantly 
monitored as it evolves.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
Refer to the Master protocol for a complete list of objectives and endpoints for the trial. 
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this treatment-specific Module is to assess the antitumour response of 
ezabenlimab combined with BI 836880 in patients with advanced and/or metastatic solid 
tumours.
2.1.2
Primary endpoint
Refer to the Master protocol document for the primary endpoint.
2.1.3
Secondary endpoints
Refer to the Master protocol document for a list of the secondary endpoints.
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase II, open-label, non-randomised, multicentre trial of BI 836880 administered in 
combination with ezabenlimab to patients in one of five cohorts shown below.

Cohort 1 GEC: Patients with locally advanced, unresectable or metastatic gastric 
adenocarcinoma or gastro-oesophageal adenocarcinoma with ≥1 prior systemic 
treatment, who have failed standard treatment, for whom no further therapy of proven 
efficacy exists, and with no prior anti-PD-1 or anti-PD-L1 based treatment. 

Cohort 2: Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based 
therapy: Any advanced or metastatic solid tumour (excluding NSCLC and all 
melanoma) with previous anti-PD-1 or anti-PD-L1 based treatment which progressed 
after achieving benefit (at least stable disease [SD] with a minimum duration of 
benefit of 4 months and minimum treatment duration of 2 months on the previous 
anti-PD-1 or anti-PD-L1 based treatment without experiencing disease progression 
during that period.

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
Cohort 3: Patients with primary resistance to anti-PD-1 or anti-PD-L1 based therapy: 
Select advanced or metastatic solid tumour types with previous anti-PD-1 or anti-PD-
L1 based treatment without achieving benefit (RECIST v1.1 SD <4 months or 
progressive disease in <4 months while on previous anti-PD-1 or anti PD-L1 based 
treatment).

Cohort 4 CRC: Locally advanced, unresectable or metastatic second line or greater, 
microsatellite stable (MSS) colorectal cancer with no prior anti-PD-1 or anti-PD-L1 
based treatment.

Cohort 5 Endometrial: Patients with advanced endometrial carcinoma that is not 
microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and 
who have documented disease progression following  one line of chemotherapy and 
are not candidates for curative surgery or radiation and have not been treated 
previously with anti-PD1 or anti-PDL1. Hormonal monotherapy does not count as a 
line of therapy.  Patients may have received up to one additional line of chemotherapy 
if given in the neoadjuvant or adjuvant treatment setting. Patients who have just 
received one line of chemotherapy in the neoadjuvant or adjuvant treatment setting 
and progressed without subsequent treatment are also eligible.

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Figure 3.1: 1
Study schema
Patients in this Module of the clinical trial will receive ezabenlimab and BI 836880 by i.v. 
infusion after signing the Master and Module informed consent forms (ICFs) and completing 
the screening processes. Treatment cycles will be 3 weeks (21 days). Safety laboratory 
assessments will be performed locally according to the Flow Chart (see Module C flow 
chart). Both Module C and the Master protocol must be followed. Where there are differences 

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in stringency or cut-off values between the Master protocol and specific module, the specific 
module takes precedence.
Tumour assessments will be performed using RECIST v1.1 and/or Immune RECIST
(iRECIST) at screening and afterwards can be performed according to institutional practices  
and SOC after acknowledgement of this protocol amendment using the same radiographic 
procedure. 
Patients will continue study treatment until disease progression (PD) according to RECIST 
v1.1 or iRECIST, withdrawal of patient consent, an unacceptable toxicity occurs, or 53 cycles 
[approximately 3 years] from the start of first treatment administration, whichever occurs 
first. Patients will be allowed to stay on treatment in the case of initial radiological PD, until 
progression is confirmed or up to 53 cycles from the start of the first treatment duration if the 
Investigator considers that it is in the patient’s best interest (see Section 4.2.8, “Treatment 
duration” for full details).
A new informed consent will be required if the patient remains on study with radiological 
PD.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
Not applicable.
3.3
SELECTION OF TRIAL POPULATION
Screening of patients for this Module of the trial is competitive, i.e. screening for this Module 
of 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 Module of the 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 (e.g., 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
Please refer to Section 8.3.1 (Source Documents) in the Master protocol for the 
documentation requirements pertaining to the inclusion and exclusion criteria. Patients must 
have one of the tumour types described in item number 2, Section 3.3.2.
3.3.2
Inclusion criteria
For inclusion in the Module, patients must fulfil all of the following criteria in addition to the 
inclusion criteria described in the Master protocol.

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1. Patient must have completed the screening process according to the Master protocol. 
Provision of signed and dated written ICF prior to any trial-specific procedures, sampling, 
or analyses (Master ICF and Module ICF).
2. Histologically confirmed diagnosis of one of the following cohorts:

Cohort 1 GEC: Locally advanced, unresectable or metastatic gastric 
adenocarcinoma or GEC.
-
Must have had no prior anti-PD-1/PD-L1 based therapy
-
Patients who have failed standard treatment or for whom no further 
therapy of proven efficacy exists
-
Patients must have been treated with at least one prior systemic treatment

Cohort 2: Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based 
therapy: Any advanced or metastatic solid tumour (excluding NSCLC and all 
melanoma) with previously anti-PD-1 or anti-PD-L1 based treatment which 
progressed after achieving benefit.
-
Must have had ≥1 line of prior systemic anticancer treatment; only one 
prior anti-PD-1/PD-L1 based therapy with the exception of BI PD-1 
investigational agent allowed. Prior anti-PD-1 or anti-PD-L1 secondary 
resistance is defined as a minimum duration of benefit (i.e., at RECIST 
v1.1 SD) of 4 months and minimum treatment duration of 2 months on the 
previous anti-PD-1 or anti-PD-L1 based treatment without experiencing 
disease progression during that period. 

Cohort 3: Patients with primary resistance to anti-PD-1 or anti-PD-L1 based 
therapy: Select advanced or metastatic solid tumour types with previous anti-PD-
1/PD-L1 based treated tumour without achieving benefit.
-
Must have had ≥1 line of prior systemic anticancer treatment; only 1 prior 
anti-PD-1/PD-L1 based therapy with the exception of BI PD-1 
investigational agent allowed.
-
Anti-PD-1 or anti-PD-L1 with primary resistance is defined as RECIST 
v1.1 stable disease (SD) less than 4 months or progressive disease in less 
than 4 months while on previous anti-PD-1 or anti-PD-L1 based treatment. 
-
Included tumour types: 
o
Previously treated CRC
o
Merkel cell carcinoma
o
Squamous cell skin carcinoma
o
Other squamous cancers:  head and neck, cervical, anal, penile, 
oesophageal and vulvar 
o
Other gastrointestinal (GI) cancers: biliary tract, gastric, 
oesophageal, GIST
o
Other thoracic cancers: small cell lung cancer (SCLC), 
mesothelioma
o
Urothelial cancers, renal cell carcinoma
o
Neuroendocrine tumours, soft-tissue sarcomas, thyroid cancer
o
Gynaecological tumours: Ovarian, endometrial and cervical
o
Other tumour types for which no therapy of proven efficacy exists, 
or which are not amenable to standard therapies and where anti-
PD-1/PD-L1 therapy may be considered in exceptional cases upon 
discussion with the Medical Monitor.

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
Cohort 4 CRC: Locally advanced, unresectable or metastatic second line or 
greater, microsatellite stable (MSS) colorectal cancer.
-
Must have had no prior anti-PD-1/PD-L1 based therapy
-
Recurrence within 6 months after completion of adjuvant therapy is 
considered as a line in the metastatic setting
-
Must have microsatellite stable disease (identified using any validated test)

Cohort 5 Advanced Endometrial cancer: Endometrial carcinoma that is pMMR 
(Mismatch Repair-Proficient)/MSS and is advanced, recurrent, or persistent and 
has relapsed or is refractory to curative therapy. 
-
Documented disease progression following one line of chemotherapy and 
may have received up to one additional line of chemotherapy if given in 
the neoadjuvant or adjuvant treatment setting. Hormonal monotherapy 
does not count as a line of therapy.
-
Must have not been treated previously with anti-PD1 or anti-PDL1
-
Patients who have just received one line of chemotherapy in the
neoadjuvant or adjuvant treatment setting and progressed without 
subsequent treatment are also eligible.
-
Must have microsatellite stable disease (identified using any validated test)
3. All patients must have at least one measurable lesion according to RECIST v1.1. Tumour 
lesions that have been irradiated at least ≥4 weeks before the start of treatment, and have 
subsequently had documented progression, may be chosen as target lesions only in the 
absence of measurable lesions that have not been irradiated.
4. Patient must agree to pre- and on-treatment tumour biopsies. If archived tumour tissue is 
available from the last treatment failure, sections may be supplied instead of a pre-
treatment biopsy.
3.3.3
Exclusion criteria
Patients must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Any exclusion criteria listed in the Master protocol.
2. Unresolved, Grade >1 toxicity before the start of treatment with the study drug except for 
hair loss (alopecia) and hypothyroidism that requires thyroid hormone supplements but is 
asymptomatic under therapy.
3. Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, 
unstable angina, history of infarction within past 6 months, congestive heart failure > 
New York Heart Association [NYHA] II):

Uncontrolled hypertension is defined as: blood pressure in rested and relaxed 
condition ≥140 mmHg, systolic or ≥90 mmHg diastolic (with or without 
medication), measured in triplicate, taken 2-5 minutes apart and averaged
according to Appendix 10.7. 

Patients with personal or family history of QT prolongation and/or long QT 
syndrome, or prolonged QTcF at baseline (> 470 ms).

LVEF < 50%
4. History of severe haemorrhagic or thromboembolic event in the past 12 months 
(excluding central venous catheter thrombosis and peripheral deep vein thrombosis).

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5. Known inherited predisposition to bleeding or to thrombosis, in the opinion of the 
investigator.
6. Patients who require full-dose anticoagulation (according to local guidelines). Only 
LMWH and ASA at doses for prevention/prophylaxis are allowed.
7. Prior anti-angiogenic therapy (with the exception of CRC Cohort [Cohort 4]). 
8. 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).
3.3.3.1
Withdrawal of patients from treatment or assessments
Refer to the Master protocol for withdrawal of patients from treatment or assessments 
guidance.
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
4.1.1.1
BI 836880
Details of the drug product, BI 836880, are presented in Table 4.1.1.1: 1. Additional details 
are presented in the BI 836880 IB and the Module C Pharmacy Manual.
Table 4.1.1.1: 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
Infusion on Day 1 of each 3-week cycle
Route of administration:
i.v. infusion
Duration of use:
Until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles
4.1.1.2
Ezabenlimab
Details of the drug product ezabenlimab are presented in Table 4.1.1.2: 1 and Table 4.1.1.2: 
2. Additional details are presented in the ezabenlimab IB and the Module C Pharmacy 
Manual.

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Table 4.1.1.2: 1
Ezabenlimab – CMC 1
Substance:
Ezabenlimab (BI 754091)
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg/mL (vial with 15 mL filling volume)
Posology:
Infusion on Day 1 of each 3-week cycle
Route of administration:
i.v. infusion
Duration of use:
Until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles
Table 4.1.1.2: 2
Ezabenlimab – CMC 2
Substance:
Ezabenlimab (BI 754091)
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg/mL (vial with 12 mL filling volume)
Posology:
Infusion on Day 1 of each 3-week cycle
Route of administration:
i.v. infusion
Duration of use:
Until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles
4.2
SELECTION OF DOSES IN THE TRIAL
Ezabenlimab and BI 836880 will be diluted and administered separately via i.v. infusion once 
every three weeks according to the details in the Module C ‘Instructions for Pharmacist’ 
Manual.
4.2.1
BI 836880
The selected dose of BI 836880 to be used in combination with ezabenlimab 240 mg is 720
mg administered via i.v. infusion once every 3 weeks. This dose of BI 836880 in combination 
with the selected dose of ezabenlimab 240 mg was selected based on the dose escalation data 
obtained in the ongoing trial 1336-0011 (refer to the BI 836880 Investigator’s Brochure [IB]).

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4.2.2
Ezabenlimab
The selected dose of ezabenlimab to be used in combination with other agents is 240 mg 
every 3 weeks. This dose was selected by using the most recent clinical information from the 
ongoing trial BI 1381.1, administering ezabenlimab monotherapy to patients with advanced 
solid tumours. PK data were collected and clinical response was observed during the conduct 
of trial BI 1381.1, providing a basis to investigate a combination approach (Ezabenlimab
Investigator Brochure).
4.2.3
Method of assigning patients to treatment groups
After assessment of all inclusion and exclusion criteria, each eligible patient will be assigned 
to the applicable open cohort. Site personnel will enter the medication number in the case 
report form (CRF).
4.2.4
Blinding and procedures for unblinding
Not applicable in this open-label trial.
4.2.5
Packaging, labelling, and re-supply
Refer to the Master protocol for this information.
4.2.6
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.
4.2.7
Drug accountability
Refer to the Master protocol for this information.
4.2.8
Dose administration and modifications
The two study drugs will be prepared and handled according to the ‘Instruction for 
Pharmacists’ Manual which will be filed in the ISF. Upon notification that a patient entered 
the study; the pharmacy will prepare the study drug in the assigned dosage for administration 
to the patient.
Ezabenlimab and BI 836880 will be given every 3 weeks as 2 separate, consecutive intra-
venous infusions by authorized site staff in a specialized unit where emergency care can be 
provided (e.g., intensive care unit available, medical personnel trained in advanced life 
support) according to ‘Instruction for Pharmacists’. The planned infusion time is 60 minutes 
(+/- 10 minutes) for ezabenlimab and 60 minutes (+/- 10 minutes) for BI 836880; 
Ezabenlimab will be administered first, then 15 minutes (+/- 10 min) after the end of the 
ezabenlimab infusion, BI 836880 will be administered. Infusion of BI 836880 should not be 
prolonged to more than 6 hours. Appropriate drugs and medical equipment to treat 

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anaphylactic reactions must be immediately available and study personnel must be trained to 
recognize and treat anaphylaxis.
In the event of an infusion-related reaction ≤ Grade 2, treat the symptoms accordingly with 
antihistamine or corticosteroids if needed. Steroids, if used to manage an infusion-related 
reaction, are to be limited to prednisone 10 mg qd or equivalent. The infusion rate of study 
drug(s) may be decreased by 50% or interrupted until resolution of the event and re-initiated 
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 an infusion-related reaction is Grade 3 or higher in severity at any point during the 
study, study drug(s) will be permanently discontinued (refer to the safety section in the 
Master protocol) and adequate therapy should be initiated to treat the AE.
Infusion rate and premedication for further treatment cycles should be adapted according to 
Investigator decision, but adaption of administration scheme needs to be agreed with by the 
Sponsor.
Premedication:
No premedication will be required for BI 836880 or ezabenlimab infusions. If a patient 
expresses signs of infusion reaction at any BI 836880 treatment, premedication will be 
considered for all subsequent treatment infusions (dosage and schedule according 
Investigator’s decision), comparable to the following scheme:

Acetaminophen/Paracetamol 650-1000 mg by mouth (p.o.), or equivalent

Antihistamine p.o. or i.v., equivalent to diphenhydramine 50 mg i.v.
Pre-treatment should be administered at sufficient time prior to initiation of infusion to allow 
the agents to exert their effect.
Drug re-administration criteria during Cycle 1
Before initiating a new treatment cycle the health status of the patient will be assessed 
according to the Module C flow chart. To continue treatment with further cycles, all of the 
following criteria must be met:
1. Pre-infusion SBP (measured in triplicate, taken 2-5 minutes apart, and averaged) 
should be < 140 mmHg and pre-infusion DBP should be < 90 mmHg; study drug 
administration of both study drugs should be temporarily delayed until BP < 140/90 
mmHg. Please see Table 10.7:1 in Appendix 10.7, which describes the guidelines for 
BP management and study drug administration.
2. QT interval corrected per Fridericia’s formula (QTcF) ≤470 ms
3. Echocardiography if clinically indicated (based on Investigator’s judgment) with Left 
Ventricular Ejection Fraction (LVEF) ≥ 50%
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 in the opinion of investigator).

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Drug re-administration criteria after the first cycle has been completed
Before initiating a new treatment cycle the health status of the patient will be assessed 
according to the Module C flow chart. To continue treatment with further cycles, all of the 
following criteria must be met:
1. Pre-infusion SBP (measured in triplicate, taken 2-5 minutes apart and averaged) 
should be < 160 mmHg and pre-infusion DBP should be < 100 mmHg; study drug 
administration of both study drugs should be temporarily delayed until BP < 
160/100. Please see Table 10.7:1 in Appendix 10.7, which describes the guidelines 
for BP management and study drug administration. 
2. QT interval corrected per Fridericia’s formula (QTcF) ≤470 ms Echocardiography if 
clinically indicated
3. Echocardiography if clinically indicated (based on investigators judgment) with Left 
Ventricular Ejection Fraction (LVEF)  ≥ 50%
4. 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 in the opinion of investigator).
In case the above mentioned criteria 2, 3, and 4 are not fulfilled the patient should be re-
evaluated as needed. Any case of a delay in treatment cycle should be communicated to the 
Medical Monitor. The investigator in agreement with the Medical Monitor and Sponsor will 
decide about further treatment of individual patient, based on known risk/benefit of BI 
836880 and ezabenlimab.
Dose reduction guidelines
Dose escalations of BI 836880 or ezabenlimab in any patient is not allowed. 
Dose reductions are not allowed for ezabenlimab in any patient.
Dose reductions are allowed only for BI 836880.
Dose reduction recommendations for BI 836880: 
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
480 mg
A dose reduction of BI 836880 from 720 mg to 480 mg is allowed, if investigator can 
attribute the AE unequivocally to the BI 836880 (for e.g., hypertension). If the reduced dose 
is still intolerable, the dose may be delayed (please see below the sub-section “Delay of 
treatment”). If the reduced dose is tolerable, and where deemed in the best interest of the 
patient, the investigator should re-escalate to the originally assigned dose of 720 mg of BI 
836880 as soon as deemed clinically appropriate.
Delay of treatment:
During combination therapy, if treatment is held or discontinued, both BI 836880 and 
ezabenlimab will be held or discontinued together. If treatment is to be restarted, preferably 
both BI 836880 and ezabenlimab must be started together. 
In some cases, in discussions with the Sponsor, treatment with one of the two investigational 
drugs can be allowed if there is an AE reported which can be clearly attributed to one of the 

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two drugs and further warrants a temporary discontinuation of this drug in the interest of the 
patient.
Treatment duration:
Treatment with BI 836880 plus ezabenlimab may continue until disease progression, undue 
toxicity, withdrawal of patient consent, or 53 cycles [approximately 3 years] from the start of 
first treatment administration, whichever occurs first. Patients will be allowed to stay on 
treatment also in the case of initial radiological PD, until progression is confirmed or up to 53 
cycles from the start of first treatment administration if the investigator considers that the 
treatment is beneficial for the patient.
Investigators may consider discontinuing BI 836880 and continue therapy with ezabenlimab
for up to 53 cycles from the start of the first treatment administration if the patient has been 
on therapy ≥ 6 months, has achieved at least SD by RECIST 1.1 and can tolerate the therapy, 
and if the investigator considers this to be in the best interest of the patient.
For any patient still on treatment with the investigational combination of BI 836880 plus 
ezabenlimab for 53 cycles from the start of the first treatment administration, treatment 
extension will be considered on a case-by-case basis upon request by the investigator for a 
maximum additional 6 cycles, to complete no later than 30 April 2025, if the investigator 
considers this to be in the best interest of the patient. After this date treatment with the 
investigational combination BI 836880 plus ezabenlimab will no longer be available.
Investigators are requested to prepare for discontinuation of patients from the current 
investigational treatment of BI 836880 plus ezabenlimab and to switch them to alternative 
available treatment options outside of the current protocol no later than by the final 
availability date of 30 April 2025.
4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.3.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used in this trial or special emergency 
procedures to be followed. Recommendations for the management of immune-related AEs
(irAEs) can be found in Appendix 10.2.
4.3.2
Restrictions
4.3.2.1
Restrictions regarding concomitant treatment
Concomitant therapy, with reasons for the treatment, must be recorded in the electronic case 
report form (eCRF) during the screening and treatment periods, starting at the date of 
signature of ICF and ending at the 30-day follow-up visit. After the 30-day follow up, only 
concomitant therapy indicated for treatment of a related AE has to be reported. If a new anti-
cancer treatment is started, it will be documented in the eCRF, on a separate page of follow-
up therapy, different from the concomitant therapies pages.

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4.3.2.2
Permitted concomitant medications

If medically feasible, patients taking regular medication should be maintained on it 
throughout the trial.

To reduce the risk of infusion related reactions, patients may be pre-treated with an 
antihistamine and acetaminophen or paracetamol. Pre-treatment should be 
administered at sufficient time prior to initiation of infusion to allow the agents to 
exert their effect.

Supportive care and other medications that are considered necessary for the patient’s 
well-being may be given at the discretion of the Investigator. This includes 
medications for the management of nausea, diarrhoea, and vomiting for which the 
patient must be treated according to institutional standards.

Blood or cell packet transfusions are allowed at any time after the start of the trial, 
except to meet inclusion criteria. There must be at least 4 weeks between a patient’s 
last transfusion and their screening laboratory assessment. Exceptions to this will be 
considered by the Sponsor on a case-by-case basis.

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 4 
weeks before the start of treatment and during the first 3 weeks of any cohort, but may 
be started thereafter.
4.3.2.3
Restricted concomitant medications

Previous anti-cancer therapy must have been discontinued before first administration 
of trial drug and the patient must have recovered from all clinically relevant reversible 
toxicities.

Concomitant anti-cancer therapy is not allowed.

Full-dose anticoagulation (according to local guidelines) is not allowed during the 
trial conduct; only low-molecular-weight heparin (LMWH) or ASA at 
prevention/prophylaxis doses are allowed.

Any concomitant medication known to prolong the QT interval is not allowed.

The following caveats apply for immunosuppressive medications:
o
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 (TNFα) blockers 
are prohibited. Use of immunosuppressive medications for the management of 
investigational product-related AEs (except irAEs from prior anti-PD-1/anti-
PD-L1 therapy) or in patients with contrast allergies is acceptable, and does 
not necessarily warrant immediate treatment discontinuation. In addition, use 
of inhaled, topical, or 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 

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contrast hypersensitivity) are acceptable upon discussion with the Medical 
Monitor.
o
For the treatment of 
 release syndrome (CRS), supportive therapy 
including steroids and/or interleukin 6 receptor (IL6R) antagonists (R15-0031) 
may be used as clinically indicated.

Other restrictions on concomitant medications are:
o
Live attenuated vaccines are prohibited during the trial through 30 days after 
the last dose of investigational product.
o
Herbal preparations/medications are not allowed throughout the trial unless 
agreed to by the Principal Investigator. These herbal medications include, but 
are not limited to: St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. If 
instructed by the Principal Investigator, patients should stop using these herbal 
medications 7 days prior to first dose of study treatment.
o
Granulocyte colony stimulating factors should not be used prophylactically 
during the first 3 weeks of treatment. Thereafter, prophylactic colony 
stimulating factors may be used according to institutional standards.
o
Palliative radiotherapy is not allowed during the first cycle for any lesion.
Palliative radiotherapy is allowed only for non-target lesions, following 
discussion with the Medical Monitor, provided that the reason for radiotherapy 
does not reflect PD and does not interfere with response assessment. 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. Unless in emergency situations, the Medical Monitor should be 
contacted prior to the administration of palliative radiotherapy in the 
expansion phase.
4.3.2.4
Restrictions on diet and life style
No restrictions.
4.3.2.5
Contraception requirements
Women of childbearing potential must use the contraception methods described in the patient 
information. Due to the advanced stage of disease of Phase I trial patient populations and the 
high medical need, females of childbearing potential can be included in this trial provided 
that they agree to use a highly-effective contraception method. These are methods of birth 
control per the International Committee on Harmonisation (ICH) M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly.
Highly-effective methods of contraception include:

Combined (oestrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation 
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
oral

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o
injectable
o
implantable

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomised partner
o
provided that partner is the sole sexual partner of the WOCBP trial participant 
and that the vasectomised partner has received medical assessment of the 
surgical success.

Sexual abstinence
o
defined as refraining from heterosexual intercourse during the entire period 
(stated above) of risk associated with the study treatments. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
Details of these contraception methods are described in the patient information in the ICF.
Women of childbearing potential must follow these methods during the trial and for at least 6 
months after the end of the trial treatment. Although use of a contraceptive pill is considered 
a highly-effective method of birth control, women of childbearing potential taking a 
contraceptive pill must use an additional barrier method for the entire duration of the trial 
treatment intake and for 6 months after the end of the trial treatment intake.
Male patients with partners of childbearing potential must agree to use condoms and ensure 
their partner is using an additional highly-effective method of birth control, during the trial 
and until at least 6 months after the end of the trial treatment.
4.4
TREATMENT COMPLIANCE
The investigational products should only be used as directed in this protocol.
4.4.1
Ezabenlimab
Refer to the Master protocol Section 4.3.
4.4.2
BI 836880
BI 836880 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 methods of collecting dosing information assure 
that total exposure can be calculated programmatically taken into account any missing doses.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
To review the section on assessing efficacy according to RECIST v1.1 (R09-0262) and 
iRECIST (R17-0923) refer to the Master protocol.

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As of the decision of Boehringer Ingelheim in December 2021 no additional patients will be 
included to this trial. From the acknowledgement of this amendment forward tumour 
assessment can be performed according to institutional practices and SOC; and not required 
to follow master protocol specified schedule.
5.2
ASSESSMENT OF SAFETY
The safety of ezabenlimab and BI 836880 will be assessed by a descriptive analysis of 
incidence and severity of AEs graded according to CTCAE (version 5.0), laboratory data, and 
results of physical examinations. Safety will be assessed in a descriptive way without 
confirmatory analysis.
Refer to the Master protocol for descriptions of the safety assessments (physical examination, 
laboratory parameters, and ECGs).
For Module C, on days of study drug administrations, blood pressure (in triplicate, taken 2-5 
minutes apart and averaged) and heart rate will be evaluated at two time points:
1. Pre-dose (-60 min. to -5 min.), before infusion of ezabenlimab; the results should be 
assessed using the BP management and study drug administration guidelines in
Appendix 10.7.
2. 5 to 10 minutes after infusion of BI 836880.
In case of an infusion-related reaction, the Investigator should decide whether to intensify or 
prolong monitoring of vital signs of the patient.
Frequency of blood pressure measurements at each time point 
Systolic and diastolic blood pressure as well as pulse rate (electronically or by palpation, 
count for 1 minute) will be measured after 5 minutes of rest in the seated position.
In addition to the laboratory safety samples described in the Master protocol, indirect and 
direct bilirubin, haptoglobin, and reticulocytes will be measured.
Screening for infections will also be conducted.  HIV-1 and HIV-2 antibody (qualitative, as 
per applicable local regulations, at the discretion of the Investigator where clinically
indicated). Hepatitis B serology (HBsAg, anti-HBc qualitative) and Hepatitis C serology 
(anti-HCV qualitative) for screening active Hepatitis B and Hepatitis C.
5.2.1
Other safety parameters
Not applicable.
5.2.2
Adverse events of special interest (AESI)
Adverse events of special interest are listed within Section 5.2.6.1.3 of the Master protocol
and in addition for Module C, the event described below in Section 5.2.2.1.

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5.2.2.1
Persistent Hypertension Unresponsive to Treatment
A hypertensive episode will be considered an AESI if:

Systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 
mmHg which persists 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.
5.2.3
All other AEs
Refer to the Master protocol for assessment of AEs.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
As of  the decision of Boehringer Ingelheim in December 2021 no additional blood samples 
for pharmacokinetics will be collected.
Blood for PK analysis of ezabenlimab and BI 836880 will be collected at the visits specified 
in the Module C flow chart and in Appendix 10.4.
Pre-dose plasma concentrations shortly before the start of infusion and plasma concentrations 
after end of infusion of ezabenlimab and BI 836880, will be evaluated descriptively 
according to BI internal Standard Operating Procedure (SOP) (001-MCS-36-472_RD-01 
[2.0] and Venn Life Sciences SOP ‘SOP-1.PKA.03 Non-compartmental PK/PD Analysis’).
Sampling in the study will be limited to sparse sampling to primarily support an exploratory 
model based analysis. The plasma concentrations observed in study 1381-0009 will be pooled 
with data from other studies for a pooled model based analysis. The model based analysis 
will be planned and documented separately according to internal and external guidelines and 
BI SOP.
5.3.2
Methods of sample collection
Blood samples should not be obtained from the arm used for infusion. In case a central 
venous access is used for infusion, the blood samples can be collected from either forearm or 
central line. The actual sampling date and time (24-hour time clock) for each sample has to 
be recorded accurately.
For quantification of analyte plasma concentrations, blood will be drawn for both 
ezabenlimab and BI 836880 at the time points specified in the PK time schedule 
in Appendix 10.4.
Samples may be used for further methodological investigations (e.g., stability testing). 
However, only data related to this trial, the analyte or bioanalytical assay will be generated by 
these additional investigations (i.e., using the sample for 
or biomarkers for PK if 

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sample volume allowed). The trial samples will be discarded after completion of the 
additional investigations.
Details on sample collection for BI 836880 and ezabenlimab characteristics, processing, 
handling, and shipment are provided in the Module C Laboratory Manual. 
If only 1 of the 2 drugs has been administered at the time of the PK sample collection, it 
should be noted. See the laboratory manual for further instructions.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a PK/pharmacodynamic relationship is planned.

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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after biobanking informed consent has been given in accordance 
with local ethical and regulatory requirements. Banked samples may be analysed in the future 
for scientific evaluations or to further, for example, the mechanistic understanding of drug 
effects and/or to identify genetic or other factors associated with response to therapy or the 
risk of adverse drug reactions.
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 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, including an audit trail for clinical 
data and samples to identify and destroy such samples according to the ICF, is in place.

A fit-for-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 consent.
The leftovers of biopsied samples as specified in Module C Section 5.4.2.3 may be banked.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and exclusion criteria for the Master and Module C and who 
have signed a written ICF (Master and Module C) are eligible for participation in this 
Module. Patients will visit the clinical site at the time points specified in the flow chart (see
Module C flow chart). If a patient misses a scheduled visit and reports to the Investigator
between the missed visit and the next scheduled visit, the assessments for the missed visit 
must be done with the actual date and the reason must be given for the delayed visit.
Once the decision is made for any reason for a patient to stop the treatment with the 
combination of BI 836880 plus ezabenlimab, an EOT visit must occur as soon as possible 
(preferably within 7 days). After the EOT visit, the patient must undergo a follow-up 
evaluation 30 (+2) days after the last administration of study therapy.
The trial will be conducted according to the principles of good clinical practice (GCP).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The procedures required at each trial visit in both portions of the trial are presented in the 
flow chart of this protocol (Module C flow chart). The key procedures required include:

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
Reporting of all AEs occurring from signing the ICF onwards until 30 days or the end 
of residual effect period (REP).

Baseline and on-treatment blood biomarker and immunogenicity assessments.

Tumour assessments (based on CT/positron emission tomography [PET] and/or 
magnetic resonance imaging [MRI] scans) according to RECIST v1.1 and iRECIST 
will be performed according to institutional practices and SOC from the 
acknowledgement of this protocol amendment forward.
6.2.1
Screening period
The screening period may occur over a period of 28 days (period within the trial and before 
the first intake of BI 836880 and ezabenlimab). For the detailed description of the tests to be 
performed during this period and their timing, please refer to the appropriate flow chart.
6.2.2
Treatment period
Please refer to the Module C flow chart for a detailed presentation of each visit during the 
treatment period.
6.2.3
Follow-up period and trial completion
6.2.3.1
End-of-treatment visit
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason, as soon as possible but no later than 7 days after discontinuation of the trial 
medication, or when the Investigator decided with the patient to permanently discontinue the 
trial medication or became aware that the trial medication had been terminated.
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 treatment discontinuation, unless it has been done within the past 
4 weeks.
The intent is to complete the EOT as soon as the decision is to remove the patient from 
treatment. The decision can occur at a scheduled visit, or in between visits. If it happens on a 
scheduled visit, the site is to complete the EOT visit assessments for that day. If it happens in 
between visits, they should have patient return within 7 days of last dose (if possible) and 
complete EOT instead of what that next scheduled visits would have been.
6.2.3.2
30-day post-treatment safety visit
The safety follow-up visit is performed 30 (+2) days after the decision to discontinue the trial 
medication. 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 if he/she discontinues because of 
PD and has performed the safety follow-up visit 30 days after EOT, or was lost to follow up, 
or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for any 
other reason, he/she will be considered as withdrawn.

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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
Refer to the Master protocol for the description of a Bayesian hierarchical model (BHM) 
approach, which effectively uses the information from different patients’ cohorts in the 
assessment of the efficacy.
Prior distribution
A non-informative normal distribution with mean 0 and standard deviation of 2 is specified 
for the mean . For the inter-cohort heterogeneity parameter τ, a half normal distribution with 
parameter 1 is used which is a very conservative assumption regarding between-cohort 
variability and hence leads to only little borrowing of data across patient cohorts because 
there is little prior information on the strength of the correlation between the treatment effects 
across cohorts
7.2
NULL AND ALTERNATIVE HYPOTHESES
This is an exploratory trial. No formal hypothesis testing is planned in this trial.
7.3
PLANNED ANALYSES
7.3.1
Primary endpoint analyses
Refer to the Master protocol.
7.3.2
Secondary endpoint analyses
Refer to the Master protocol.
7.3.4
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 AEs with an onset 
between start of treatment and end of the REP, a period of 30 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.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent adverse 
events (TEAEs, i.e., all AEs 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 AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of 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.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Please refer to Section 5.3.1.
7.4
INTERIM ANALYSES
Refer to the Master protocol.
An interim futility analysis will be performed for each cohort in the Module, if applicable.
Until any decision from the futility analysis is made, the enrolment of further patients will not 
be stopped. The two-stage design is planned to stop further recruitment of patients if the 
defined efficacy boundary (see Table 7.7: 1) is not met at the first stage.
The interim analyses will be conducted when:
•
After the 15th patient in each cohort has completed the third on-treatment 
imaging assessment (i.e. end of cycle 6).
If the 15th patient in any cohort discontinues earlier than the third on-treatment imaging, the 
interim futility analysis will be triggered at approximately 4 months after the first 
administration of that patient.
If the cohort completes the recruitment when the time point for interim analyses reaches, the 
futility analyses will not be performed.
In addition, interim analyses may be performed as each cohort is finished. Subsequent upon 
the decision of Boehringer Ingelheim in December 2021 that no additional patients will be 
included in this trial, no interim analyses will be performed.
7.5
HANDLING OF MISSING DATA
Refer to the Master protocol.

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7.6
RANDOMISATION
For general aspects please refer to the Master protocol.
7.7
DETERMINATION OF SAMPLE SIZE
For cohort 1, around 10% ORR with anti-PD-1 antibody monotherapy is assumed. In
KEYNOTE-059 (R17-3847) which is a phase II trial with pembrolizumab in patients with
advanced gastric or esophagogastric junction adenocarcinoma, the ORR in cohort 1
(pembrolizumab monotherapy in previously treated patients) was 11.2% [95%CI, 7.6-15.7]
(N=259).
For cohorts 2, 3, and 4, no literature is available for the target patients. As there are no 
treatments of proven efficacy for this population, ORR is assumed to be around 5% (cohort 2) 
and 0% (cohorts 3 and 4) respectively with anti-PD-1 antibody monotherapy.
For cohort 5, it is assumed that the ORR with standard of care is around 10%. In a phase II 
study of oxaliplatin as second-line chemotherapy in endometrial carcinoma (R20-0809), the 
ORR was 13.5% (N=52). In a phase II trial of the pegylated liposomal doxorubicin in 
previously treated metastatic endometrial cancer (R20-0810), the ORR was 9.5% [95%CI, 
2.7-22.6] (N = 42). In a phase II study evaluating docetaxel in the treatment of recurrent or 
persistent endometrial carcinoma (R20-0811), the ORR was 7.7% (N=26). In a phase II study 
of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma (R20-
0812), the ORR was 9% (N=22).
The futility boundary and early stopping probability for each cohort is described in Table 7.7: 
1.
About 30 patients each will be included in each cohort. Different homogeneous scenarios and 
heterogeneous scenarios as well as different sample sizes are considered in the simulations to 
assess the frequentist operating characteristics of the BHM approach. The simulation results 
as shown in Table 7.7: 2 below show that, with the proposed cohort size, the BHM approach 
has reasonable probability of reaching the pre-specified response rate under a wide range of 
scenarios.
Table 7.7: 1
Early stopping probabilities at interim based on observed ORR under 
different scenarios
Scenario (ORR (%)
in each patient cohort)
Early stopping criterion 
(observed ORR (%)
Early stopping probability
(30, 25, 15, 20, 30)
(<15, <10, <5, <5, <15)
12%,9%,9%,3%,14%
(20, 15, 7.5, 10, 20)
42%,32%,33%,20%,38%
(10, 5, 0, 0, 10)
82%,86%,100%,100%,78%
(10, 25, 15, 0, 10)
82%,10%,10%,100%,82%
(30, 25, 0, 20, 30)
11%,7%,100%,4%,12%
(30, 5, 0, 5, 30)
12%,83%,100%,48%,14%
(10, 5, 15, 0, 10)
82%,82%,8%,100%,81%

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Table 7.7: 2
Operating characteristics of the Bayesian Hierarchical Modelling 
approach for final analysis under different scenarios after continuing 
at the interim
Sample 
Size
Scenario 
(ORR 
(%) in 
each 
patient 
cohort)
Probability 
of 
shrinkage 
estimator 
of the 
ORR(%) >
(25, 20, 
10,15,25) 
in at least 
one cohort 
at final
Probability of shrinkage 
estimator of the ORR(%) 
> (25, 20, 10, 15,25) in 
each cohort at final
Probability 
of 
shrinkage 
estimator 
of the 
ORR(%) > 
(30, 25,
15, 20,30) 
in at least 
one cohort 
at final
Probability of shrinkage 
estimator of the ORR(%) 
> (30, 25, 15, 20,30) in 
each cohort at final
(30, 
30, 
30, 
30,30)
(30, 25, 
15, 20, 
30)
99%
82%,85%,90%,92%,79%
80%
52%,50%,51%,51%,51%
(20, 15, 
7.5, 10, 
20)
39%
11%, 13%, 24%, 
13%,12%
7%
2%,2%,1%,1%,1%,3%
(10, 5, 
0, 0, 10)
0%
0%,0%,0%,0%,0%,0%
0%
0%,0%,0%,0%,0%
(10, 25, 
15, 0, 
10)
77%
1%,56%,63%,0%,1%
41%
0%,27%,25%,0%,0%
(30, 25, 
0, 20, 
30)
97%
76%,80%,0%,88%,77%
72%
45%,46%,0%,44%,47%
(30, 5, 
0, 5, 30)
75%
57%,0%,0%,4%,59%
49%
30%,0%,0%,0%,34%
(10, 5, 
15, 0, 
10)
49%
0%,0%,49%,0%,0%
19%
0%,0%,19%,0%,0%
Number of simulations = 1000
Therefore, a total sample size of approximately 150 patients is expected.
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
Refer to Section 8 in the Master protocol for this information.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
Refer to the Master protocol.

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8.2
DATA QUALITY ASSURANCE
Refer to the Master protocol.
8.3
RECORDS
Refer to the Master protocol.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
Refer to the Master protocol.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Refer to the Master protocol.
8.6
TRIAL MILESTONES
Refer to the Master protocol.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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;45:228-47.
R12-3593
Falcon BL, Hashizume H, Koumoutsakos P, Chou J, Bready JV, Coxon A, et 
al. Contrasting actions of selective inhibitors of angiopoietin-1 and 
angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol.
2009;175(5):2159-70.
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;10:165-77.
R13-0448
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of 
angiogenesis. Nature. 2011;473:298-307.
R15-0031
Maude SL, Barrett D, Teachey DT, Grupp SA. Managing 
 release 
syndrome associated with novel T-cell-engaging therapies. Cancer J.
2014 Mar-Apr;20(2):119-22.
R15-1222
Avastin (bevacizumab) solution for intravenous infusion (Genentech) (U.S. 
prescribing information, revised: 11/2014). 2014.
R15-1719
Hassanzadeh-Ghassabeh G, Devoogdt N, de Pauw P, Vincke C,
Muyldermands S. Nanobodies and their potential applications. Nanomedicine 
(Lond). 2013;8(6):1013-26.
R15-1720
Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. 
Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin 
Oncol. 2009;6(6):327-38.
R17-3847
KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) 
monotherapy in patients with previously treated advanced gastric cancer. 
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.
R17-4036
Gabrilovich D, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to 
r enhance the efficacy of cancer 
immunotherapy by improving endogenous dendritic cell function. Clin Cancer 
Res. 1999 Oct;5(10):2963-70.

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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):1115-24.
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):6171-80.
R20-0809
Fracasso PM, Blessing JA, Molpus KL, Adler LM, Sorosky JI, Rose PG. 
Phase II study of oxaliplatin as second-line chemotherapy in endometrial 
carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 
2006;103:523-6.
R20-0810
Muggia FM, Blessing JA, Sorosky J, Reid GC. Phase II trial of the pegylated 
liposomal doxorubicin in previously treated metastatic endometrial cancer: a 
Gynecologic Oncology Group study. J Clin Oncol. 2002 May 1;20:2360-4.
R20-0811
Garcia AA, Blessing JA, Nolte S, Mannel RS; Gynecologic Oncology Group. 
A phase II evaluation of weekly docetaxel in the treatment of recurrent or 
persistent endometrial carcinoma: a study by the Gynecologic Oncology 
Group. Gynecol Oncol. 2008;111:22-6.
R20-0812
Miller DS, Blessing JA, Lentz SS, Waggoner SE. A phase II trial of topotecan 
in patients with advanced, persistent, or recurrent endometrial carcinoma: a 
gynecologic oncology group study. Gynecol Oncol. 2002;87:247-51.
9.2
UNPUBLISHED REFERENCES
c02353883-09
 Investigator’s Brochure BI 836880 Version 9 of 03 Nov 2021.
c07895879-06
 Investigator’s Brochure ezabenlimab Version 6 of 19 January 
2022.

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10.
APPENDICES
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST
Refer to the Master protocol Appendix 10.1.
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS
Refer to the Master protocol Appendix 10.2.
10.3
PHARMACOKINETIC METHODS AND ANALYSES 
Not applicable.

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10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD SAMPLING 
10.4.1
Schedules for PK, 
 and 
 blood sampling 
According to Section 4.2.8 of the protocol, the infusion time may be adapted for BI 836880. PKs are timed from the start of ezabenlimab
infusion. In this case, the PK sampling referring to the ‘end’ time of the infusion should be performed shortly after the end of infusion including
flushing of the tubes, no matter the duration of the infusion. The subsequently requested PK sampling should be drawn as planned. Do not adapt 
the time because of the variation of the duration of the infusion schema.
Table 10.4.1:1
Time schedule for PK, 
 and 
 blood sampling in Cycle 1
Day
Time Point 
[hh:min]/ 
event
CRF Time
/PTM
PKa
BI 836880
PKa
Ezabenlimab
 
Ezabenlimab
and
 BI 836880
and
1
Just before drug 
infusion
-0:05
X
X
X
X
X
X
X
Ezabenlimab
infusion
0:00
BI 836880 
infusion
1:15
After end of BI 
836880 infusion
2:15
X
X
2
24:00
24:00
X
X
X
X
8
168:00
X
X
X
X
15
336:00
X
X
X
X
X
X

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 BI = Boehringer Ingelheim; CRF = Case Report Form; PTM = planned time; MDSC = myeloid-derived suppressor cells; 
 
a The following windows of time are allowed for PK sampling:

Predose samples (PTM -0:05): within 1 hour before ezabenlimab infusion

On Day 1 (PTM 2:15): After end of BI 836880 infusion

On Day 2 (PTM 24:00): within ±2 hours of designated time

On Day 8 and 15 (PTM 168:00 and 336:00): within ±24 hours of designated time
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data evaluation.
b As of 01 June 2021, 
samples are no longer collected.
From December 2021 on, no further blood samples should be obtained for central lab shipments.

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Table 10.4.1: 2  
Time schedule for PK, 
 and 
 blood sampling from Cycle 2 onwards
Cycle
Day
Time Point 
[hh:min]/ event
CRF 
Time
/PTM
PKa
BI 836880
PKa
Ezabenlimab
 
Ezabenlimab 
and 
BI 
836880
and
2, 4, 8
1
Before start of 
infusion
-0:05
X 
X
X (C4 & C8)
X (only cycle 
2 and 4)
X (only cycle 2 
and 4)
X (only cycle 
2 and 4)
Ezabenlimab
infusion
0:00
BI 836880 
infusion
1:15
After end of BI 
836880 infusion
2:15
X
X
5, 6
Before start of 
infusion
-0:05
X
X
3, 12, 
16
Before start of 
infusion
-0:05
X
X
X
X (only 
cycle 3)
EOT
X
X
X
30-Day 
FU
X
X
X
 BI = Boehringer Ingelheim; CRF = Case Report Form; PTM = planned time; EOT = end of treatment; FU = follow up; MDSC = myeloid-derived suppressor cells; 
a The following windows of time are allowed for PK sampling:

Predose samples (PTM -0:05): within 1 hour before next ezabenlimab infusion

Postdose samples (PTM 2:15): After end of BI 836880 infusion
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data evaluation.
b As of 01 June 2021, 
 samples are no longer collected.
From December 2021 on, no further blood samples should be obtained for central lab shipments.

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10.5
TRIAL BIOMARKER PLAN
Biomarker collections are included in Appendix 10.4.1.
10.6
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 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 and pulse measurements will be taken 2-5 minutes apart and all three results have to be 
entered in the eCRF. The average of the 3 readings must meet criteria.
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 measurements 
(SBPM) communicated from patient to investigator are not considered valuable for study 
related decisions.

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10.7
BLOOD PRESSURE MANAGEMENT AND STUDY DRUG
ADMINISTRATION GUIDELINES
Table 10.7:1 BP management and study drug administration guidelines following completion 
of Cycle 1, based on pre-infusion SBP and DBP measured on study 
drug administration visits. Prior to Cycle 2, BP guidelines follow 
inclusion/exclusion criteria. 
Pre-infusion clinic 
BP (mmHg) on 
pre-planned 
infusion visits
SBP <160 and 
DBP <100
SBP 160-179 or 
DBP 100-109
SBP≥180 or 
DBP≥110
Hypertensive 
crisis**
Action to be taken 
with BI 836880 
and ezabenlimab
Proceed with 
study drug 
administration 
as scheduled / 
re-start.
Temporarily delay 
administration of both study 
drugs until BP < 160/100.
Delay 
administration 
of both study 
drugs until next 
pre-scheduled 
study drug 
administration.
Discontinue 
both study 
drugs.
Antihypertensive
treatment
As deemed 
necessary by 
the 
investigator.*
Wait 10-15 minutes and 
ensure patient is relaxed, 
and re-measure BP:
If BP <160/100 on re-
assessment, administer both 
study drugs;
If SBP remains 160-179 or 
DBP 100-109, initiate / 
modify antihypertensive 
regimens, delay 
administration of both study 
drugs, and re-assess within 
12-48 hours of 
antihypertensive agent 
initiation/modification.
After 12-48 hours:
If BP <160/100, administer 
both study drugs.
If BP remains ≥160/100, 
repeat after 10-15 minutes; 
if BP remains ≥160/100 
hold study drug 
administration until next 
pre-planned infusion visit, 
and initiate / modify 
antihypertensive regimens.
Initiate / modify 
antihypertensive 
regimens, and 
re-assess at the 
next scheduled 
infusion visit. 
Emergency 
admission
for in-patient 
care
* Investigators should consider initiating / modifying antihypertensive regimens if SBP < 160 mmHg or DBP > 90 mmHg if 
their medical assessment is that lowering BP further is clinically indicated (for example, patient has cardiovascular 
risk factors), and discontinuing or modifying antihypertensive agents if there are symptoms /signs of hypotension.
** Hypertensive crisis defined as patients with significantly elevated blood pressure with signs or symptoms of acute, 
ongoing target-organ damage.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
14 Jul 2021
EudraCT number
EU number
2018-002344-81
BI Trial number
1381-0009
BI Investigational Medicinal 
Product(s)
Ezabenlimab (BI 754091 [anti-PD-1])
BI 836880 (anti-VEGF/Ang2)
Title of protocol
An open-label, Phase II trial evaluating the safety 
and efficacy of BI 836880 in combination with 
ezabenlimab in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced 
and/or metastatic solid tumours who have had at 
least one line of systemic therapy
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
BI Investigational Medicinal Products
Description of change
Ezabenlimab (BI 754091 [(anti-PD-1]))
BI 836880 (anti-VEGF/Ang2)
Rationale for change
Ezabenlimab is the new name for BI 754091.
Section to be changed
Title 
Description of change
An open-label, Phase II trial evaluating the safety 
and efficacy of BI 836880 in combination with 
ezabenlimabBI 754091 in PD-(L)1 naïve and 
PD-(L)1 pretreated patient populations with 
advanced and/or metastatic solid tumours who 
have had at least one line of systemic therapy  

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Rationale for change
Ezabenlimab is the new name for BI 754091.
Section to be changed
Lay Title
Description of change
Platform trial module evaluating safety and 
efficacy of BI 836880 in combination with 
ezabenlimabBI 754091 in PD-(L)1 naïve and 
PD-(L)1 pretreated patient populations with 
advanced/metastatic solid tumours.
Rationale for change
Ezabenlimab is the new name for BI 754091.
Section to be changed
Coordinating Investigator
Description of change
Rationale for change
 will replace 
 as the 
coordinating investigator.
Section to be changed
Synopsis Trial design
Description of change
Open-label, multicentre, Phase II, Master design 
with treatment-specific Modules. Both Module C 
and the Master protocol must be followed. 
Where there are differences in stringency or 
cut-off values between the Master protocol and 
specific module, the specific module takes 
precedence.
Rationale for change
To clarify that the Module values take precedence 
over the Master protocol.
Section to be changed
Synopsis Diagnosis and Section 3.1 Overall Trial 
Design and Plan and Section 3.3.2 Inclusion 
criteria
Description of change
Cohort 2: Patients with secondary resistance to 
anti-PD-1 or anti-PD-L1 based therapy: Any 
advanced or metastatic solid tumour (excluding 
non-squamous non-small cell lung cancer 
([NSCLC]) and all melanoma)…
Cohort 5…. Hormonal monotherapy does not 
count as a line of therapy.
Rationale for change
To clarify criteria for the trial cohorts. 
Section to be changed
Synopsis Main in- and exclusion criteria and 
Section 3.3.2 Inclusion criteria
Description of change
Patient must agree to pre- and on-treatment 
tumour biopsies. If archived tumour tissue is 
available from the last treatment failure, sections 
may be supplied instead of a pre-treatment 
biopsy. If the patient does not have an archival 
tumour tissue sample and is not biopsiable 

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because of a safety concern the patient could be 
considered for study after discussion with the 
Medical Monitor to allow for a tumour type of 
interest.
Rationale for change
To clarify which patients are eligible for 
enrolment. 
Section to be changed
Synopsis Main in- and exclusion criteria
Description of change
2 Persistent toxicity from previous treatments that 
has not resolved to ≤Grade 1 with the exception 
of alopeciaUnresolved, Grade >1 toxicity 
before the start of treatment with the study 
drug except for hair loss (alopecia) and 
hypothyroidism that requires thyroid hormone 
supplements but is asymptomatic under 
therapy. 
Rationale for change
To clarify exclusion criteria guidelines for 
toxicity related to prior treatment. 
Section to be changed
Synopsis Main in- and exclusion criteria
Description of change
4 Uncontrolled hypertension defined as: blood 
pressure in rested and relaxed condition ≥ 140 
mmHg systolic or ≥ 90 mmHg diastolic (with or 
without medication) measured in triplicate, 
taken 2-5 minutes apart and averaged.
Rationale for change
To clarify BP exclusion criteria for the Module. 
Section to be changed
Flow Chart Module C BI 1381-0009
Description of change
Added a new column to separate assessments to 
be done within 28 days and within 14 days 
Rationale for change
To clarify the time window for screening and 
baseline assessments. 
Section to be changed
Flow Chart Module C BI 1381-0009
Description of change
Added triplicate BP and pulse to the flow chart
Rationale for change
To highlight BP and pulse measurements during 
the trial. 
Section to be changed
Flow Chart Module C BI 1381-0009 footnotes a, 
b, and d
Description of change
The date of an assessment is considered Day 1 
of the window.
Rationale for change
To highlight the assessment time window.
Section to be changed
Flow Chart Module C BI 1381-0009 footnote d

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Description of change
(BP to be conducted in triplicate, taken 2-5 
minutes apart and averaged), electrocardiogram 
(ECG)
Rationale for change
To highlight and clarify BP measurement 
methods.
Section to be changed
Flow Chart Module C BI 1381-0009 text moved 
from footnote d to i. 
Description of change
Tumour assessments (scans) should be 
performed ≤28 days prior to initiation of 
treatment and copies may be collected by the 
Sponsor or designee.
Rationale for change
To provide tumor assessment information in the 
appropriate location.
Section to be changed
Flow Chart Module C BI 1381-0009 footnote m
Description of change
Patients enrolling in another open second
Module will be required to provide pre- and on-
treatment tumour biopsy samples. In addition, an 
optional biopsy should be taken after treatment 
discontinuation, if possible.
Rationale for change
To clarify that patients may enrol on another 
Module in the trial. 
Section to be changed
Flow Chart Module C BI 1381-0009 footnote n
Description of change
See Appendix 10.7 for BP and HR management 
and see Appendix 10.6 for the BP monitoring 
and study drug administration guidelines. BP and 
HR should be measured before and after study 
drugs have been administered.  BP and HR 
should be measured in triplicate, taken 2-5 
minutes apart and averaged. 
Rationale for change
To highlight and clarify BP measurement 
methods.
Section to be changed
Flow Chart Module C BI 1381-0009 footnote o
Description of change
human immunodeficiency virus (HIV)-1 and 
HIV-2 antibody performed at the discretion of 
the Investigator where clinically indicated(at 
the discretion of the Investigator where clinically 
indicated) will be performed.
Rationale for change
To clarify guidance for HIV antibody testing 
criteria for patients. 
Section to be changed
Flow Chart Module C BI 1381-0009 footnote p
Description of change
Echocardiogram must be collected ≤28 days 
prior to the initiation of treatment.

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Rationale for change
To clarify when screening echocardiograms 
should be taken.
Section to be changed
Flow Chart Module C BI 1381-0009 footnote q, 
Section 
 
Section to be changed
Section 1.2.1 BI 836880
Description of change
At the time of data cut-off for this protocol (17 
Aug 202011 Nov 2019), at total of 14368 patients 
with solid tumours have been exposed to BI 
836880. Of these, 562 patients had been treated 
with BI 836880 monotherapy in 3 Phase I clinical 
trials testing either an every-3-week schedule or a 
weekly schedule, and 8112 additional patients 
with solid tumoursNSCLC received BI 836880 
in combination with the checkpoint inhibitor BI 
754091 in a Phase Ib trial (1336-011). In the part-
A Part A of 1336-0011 tirial, 3 patients each were 
dosed at 360 mg and 500 mg dose while 6 
patients were dosed at 720 mg dose in 
combination with 240 mg of BI 754091 in the 
q3w regimen. 720 mg q3w of BI 836880 and 
240 mg of BI 754091 was chosen as the 
recommended phase 2 dose and this dose was 
additionally tested in the expansion cohorts of 
different indications in the Part B of the trial.
For patients treated with BI 836880 monotherapy, 
the most frequent adverse events (AEs) were 
hypertension (545.84%, including 245.20% of 
Grade 3), asthenia (4853.46%, including 109.7% 
of Grade 3), nausea (2730.4%, including 1 case 
[1.68%] of Grade 3), vomiting (278.46%, 
including 1 case [1.68%] of Grade 3), diarrhoea 
(25.8%, including 4.8% of Grade 3),
constipation (246.28%; no AEs of Grade ≥3), 
diarrhoea (26.8%, including 5.4% of Grade 3), 

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and increased AST (225.60%, including 45.84% 
of Grade 3 and 1 case [1.8%] of Grade 4). Few 
patients were reported with AEs requiring 
dose reductions or with AEs leading to 
treatment discontinuation. Infusion−related 
reactions and corresponding symptoms were 
reported for 5 patients (8.1%). Adverse events 
under the Standard MedDRA Query (SMQ) 
haemorrhages occurred in 9 patients (14.5%), 
with 1 patient (1.6%) presenting an AE of 
Grade 3. Serious AEs (SAEs) were reported 
for 27 patients (43.5%) and the most 
frequently reported SAEs were hypertension 
and pleural effusion, with 3 patients each 
(4.8%).
For patients treated with BI 836880 in 
combination with BI 754091, the most frequent 
adverse events (AEs) were hypertension 
(1958.83%, including 825.60% of Grade 3), 
followed by Grade 1 or 2 nausea (12.3%), and 
Grade 1 or 2 Cough and diarrhoea (11.1%). 
No patients were reported with AEs requiring 
dose changes; 3 patients (3.7%) had an AE 
leading to treatment discontinuation. Infusion-
related reactions and corresponding symptoms 
were reported in 8 patients (9.9%), with no 
AEs being higher than Grade 3. Adverse 
events under the SMQ haemorrhages occurred 
in 4 patients (4.9%), with 2 patients (2.5%) 
presenting AEs of Grade 3 and 1 patient 
presenting a Grade 5 AE. Eleven patients 
(13.6%) were reported with immune-related 
AEs according to investigator’s judgement; 1 
AE was of Grade 3 and 1 was of Grade 4. 
vomiting (41.7%; no AEs of Grade ≥3), nausea 
(33.3%, no AEs of Grade ≥3), asthenia (33.3%, 
no AEs of Grade ≥3), cough (25.0%, no AEs of 
Grade ≥3), and dyspnoea (25%, including 8.3% 
of Grade 3). Peripheral oedema was reported in 1 
patient (8.3%). One patient (8.3%) was reported 
with an infusion-related reaction of hypertension 
(Grade 3). Bleeding AEs occurred in 2 patients 
(16.7%). Five patients (41.7%) were reported 
with immunerelated AEs according investigator’s 
judgement; all of them were of Grade 1 or 2.

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There was no dose-dependent increase in the 
frequency of any AEs, SAEs, AEs of worst 
CTCAE Grade ≥3, or AEs of special interest. No 
patients were reported with AEs requiring dose 
changes; 1 patients had an AE leading to 
treatment discontinuation. Hypertension, was 
reported for two-thirds of patients in the lower 
dose groups (360 mg or 500 mg every 3 weeks) 
and for half of patients in the highest dose group 
(720 mg every 3 weeks). Based on laboratory 
values in all conducted trials, 5 patients were 
reported with AST/ALT >3x ULN simultaneous 
with ALKP <2x ULN, but none of those events 
met Hy’s law criteria.Laboratory values from 
all conducted trials did not show any event 
that met Hy’s law criteria.
Rationale for change
To provide updated clinical safety data for 
BI 836880.
Section to be changed
Section 1.2.1 BI 836880
Description of change
The pharmacokinetics, pharmacodynamics and 
immunogenicity of BI 836880 were
investigated based on data from the monotherapy 
Phase I study 1336.0001 with a every 3 weeks 
dosing scheme. Maximum plasma concentrations 
were reached shortly after the end of infusion. BI 
836880 plasma concentration remained around 
the maximum for up to 8 h and started to decline 
afterwards slowly. Cmax and AUC increased in a 
dose-proportional manner over the entire dose 
range. As expected for a nanobody, the clearance 
was low, resulting in a terminal half-life of ~275 
h (~11 days). The volume of distribution was also 
low and in the range of the average blood volume. 
An accumulation ratio of 1.11 to 1.54 was 
observed, showing slight accumulation of BI 
836880 after multiple dosing. A PopPK/PD 
model showed that the preliminary results of the 
combination of BI 836880 and BI 754091 are 
consistent with PK results from the BI 836880 
monotherapy studies.

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Pre-existing 
 were 
detected in approximately half of patients, and an 
additional 33.3% of the patients developed 
 
during treatment. There was no dose dependency 
observed in the development of treatment-
induced BI 836880 
. The PK was not 
influenced by the development of 
.
After evaluating all available PK, PD, efficacy, 
and safety data, a dose of 720 mg BI836880 every 
3 weeks in combination with 240 mg BI 754091 
was determined as the recommended Phase II 
dose (RP2D), and this was endorsed by the Safety 
Monitoring Committee.
The Residual Effect Period (REP) is the period 
after the last administration of study drug with 
measurable drug levels and/or pharmacodynamics 
effects still likely to be present. The REP of BI 
836880 and BI 754091 is up to 30 days.
For a more detailed description of the BI 836880 
and BI 754091 profiles please refer to the current 
Investigator’s Brochures (IBs).
Rationale for change
To provide updated and abbreviated clinical PK 
information for BI 836880.  
Section to be changed
Section 1.2.2 BI 754091 (Ezabenlimab)
Description of change
Refer to the Master protocol.Ezabenlimab (BI 
754091) is a mouse derived; monoclonal 
IgG4Pro antibody (mAb) targeted to the 
human programmed cell death 1 (PD-1) 
immune checkpoint inhibitor. Ezabenlimab is 
extensively humanized and potently blocks 
PD-1/PD-L1 and PD-1/PD-L2 interactions in 
vitro. The mAb is devoid of Complement 
Dependent Cytotoxicity (CDC) and Antibody-
Dependent Cell-mediated Cytotoxicity 
(ADCC) activities.
As of November 1st 2020, 117 patients with 
advanced/metastatic solid tumours have been 

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treated with single agent ezabenlimab, 111 of 
these patients were treated with the 240 mg 
q3w recommended phase II dose (RP2D). 
Additionally, 601 patients have been treated 
with the RP2D of ezabenlimab in combination 
with other agents. Three hundred and ninety 
three patients treated in combination with 
BI754111 (anti-LAG-3 mAb), 160 patients 
were treated in combination with BI 836880 
(VEGF/Ang-2 inhibitor), 37 patients were 
treated in combination with BI 891065 (SMAC 
mimetic) and 11 patients were treated in 
combination with BI 754111 and BI 907828 
(MDM2-p53 antagonist).
The currently available ezabenlimab clinical 
data demonstrate that it is well tolerated. The 
most common AEs reported in patients treated 
with ezabenlimab monotherapy were fatigue 
(39.3%), nausea (29.1%) and decreased 
appetite (21.4%). There were no grade 5 or 
treatment related Grade 4 events reported in 
patients treated with ezabenlimab 
monotherapy. Immunerelated AEs (irAEs) 
were reported in 34 patients (29.1%) on 
ezabenlimab monotherapy, the vast majority 
were Grade 1 and 2. There were no Grade 4 or 
Grade 5 irAEs and no infusion related reaction 
of any grade reported in patients treated with 
ezabenlimab monotherapy.
Preliminary efficacy analysis shows overall 
objective response rate ezabenlimab 
monotherapy of 13.7% across all cohorts (14 
patients with confirmed partial response [PR] 
and 2 patients with complete responses [CR]) 
(95% CI 8.0, 21.3). Both patients with CRs and 
7 of the 14 patients with PR were still on 
treatment at the time of last data cut-off. 
Responding patients had the following tumour 
types: anal (2 patients) , breast cancer (2 
patients), cervical cancer (2 patients), vulvar 
cancer (2 patients), angiosarcoma, oesophageal
cancer, endometrial cancer, fallopian tube 
cancer, renal cancer, left supraclavicular nodal 
mesothelial cancer, and squamous cell 
carcinoma of the skin (1 patient each).

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The available PK data show that ezabenlimab 
has a (at least) bi-phasic distribution. The 
volume of distribution ranged between 4.71 L 
and 5.88 L. The systemic clearance of 
ezabenlimab ranged between 0.00987 L/h 
(80mg dose) and 0.0119 L/h (400mg dose) (i.e. 
approx. 0.0237 - 0.0286 L/day) resulting in 
gMean half-life estimates of 13.8 to 17.8 days. 
Volume of distribution ranged from 5.29L to 
5.88 L in BI 1381.1. The small total volume of 
distribution is consistent with a limited 
extravascular disposition as expected for a 
therapeutic antibody. Steady state exposure is 
estimated to be achieved after ~12-15 weeks 
(q3w, 4-5 cycles).
For a more detailed description of the 
ezabenlimab profile please refer to the current 
Investigator’s Brochures (IBs) and the Master 
protocol.
Rationale for change
To provide updated clinical safety and PK data 
for ezabenlimab.
Section to be changed
Section 1.4 Benefit-Risk Assessment 
Description of change
In total, 65 dose limiting toxicities were reported. 
In trial 1336-00011(q3w dosing) one patient 
treated on the highest dose level (1000 mg) 
experienced a pulmonary embolism. In trial 1336-
0006 (q1w) 54 patients experienced DLTs ( 2 
patients each with proteinuria and hypertension 
and 1 patient each with sepsis proteinuria, and 
respiratory distress, hypertension and 
respiratory distress one patient each).
Rationale for change
To provide updated benefit-risk information for 
the study.
Section to be changed
Section 1.4.1 COVID-19 Related Risks
Description of change
COVID-19 Related Risks
To date, there is no evidence suggesting a link 
between susceptibility to COVID-19 infections 
and the inhibition of VEGF-A and Ang2 
targeted by BI 836880. Also, there is no 
evidence suggesting a link between 
susceptibility to COVID-19 infections and the 
inhibition of PD-1/PDL-1 by ezabenlimab. 
Available non-clinical and clinical data from 
completed clinical trials have not shown an 

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increased risk of infections with BI 836880 and 
ezabenlimab.
Considering the limited and sparse data on 
immune activation and the role of 
inflammation as well as other underlying 
factors that may increase the severity and 
mortality from COVID-19 infection, there may 
be some factors representing the risk for using 
inhibitors of VEGF/Ang2 or PD1 that are 
currently still unknown. The information 
about the risk factors, the severity and the 
activity of immune response in patients with 
COVID-19 infections will be constantly 
monitored as it evolves.
Rationale for change
To provide benefit-risk information for the study 
as it related to COVID-19.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Both Module C and the Master protocol must 
be followed. Where there are differences in 
stringency or cut-off values between the 
Master protocol and specific module, the 
specific module takes precedence.
Rationale for change
To clarify that the Module values take precedence 
over the Master protocol.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
A new informed consent will be required if the 
patient remains on study with radiological PD.
The patient will be required to sign a new ICF to 
continue treatment.
Rationale for change
To clarify that patients who receive treatment 
after an initial radiological PD, but not patients 
who continue to benefit from treatment after a 
year will need to provide further consent for 
treatment.
Section to be changed
Section 3.3.2 Inclusion criteria 2
Description of change
Patients must have had ≥ 1 line of prior systemic 
anticancer treatment in the metastatic setting
Rationale for change
To clarify inclusion criteria related to prior 
therapy.
Section to be changed
Section 3.3.2 Inclusion criteria 3
Description of change
Tumour lesions that have been irradiated at 
least ≥4 weeks before the start of treatment, 

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and have subsequently had documented 
progression, may be chosen as target lesions 
only in the absence of measurable lesions that 
have not been irradiated.
Rationale for change
To clarify inclusion criteria related to target 
lesions.
Section to be changed
Section 3.3.3 Exclusion criteria 2
Description of change
Persistent toxicity from previous treatments that 
has not resolved to ≤Grade 1 with the exception 
of alopeciaUnresolved, Grade >1 toxicity 
before the start of treatment with the study 
drug except for hair loss (alopecia) and 
hypothyroidism that requires thyroid hormone 
supplements but is asymptomatic under 
therapy. 
Rationale for change
To clarify exclusion criteria related to toxicity 
associated with prior treatment.
Section to be changed
Section 3.3.3 Exclusion criteria 3
Description of change
Uncontrolled hypertension is defined as: blood 
pressure in rested and relaxed condition ≥ 140 
mmHg, systolic or ≥ 90 mmHg diastolic (with or 
without medication), measured in triplicate, 
taken 2-5 minutes apart and averaged
according to Appendix 10.710.5.
Patients with personal or family history of QT 
prolongation and/or long QT syndrome, or 
prolonged QTcF at baseline (> 470480 ms).
Rationale for change
To clarify exclusion criteria related to BP and 
QTcF.
Section to be changed
Section 3.3.3 Exclusion criteria 6
Description of change
Patients who require full-dose anticoagulation 
(according to local guidelines). No Vitamin K 
antagonist and other anticoagulation allowed; 
Only LMWH and ASA at doses for 
prevention/prophylaxis are allowed only for 
prevention not for curative treatment.
Rationale for change
To clarify exclusion criteria related to 
anticoagulant medications.
Section to be changed
Section 3.3.3 Exclusion criteria 7
Description of change
Prior anti-angiogenic therapy (with the exception 
of CRC Cohort [Cohort 4]).
Rationale for change
To clarify that the CRC cohort is Cohort 4. 

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Section to be changed
Section 4.2.8 Dose administration and 
modifications
Description of change
The plannedexpected infusion time is 60 minutes 
(+/- 10 minutes) for BI 754091 and 60 minutes 
(+/- 10 minutes) for BI 836880; BI 754091 will 
be administered first, then 15 minutes (+/- 10 
min) after the end of the BI 754091 infusion, BI 
836880 will be administered. In case no relevant
infusion reactions are observed, this Infusion of 
BI 836880 infusioncan be shortened to about 30 
minutes but should not be prolonged to more than 
6 hours for BI 836880. Appropriate drugs and 
medical equipment to treat anaphylactic reactions 
must be immediately available and study 
personnel must be trained to recognize and treat 
anaphylaxis.
In the event of an infusion-related reaction ≤ 
Grade 2, treat the symptoms accordingly with 
antihistamine or corticosteroids if needed. 
Steroids, if used to manage an infusion-related 
reaction, are to be limited to prednisone 10 mg 
qd or equivalent.
Rationale for change
To provide guidance related to treatment infusion.
Section to be changed
Section 4.2.8 Dose administration and 
modifications
Description of change
Pre-treatment should be administered at 
sufficient time prior to initiation of infusion to 
allow the agents to exert their effect.
Rationale for change
To provide guidance for the administration of 
pre-treatment medications.
Section to be changed
Section 4.2.8 Dose administration and 
modifications
Description of change
Drug re-administration criteria during Cycle 1
Before initiating a new treatment cycle the health 
status of the patient will be assessed according to 
the Module C flow chart. To continue treatment 
with further cycles, all of the following criteria 
must be met:
1. Pre-infusion SBP (measured in triplicate, 
taken 2-5 minutes apart, and averaged) 
should be < 140 mmHg and pre-infusion 
DBP should be < 90 mmHg; study drug 
administration of both study drugs should be 
temporarily delayed until BP < 140/90 

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mmHg. Please see Table 10.7:1 in Appendix 
10.7, which describes the guidelines for BP 
management and study drug administration.
2. QT interval corrected per Fridericia’s 
formula (QTcF) ≤470 ms.
3. Echocardiography if clinically indicated 
(based on Investigator’s judgment) with Left 
Ventricular Ejection Fraction (LVEF) ≥ 50%. 
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 in the opinion of 
investigator).
Rationale for change
To clarify the parameters for Cycle 1. 
Section to be changed
Section 4.2.8 Dose administration and 
modifications
Description of change
Pre-infusion SBP (measured in triplicate, taken 
2-5 minutes apart and averaged) should be < 
160 mmHg and pre-infusion DBP should be < 
100 mmHg (according to Exclusion-Criterion #3 
of Module C).
Rationale for change
To highlight and clarify BP measurement 
methods.
Section to be changed
Section 4.2.8 Dose administration and 
modifications.
Description of change
QT interval corrected per Fridericia’s formula 
(QTcF) ≤470 ms (according to Exclusion-
Criterion #8 of Master).
Rationale for change
To correct a conflict between Module C and the 
Master protocol. 
Section to be changed
Section 4.2.8 Dose administration and 
modifications.
Description of change
If the reduced dose is tolerable, and wWhere 
deemed in the best interest of the patient, the 
investigator should re-escalate to may restart at 
the originally assigned dose of 720 mg of BI 
836880 as soon as deemed clinically appropriate.
Rationale for change
To update guidance for re-dosing after a dose 
reduction.
Section to be changed
Section 4.2.8 Dose administration and 
modifications.

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Description of change
During combination therapy, if treatment is held 
or discontinued due to an AE(s), both BI 836880 
and BI 754091 will be held or discontinued 
together. If treatment is to be restarted after 
resolution (≤ Grade 1 or baseline) of the AE, 
preferably both BI 836880 and BI 754091 must 
be started together.
In some cases, in discussions with the Sponsor, 
treatment with one of the two investigational 
drugs can be allowed if there is an AE 
reported which can be clearly attributed to one 
of the two drugs and further warrants a 
temporary discontinuation of this drug in the 
interest of the patient.
Rationale for change
To provide guidance for treatment holds, 
discontinuations, or re-dosing after an AE.
Section to be changed
Section 4.3.2.2 Permitted concomitant 
medications
Description of change

If medically feasible, patients taking regular 
medication should be maintained on it 
throughout the trial. This includes medications 
for the management of nausea, diarrhoea, and 
vomiting for which the patient must be treated 
according to institutional standards.

To reduce the risk of infusion related 
reactions, patients may be pre-treated with 
an antihistamine and acetaminophen or 
paracetamol. Pre-treatment should be 
administered at sufficient time prior to 
initiation of infusion to allow the agents to 
exert their effect.

Pre-medication will not be required, but may 
be utilised following the first dose of 
combination therapy, as appropriate. 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. This includes medications for 
the management of nausea, diarrhoea, and 
vomiting for which the patient must be 
treated according to institutional standards.

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Rationale for change
To update guidance for the use of concomitant 
medications.
Section to be changed
Section 4.3.2.3 Restricted concomitant 
medications.
Description of change
Full-dose anticoagulation (according to local 
guidelines) with Vitamin K antagonist and other 
anticoagulation is not allowed during the trial 
conduct; only low-molecular-weight heparin 
(LMWH) or ASA at prevention/prophylaxis 
doses are is allowed only for prevention not for 
curative treatment.
Any concomitant medication known to prolong 
the QT interval is not allowed.
Rationale for change
To update guidance for the use of concomitant 
medications.
Section to be changed
Section 5.3.2 Methods of sample collection
Description of change
If only 1 of the 2 drugs has been administered 
at the time of the PK sample collection, it 
should be noted. See the laboratory manual for 
further instructions.
Rationale for change
To clarify guidelines for the collection of PK 
samples when only 1 of 2 treatment drugs is 
administered.
Section to be changed
Section to be changed
Section 6.2.3.1 End-of-treatment visit
Description of change
The intent is to complete the EOT as soon as 
the decision is to remove the patient from 
treatment. The decision can occur at a 
scheduled visit, or in between visits. If it 
happens on a scheduled visit, the site is to 
complete the EOT visit assessments for that 
day. If it happens in between visits, they 
should have patient return within 7 days of 
last dose (if possible) and complete EOT 

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instead of what that next scheduled visits 
would have been.
Rationale for change
To provided updated guidance for the EOT visit. 
Section to be changed
Section 6.2.3.2 30-day post treatment safety visit
Description of change
The safety follow-up visit is performed 30 (+2) 
days after the decision to discontinueation of the 
trial medication. 
Rationale for change
To clarify when the 30-day post treatment safety 
visit occurs.
Section to be changed
Section 10.4.1 10.4.1
Schedules for PK, 
 
and 
 blood sampling
Description of change
PKs are timed from the start of BI 754091 
infusion.
Rationale for change
To clarify the timing of PK collections. 
Section to be changed
Table 10.7.1 
Description of change
BP management and study drug administration 
guidelines following completion of Ccycle 1, 
based on pre-infusion SBP and DBP measured on 
study drug administration visits. Prior to Cycle 
1, BP guidelines follow inclusion/exclusion 
criteria. 
Rationale for change
To clarify BP measurement prior to Cycle 1 
following inclusion/exclusion criteria.
11.2
GLOBAL AMENDMENT 2
Date of amendment
28 Mar 2022
EudraCT number
EU number
2018-002344-81
BI Trial number
1381-0009
BI Investigational Medicinal 
Product(s)
Ezabenlimab (BI 754091 [anti-PD-1])
BI 836880 (anti-VEGF/Ang2).
Title of protocol
An open-label, Phase II trial evaluating the safety 
and efficacy of BI 836880 in combination with 
ezabenlimab in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced 
and/or metastatic solid tumours who have had at 
least one line of systemic therapy.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities

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To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page Trial Clinical Monitor
Description of change
Phone: 
Phone: 
Fax: 
Rationale for change
The TCM changed over to 
Section to be changed
Synopsis – Duration of treatment
Description of change
From:
Treatment will continue until progression of 
disease (PD), unacceptable toxicity, a maximum 
treatment duration of 1 year, or withdrawal of 
patient consent. Patients will be allowed to stay 
on treatment in case of initial radiological PD, if 
the Investigator feels 
that is in the patient’s best interest. If the patient 
is benefiting clinically at 1 year, he/she may 
continue on treatment after a case-by-case review 
with the Medical Monitor and the Sponsor. A 
new informed consent will be required if the 
patient remains on study with radiological PD.
To: 
Treatment may continue until progression of 
disease (PD), unacceptable toxicity, withdrawal 
of patient consent, or 53 cycles [approximately 3 

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years] from the start of first treatment 
administration, whichever occurs first. Patients 
will be allowed to stay on treatment in case of 
initial radiological PD, until progression is 
confirmed or 53 cycles from the start of first 
treatment administration if the Investigator 
considers that the treatment is beneficial for the 
patient
Rationale for change
Treatment duration limitation added due to 
program discontinuation.
Section to be changed
Flow Chart (treatment duration)
Description of change
Total number of cycles limited to 53
Rationale for change
Treatment duration limitation added due to 
program discontinuation.
Section to be changed
Flow Chart (Survival)
Description of change
Progression-free survival follow-up visits 
removed including footnote h. 
Rationale for change
PFS and OS will not be captured per sponsor 
decision.
Section to be changed
Flow Chart (biopsies and central lab samples)
Description of change
Biopsies, blood samples for PK, levels of BI
836880 and ezabenlimab, 
, and 
removed
Rationale for change
No more biopsies and samples will be required 
due to program discontinuation
Section to be changed
Flow Chart (Echocardiogram)
Description of change
Echocardiogram removed from footnote d (safety 
laboratory) with requirement to be done ≤14 days 
prior to the initiation of treatment.
Rationale for change
Echocardiogram already entered under footnote p 
to be collected ≤28 days prior to the initiation of 
treatment.
Section to be changed
Flow Chart (Tumour Assessments)
Description of change
From:
Tumour assessments …every 2 cycles (6 weeks 
±3 days) for the first 6 months of treatment, once 
every 3 cycles (9 weeks ±3 days) thereafter, at the 
EOT visit (if not performed within the previous 4 
weeks), and at the discretion of the Investigator.
To: 

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...afterwards can be performed according to 
institutional practices and SOC from the 
acknowledgement of the amendment.
Rationale for change
Imaging adjusted to be performed according to 
institution practices and SOC to reduce patient 
burden.
Section to be changed
Section 1.2 Drug profile 
Description of change
Safety update according to last IB BI 836880 
version 9 issued 03 Nov 2021 and BI 
ezabenlimab version 6 issued 19 Jan 2022
Rationale for change
New safety information available
Section to be changed
Section 1.3 Rationale for performing the trial
Description of change
Addition:
DECISION TO TERMINATE THE TRIAL
Although a preliminary assessment of the 
available data from the ongoing clinical program 
for the ezabenlimab + BI 836880 combination 
exhibit signs of antitumour activity and a 
manageable safety profile for an overall positive 
benefit risk ratio, careful review of the full data 
set performed in the context of the current 
standards of care for the indications under study 
has led to the decision taken by the sponsor in 
December 2021 to discontinue recruitment in 
study 1381-0009, and terminate further expansion 
of the study.
An important consideration in the review process 
was whether the investigational combination 
treatment under study, namely BI 836880 plus 
ezabenlimab, had demonstrated benefit that 
delivered clear improvement over the current 
standards of care, some of which had evolved 
over the course of the study. The measure used to 
evaluate efficacy was the Objective Response 
Rate (ORR) which was the primary efficacy 
endpoint of the trial. It is important to note that at 
the time of this evaluation all cohorts had 
completed planned enrolment, and sufficient data 
had been collected to support a well-informed 
decision. Based on this evaluation, the efficacy 
observed in the different indications did not show 
clear improvement over the standards of care 
relative to published efficacy results in the 

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different indications, with the one possible 
promising result in the 2L Endometrial carcinoma 
cohort. Given the evolution of the standard of 
care for 2L Endometrial carcinoma to 
combination treatment with immune checkpoint 
inhibitor plus an tyrosine kinase inhibitor 
(KEYNOTE-775), it was determined that this 
setting does no more present an opportunity for 
further development moving forward. Based on 
this evaluation, the decision was taken to 
terminate the trial.
As a part of this decision, for patients still under 
active treatment, treatment with BI 836880 plus 
ezabenlimab may continue until disease 
progression, undue toxicity, withdrawal of patient 
consent, or 53 cycles [approximately 3 years] 
from the start of first treatment administration, 
whichever occurs first (see Section 4.2.8, 
“Treatment duration” for full details).
Rationale for change
To include information regarding the program 
discontinuation decision.
Section to be changed
Section 1.4 Benefit – risk assessment.
Description of change
Updated information on BI 836880 monotherapy 
and combination trials with ezabenlimab.
Rationale for change
Update with new available information.
Section to be changed
Section 3.1 Overall trial design and plan
Description of change
Updated wording on tumour assessments and 
duration of treatment in this section to be aligned.
Rationale for change
To align information in this section.
Section to be changed
Section 4.1 Investigational treatments (tables 
4.1.1.1: 1 and 4.1.1.2: 1).
Description of change
Duration of use added as: until progression, 
unacceptable toxicity, or up to a maximum of 53 
cycles.
Rationale for change
Treatment duration limitation added due to the 
program discontinuation.
Section to be changed
Section 4.2.8 Dose administration and 
modifications.
Description of change
Addition:
Treatment duration:

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Treatment with BI 836880 plus ezabenlimab may 
continue until disease progression, undue toxicity, 
withdrawal of patient consent, or 53 cycles 
[approximately 3 years] from the start of first 
treatment administration, whichever occurs first. 
Patients will be allowed to stay on treatment also 
in the case of initial radiological PD, until 
progression is confirmed or up to 53 cycles from 
the start of first treatment administration if the 
investigator considers that the treatment is 
beneficial for the patient.
Investigators may consider discontinuing BI 
836880 and continue therapy with ezabenlimab 
for up to 53 cycles from the start of the first 
treatment administration if the patient has been on 
therapy ≥ 6 months, has achieved at least SD by 
RECIST 1.1 and can tolerate the therapy, and if 
the investigator considers this to be in the best 
interest of the patient.
For any patient still on treatment with the 
investigational combination of BI 836880 plus 
ezabenlimab 53 cycles from the start of the first 
treatment administration, treatment extension will 
be considered on a case-by-case basis upon 
request by the investigator for a maximum 
additional 6 cycles, to complete no later than 30 
April 2025, if the investigator considers this to be 
in the best interest of the patient. After this date 
treatment with the investigational combination BI 
836880 plus ezabenlimab will no longer be 
available.
Investigators are requested to prepare for 
discontinuation of patients from the current 
investigational treatment of BI 836880 plus 
ezabenlimab and to switch them to alternative 
available treatment options outside of the current 
protocol no later than by the final availability date 
of 30 April 2025.
Rationale for change
Treatment duration limitation details added due to 
the program discontinuation.
Section to be changed
Section 5.1 Assessment of efficacy
Description of change
Added:

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As of  the decision of Boehringer Ingelheim in 
December 2021 no additional patients will be 
further included to this trial. From the 
acknowledgement of this amendment forward 
tumour assessment can be performed according to 
institutional practices and SOC; and not required 
to follow master protocol specified schedule. 
Rationale for change
To reduce patient burden after program 
discontinuation decision on December 2021.
Section to be changed
Section 5.3.1 assessment of pharmacokinetics 
Description of change
Added:
As of  the decision of Boehringer Ingelheim in 
December 2021 no additional blood samples for 
pharmacokinetics will be collected.
Rationale for change
To reduce patient burden after program 
discontinuation decision on December 2021.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 
Rationale for change
Clarification.
Section to be changed
Description of change
Added:

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Rationale for change
To reduce patient burden after program 
discontinuation decision on December 2021.
Section to be changed
Section to be changed
Section 6.1 Visit schedule
Description of change
Removed: PFS follow-up wording.
Rationale for change
PFS and Overall Survival will not be captured per 
sponsor decision.
Section to be changed
Section 6.2 Details of trial procedures at selected 
visits
Description of change
Tumour assessment wording aligned for change.
Rationale for change
To clarify text
Section to be changed
Sections 6.2.3.3 (PFS) and 6.2.3.4 (Overall 
Survival status)
Description of change
Wording removed
Rationale for change
To clarify text
Section to be changed
Section 7.4 Interim analyses
Description of change
Added:
Subsequent upon the decision of Boehringer 
Ingelheim in December 2021 that no additional 
patients will be included in this trial, no interim 
analyses will be performed.
Rationale for change
To include information regarding the enrolment 
stop and decision about interim analyses.
Section to be changed
Section 9.2 Unpublished references
Description of change
References for last versions of IBs for BI 836880 
and ezabenlimab added.
Rationale for change
Added references.
Section to be changed
Section 10.4.1 Tables 10.4.1: 1 and 10.4.1: 2

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Description of change
Added “From December 2021 on, no further 
blood samples should be obtained for central lab 
shipments.”
Rationale for change
To include information regarding the decision to 
stop collection of central lab samples.
11.3
GLOBAL AMENDMENT 3
Date of amendment
13 JUN 2023
EudraCT number
EU number
2018-002344-81
BI Trial number
1381-0009
BI Investigational Medicinal 
Product(s)
Ezabenlimab (BI 754091 [anti-PD-1])
BI 836880 (anti-VEGF/Ang2)
Title of protocol
An open-label, Phase II trial evaluating the safety 
and efficacy of BI 836880 in combination with 
ezabenlimab in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced 
and/or metastatic solid tumours who have had at 
least one line of systemic therapy.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page/Clinical Trial Leader
Description of change
Trial Clinical MonitorClinical Trial Leader
Phone: +
 

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Phone: 
Rationale for change
Role of ‘Trial Clinical Monitor’ changed to 
‘Clinical Trial Leader’ due to update in role title 
within BI; role changed over to 
 
.
Section to be changed
Title Page/Coordinating Investigator and 
Synopsis
Description of change
Phone: 
Rationale for change
Updated company name.
Section to be changed
Throughout the document
Description of change
BI 754091 was changed to its INN, 
‘ezabenlimab’.
Rationale for change
Change was communicated with Global 
Amendment 1 (14 Jul 2021) but was not replaced 
throughout the document.
Section to be changed
Section 4.1.1 Identity of the Investigational 
Medicinal Products: Table 4.1.1.2: 1 Ezabenlimab
– CMC 1
Description of change
Updated CMC 1 information for ezabenlimab: 
20 mg/mL (vial with 15 mL filling volume); 
name of the table changed to ‘Ezabenlimab (BI 
754091) – CMC 1’.
Rationale for change
To provide more details on CMC 1 material 
packaging and to distinguish from CMC 2 
material.
Section to be changed
Section 4.1.1 Identity of the Investigational 
Medicinal Products
Description of change
Table 4.1.1.2: 2 Ezabenlimab – CMC 2 added.
Rationale for change
To provide details on CMC 2 material of 
ezabenlimab and show the difference with 
CMC 1 material.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29377542
4.0
clinical-trial-protocol-version-04-module-c
An open-label, Phase II trial evaluating the safety and efficacy of BI 836880 in
combination with ezabenlimab in PD-(L)1 naïve and PD-(L)1 pretreated patient
populations with advanced and/or metastatic solid tumours who have had at least one
line of systemic therapy
Author-Clinical Trial Leader
13 Jun 2023 14:42 CEST
Author-Trial Statistician
13 Jun 2023 14:43 CEST
Approval-Team Member Medicine
13 Jun 2023 18:37 CEST
Verification-Paper Signature
Completion
27 Jun 2023 09:46 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29377542
4.0