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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CLINCAL TRIAL PROTOCOL MODULE A (BI 754091+BI 754111)
TITLE PAGE
Document Number:
c25025479-03
EudraCT No.
2018-002344-81
BI Trial No.
1381-0009
BI Investigational
Medicinal Product(s)
BI 754091 (anti-PD-1)
BI 754111 (anti-LAG3)
Title
An open-label, Phase II trial evaluating the safety and efficacy of 
BI 754111 in combination with BI 754091 in 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 754111 
in combination with BI 754091 in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced/metastatic solid 
tumours.
Clinical Phase
Phase II
Trial Clinical 
Monitor
Phone: 
Fax: 
Coordinating 
Investigator
  
Phone: 
Status
Final protocol (Revised Protocol [based on Global Amendment 
2])
Version and Date
Version: 3
Date: 14 JUL 2021
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
I 
I 
Boehringer 
~111111/ lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS MODULE A (BI 754091 + 
BI 754111)
Company name
Boehringer Ingelheim 
Name of finished 
product :
N.A.
Name of active 
ingredient :
BI 754091 and BI 754111
Protocol date
08 AUG 2018
Revision date
14 JUL 2021
BI trial number
1381-0009
Title of trial
An open-label, Phase II trial evaluating the safety and efficacy of BI 
754111 in combination with BI 754091 in 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 Module is to assess the antitumour 
response of BI 754091 combined with BI 754111 in patients 
previously exposed to anti-PD-1 or anti-PD-L1 based therapy
Trial endpoints
Refer to the Master protocol.
Trial design
Open-label, multicentre, Phase II, Master design with treatment-
specific Modules
Total number of 
patients randomised
Not applicable
Number of patients on 
each treatment
Approximately 110 patients are planned for Module A.

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Diagnosis
Cohort 1 GEC: Locally advanced, unresectable or metastatic gastric 
adenocarcinoma or gastro-oesophageal adenocarcinoma with 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 with
previously anti-PD-1 or anti-PD-L1 based treatment who progressed 
after achieving benefit (at least SD with a minimum duration of 
benefit of 6 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). For patients 
with NSCLC who received anti-PD-1 or anti-PD-L1 based treatment 
as a first line regimen, the minimum duration of benefit is 8 months 
with a 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 <6 months or progressive 
disease in <6 months while on previous anti-PD-1 or anti PD-L1 
based treatment).
Main in- and exclusion 
criteria
Abbreviated Inclusion Criteria 
1.
Measurable lesions 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. If the patient is not biopsiable because of 
a safety concern the patient could be considered for study 
after discussion with the Medical Monitor to allow for
inclusion of patients with a tumour type of particular
interest.
Abbreviated Exclusion Criteria 
1.
Any exclusion criteria listed in the Master protocol.
2.
Previous treatment with an anti-LAG-3 agent
Test product(s)
BI 754091 will be co-administered in combination with BI 754111.
dose(s)
BI 754091: a fixed dose of 240 mg once every 3 weeks.
BI 754111: 600 mg once every 3 weeks.
method and route of 
administration
BI 754091 and BI 754111 by intravenous infusion
Comparator product(s)
Not applicable.
dose
Not applicable.
method and route of
administration
Not applicable.

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Duration of treatment
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. 
Statistical methods
For the response endpoints (i.e., OR, DC), a Bayesian hierarchical 
modelling approach will be used. An adjustment for different 
expected response rates across the cohorts will be applied as 
described in R18-2260. Median shrinkage estimators together with 
related credible intervals will be considered. Additionally, 
descriptive statistics of these endpoints will be provided.
Kaplan-Meier estimates will be used to analyse PFS with 95% 
confidence intervals, using Greenwood’s variance estimate.

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FLOW CHART MODULE A BI 1381.9
Module A flow chart
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Days
Screeningc
Cycles 1 
Cycles 2-4
Cycles 5-11
Cycles 12-
16
End-of-
Treatment
(EOT) Visit
30-Day
Safety 
Follow-
up
PFS 
Follow-
uph
Assessments (Days)
-28 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
X
X
X
X
Vital Signsc, d
X
X
X
X
X
X
X
X
X
X
12-Lead Digital Electrocardiogramc, d, f
X
X
(X)
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
X
Adverse Eventsc
X
X
X
X
X
X
X
X
X
X
X

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Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Days
Screeningc
Cycles 1 
Cycles 2-4
Cycles 5-11
Cycles 12-
16
End-of-
Treatment
(EOT) Visit
30-Day
Safety 
Follow-
up
PFS 
Follow-
uph
Assessments (Days)
-28 to -1
1
2
8 
(±1)
15 
(±1)
1 (±2)
1 (±2) 
1 (±2)
(within 7 days 
of EOT)
(+2)
Tumour Assessmentsc, d, i
X
X
Every 6 weeks ±3 days for the first 6 months (then every 9 weeks ±3 days 
thereafter)
Survivalh
X
Administration of Pre-Treatment 
Medicationn
X
X
X
X
BI 754111 and BI 754091 Infusionsj,l
X
X
X
X
Archival (at screening) or Fresh Tumour 
Biomarker Assessmentsm 
X
X (C3 
only)m
X (at 4 
months-
optional)
X (at PD)
Blood Sample for PK BI 754091k
X
X
X
X
X (C5, 6 & 
8)o
X (C12 & 
16)o
Xo
Xo
Blood Sample for PK BI 754111k
X
X
X
X
X (C5, 6 & 
8)o
X C12 & 
16)o
Xo
Xo

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Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Days
Screeningc
Cycles 1 
Cycles 2-4
Cycles 5-11
Cycles 12-
16
End-of-
Treatment
(EOT) Visit
30-Day
Safety 
Follow-
up
PFS 
Follow-
uph
Assessments (Days)
-28 to -1
1
2
8 
(±1)
15 
(±1)
1 (±2)
1 (±2) 
1 (±2)
(within 7 days 
of EOT)
(+2)
X
X (C3 only)k
Xo
X
X
X
X (C2 only)
Xo
Flow Chart Footnotes
a
All cycles are 3 weeks (21 days) in duration. Days are calculated as calendar days. Patients will continue treatment with the study drugs until disease progression (PD) 
by RECIST v1.1 and/or 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 IC 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 754111 and BI 754091 is administered.
b
Informed consent for Module A must be obtained ≤28 days prior to the initiation of treatment. 
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, electrocardiogram (ECG), haematology, clinical chemistry 
(sodium, potassium, phosphate, chloride, creatinine, calcium, albumin, total protein, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline 
phosphatase, bilirubin, lactate dehydrogenase, serum glucose, troponin I (only at screening, C1D1, C1D8, C1D15, C2D1, C3D1, C4D1 and anytime CPK is elevated),
creatine phosphokinase (CPK) [if CPK is elevated, then CPK-MB, troponin I, and myoglobin should be reactively tested], serum urea nitrogen (or urea), serum uric 
acid, and thyroid panel [TSH, free T4, and free T3]), urinalysis, and screening pregnancy test should be done ≤14 days prior to initiation of treatment. 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. Tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment and copies may be collected by 
the sponsor or designee. Baseline PD-L1 expression level, microsatellite instability (MSI), and tumour mutation burden (TMB) information will be collected in the 
eCRF, if locally available. Refer to the Master protocol for additional details. Vital signs are checked at every visit.

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e
Physical examinations will be done at screening, on Day 1 of each treatment cycle, at the 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 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 (see Master protocol).
h
Additional progression-free survival (PFS) follow-up visits after the 30-day safety follow-up visit will only be performed for patients who did not progress on treatment. 
These will be performed once every 12 weeks at least until PD, introduction of a new anti-cancer treatment, death, loss to follow-up, withdrawal of consent, or end of
July 2021. As of July 2021, sites may conduct one final PFS visit for each patient that is being followed. For patients who remain on treatment after July 2021, no 
separate PFS visits will be done (the 30-day post treatment safety visit will be their last study visit).
i
Tumour assessments should be done according to RECIST v1.1 and iRECIST, and should include computed tomography/positron emission tomography (CT/PET) 
scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method 
(CT/PET scan or magnetic resonance imaging [MRI]). The same radiographic procedure must be used throughout the trial. Assessments will be performed by the 
Investigator at screening and 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.
j
Dosing of BI 754111 and BI 754091 is described in Module A Section 4.1.
k
Blood samples for PKs,
 will be collected from all patients as presented in Module A Section 10.4.
l
If the decision is made to permanently discontinue study treatments during a scheduled visit, both BI 754091 and BI 754111 should be discontinued together and the 
EOT visit should be performed instead of the scheduled visit.
m
Pre-treatment and on-treatment (Cycle 3 Day 1) tumour biopsies are mandatory for the study. For fresh biopsies always use the equivalent of no less than two 14-16 
gauge needle biopsies (one for IHC and one for transcriptomics/genomics analyses).  
Mandatory: The equivalent of no less than two 14-16 gauge needle biopsies (one for IHC and one for transcriptomics/genomics analyses) must be taken between 
screening and the day before the first study drug treatment. If medically counterindicated, archived tumour tissue available from the last treatment failure may be 
supplied instead of a pre-treatment biopsy. The archival submission should include 26 (4-5 µm) sections from the archival formalin-fixed paraffin-embedded FFPE 
block pre-treatment biopsy. Another mandatory biopsy will be collected at C3D1 (±5 days). 
Optional: Patients with stable disease over 4 months should be asked for a tumour tissue biopsy at that time point. An optional biopsy is also requested at the time of PD 
(according to RECIST v1.1 and iRECIST), if possible. Patients enrolling in a 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. 
Refer to the Laboratory Manual for collection, storage and shipping details.
n
Pre-treatment medications (antihistamine and acetaminophen or paracetamol) should be administered at sufficient time prior to initiation of infusion to allow the agents 
to exert their influence.

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o
As of 01 July 2021, PK, 
samples are no longer collected, including the End of Treatment, or the 30-day 
follow-up. 

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS MODULE A (BI 754091 + BI 754111)....2
FLOW CHART MODULE A BI 1381.9................................................................................5
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................16
1.2.1
BI 754111 .............................................................................................................16
1.2.2
BI 754091 .............................................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT.....................................................................17
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................19
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........19
2.1.1
Main objectives....................................................................................................19
2.1.2
Primary endpoint................................................................................................19
2.1.3
Secondary endpoints...........................................................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS.........................................................................................21
3.3
SELECTION OF TRIAL POPULATION .......................................................21
3.3.1
Main diagnosis for trial entry ............................................................................21
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................23
3.3.3.1
Withdrawal of patients from treatment or assessments ........................................23
4.
TREATMENTS...................................................................................................24
4.1
INVESTIGATIONAL TREATMENTS ...........................................................24
4.1.1
Identity of the Investigational Medicinal Products..........................................24
4.1.1.1
BI 754111..............................................................................................................24
4.1.1.2
BI 754091..............................................................................................................24
4.2
SELECTION OF DOSES IN THE TRIAL......................................................25
4.2.1
BI 754111 .............................................................................................................25
4.2.2
BI 754091 .............................................................................................................25
4.2.3
Method of assigning patients to treatment groups...........................................25
4.2.4
Blinding and procedures for unblinding...........................................................25

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4.2.5
Packaging, labelling, and re-supply...................................................................25
4.2.6
Storage conditions...............................................................................................25
4.2.7
Drug accountability.............................................................................................25
4.2.8
Dose modifications ..............................................................................................26
4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................26
4.3.1
Other treatments and emergency procedures..................................................26
4.3.2
Restrictions ..........................................................................................................27
4.3.2.1
Restrictions regarding concomitant treatment ......................................................27
4.3.2.2
Permitted concomitant medications......................................................................27
4.3.2.3
Prohibited concomitant medications.....................................................................28
4.3.2.4
Restrictions on diet and life style..........................................................................28
4.3.2.5
Contraception requirements..................................................................................28
4.4
TREATMENT COMPLIANCE........................................................................28
5.
ASSESSMENTS..................................................................................................28
5.1
ASSESSMENT OF EFFICACY........................................................................28
5.2
ASSESSMENT OF SAFETY.............................................................................28
5.2.1
Other safety parameters.....................................................................................29
5.2.2
Assessment of adverse events.............................................................................29
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................29
5.3.1
Assessment of pharmacokinetics .......................................................................29
5.3.2
Methods of sample collection .............................................................................29
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................30
5.4.1
Methods of sample collection .............................................................................30
5.5
BIOBANKING ....................................................................................................32
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................33
6.
INVESTIGATIONAL PLAN.............................................................................34
6.1
VISIT SCHEDULE.............................................................................................34
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................34
6.2.1
Screening period..................................................................................................34
6.2.2
Treatment period ................................................................................................35
6.2.3
Follow-up period and trial completion..............................................................35
6.2.3.1
End-of-treatment visit ...........................................................................................35
6.2.3.2
30-day post-treatment safety visit.........................................................................35
6.2.3.3
Progression-free survival visits.............................................................................35

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6.2.3.4
Overall survival visits ...........................................................................................35
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................36
7.1
STATISTICAL DESIGN – MODEL ................................................................36
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................36
7.3
PLANNED ANALYSES.....................................................................................36
7.3.1
Primary endpoint analyses.................................................................................36
7.3.2
Secondary endpoint analyses .............................................................................36
7.3.4
Safety analyses.....................................................................................................36
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................37
7.4
INTERIM ANALYSES ......................................................................................37
7.5
HANDLING OF MISSING DATA ...................................................................37
7.6
RANDOMISATION ...........................................................................................37
7.7
DETERMINATION OF SAMPLE SIZE .........................................................38
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........40
8.1
TRIAL APPROVAL, PATIENT INFORMATION INFORMED 
CONSENT ...........................................................................................................40
8.2
DATA QUALITY ASSURANCE ......................................................................40
8.3
RECORDS...........................................................................................................40
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................40
8.5
STATEMENT OF CONFIDENTIALIT AND PATIENT PRIVACY...........40
8.6
TRIAL MILESTONES.......................................................................................40
9.
REFERENCES....................................................................................................41
9.1
PUBLISHED REFERENCES............................................................................41
10.
APPENDICES.....................................................................................................43
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....43
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS..............43
10.3
PHARMACOKINETIC METHODS AND ANALYSES................................44
10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................44
10.4.1
Schedules for PK, 
 sampling................................44
10.4.2
Stability testing....................................................................................................47
10.5
TRIAL BIOMARKER PLAN............................................................................48
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................49
11.1
GLOBAL AMENDMENT 1 ..............................................................................49
11.10
GLOBAL AMENDMENT 2 ..............................................................................57

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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase 
βHCG
Beta Human Chorionic Gonadotropin
BHM
Bayesian Hierarchical Model
BI
Boehringer Ingelheim
BM
Biomarker
CA
Competent Authority
CNS
Central Nervous System
CPK
Creatinine Phosphokinase
CR
Complete Response
CRC
Colorectal Cancer
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DBL
Database Lock
DC
Disease Control
DILI
Drug Induced Liver Injury
DoR
Duration of Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FFPE
Formulin fixed and paraffin embedded
GCP
Good Clinical Practice

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GEC
Gastro-oesophageal Adenocarcinoma
GEJ
Gastro-oesophageal Junction
GI
Gastrointestinal
HCC
Hepatocellular Carcinoma
HIV
Human Immunodeficiency Virus
i.v.
Intravenous
IB
Investigator’s Brochure
ICF
Informed consent form
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
irAE
Immune-related adverse events
IRB
Institutional Review Board
ISF
Investigator Site File
LAG-3
Lymphocyte-activation gene 3
LPLT
Last Patient Last Treatment
mAb
Monoclonal antibody
MDSC
Myeloid-Derived Suppressor Cell
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHC-II
Major histocompatibility complex Class II
MRI
Magnetic resonance imaging
NSCLC
Non-Small-Cell Lung Cancer
OR
Objective Response
OS
Overall Survival
PD
Progression of disease
PD-1
Programmed cell death 1 (receptor)
PDc
Pharmacodynamics
PD-L1
Programmed cell death ligand 1
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial Response
PTM
Planned Time

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RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
SAE
Serious Adverse Event
SCLC
Small-Cell Lung Cancer
SD
Stable Disease
SUSAR
Suspected Unexpected Serious Adverse Reactions
TNM
Classification of Malignant Tumours
ULN
Upper Level of Normal

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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 754111
BI 754111 is a humanised IgG4Pro mAb against LAG-3 that is being developed as an 
intravenous (i.v.) infusion for the treatment of cancer. BI 754111 has highly human 
frameworks and a low predicted immunogenicity score. 
1.2.2
BI 754091
Refer to the Master protocol.
1.3
RATIONALE FOR PERFORMING THE TRIAL  
Lymphocyte-activation gene 3 (LAG-3) is a cell-surface negative regulator of immune 
response involved in maintaining immunological tolerance via regulation of T-cell activation, 
proliferation, and response (R15-3588; R16-5355; R16-5359). LAG-3 is expressed on 
activated cytotoxic, helper and regulatory T-cells (T-regs). LAG-3 binds to major 
histocompatibility complex Class II (MHC-II) glycoproteins and negatively regulates T-cell 
activity (R16-5357; R16-5358). LAG-3 also regulates T-cell response via T-regs as loss of 
LAG-3 expression on T-regs results in loss of T-reg function (R16-5355).
Tumours use the immune-checkpoint pathways (such as the PD-1 and LAG-3 pathways) to 
evade anti-tumour immune responses. Tumour-infiltrating lymphocytes frequently express 
high levels of PD-1 in combination with other immune-checkpoint inhibitors including 
LAG-3 (R16-0876, R16-5358), while the ligands for these checkpoint inhibitors (i.e., PD-
L1/L2 and MHC-II, respectively) are expressed within the tumour microenvironment. 
Engagement of the co-inhibitory receptors PD-1 and LAG-3 by their respective ligands 
inhibits T-cell function preventing an anti-tumour immune response. It is now well 
established that blockade of the PD-1 axis of the immune-checkpoint program results in 
reactivation of T-cell function and the antitumour immune response leading to tumour growth 
inhibition in some patients. 
Immune-checkpoint inhibition based therapy is now well established as the standard of care 
at multiple treatment lines for many cancers including NSCLC, melanoma, renal cancer, 
bladder cancer and many others. However, only a subset of patients achieve durable response
to this therapy. The limited success achieved with checkpoint-inhibitor monotherapy (up to 
80% of treated patients do not respond; R15-3588, R15-3778) in some studies may, in part, 
be attributed to redundancy in immune-checkpoint inhibitor pathways. Therefore, it is 
postulated that blockade of multiple checkpoint-inhibitor pathways may result in better anti-
tumour activity and improved clinical outcome in a higher percentage of patients compared to 
checkpoint-inhibitor monotherapy. There is now sufficient evidence that show that blockage 

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of the PD-1 pathway leads to over-expression of other checkpoint inhibitors, including LAG-
3. This over expression of other checkpoint inhibitors may represent an escape pathway from 
the PD-1 pathway blockade. Therefore, it is possible that blocking multiple checkpoint 
inhibitors at the same time would lead to better response and potentially rescue some of the 
patients that have failed the PD-1 single-agent blockade, including patient with NSCLC 
(R15-3696, R16-0868, R16-0881, R16-2707, R16-5335, R16-5545). Multiple immune-
checkpoint inhibitor combinations are currently in development including the combination of 
anti-PD-1 and anti-LAG-3 mAbs with encouraging preliminary results (R16-5204, R16-
5218). 
New, more tolerable, combinations of immune-therapy treatment are needed to continue to 
improve the outcome for patients. BI 754111 in combination with BI 754091 has the 
potential to be such a combination.
The patient populations to be included in this trial were selected on the high unmet medical 
need (including poor response to currently available regimens or limited treatment options) of 
these patients and the potential for the combination checkpoint inhibitor therapy to provide 
clinical benefit for these patients. 
1.4
BENEFIT - RISK ASSESSMENT
Significant improvement in checkpoint inhibitor effect has been achieved with checkpoint 
inhibitor combination therapy. The combination of nivolumab and ipilimumab, for example, 
has resulted in significant improvement in ORR, compared to checkpoint inhibitor 
monotherapy in patients with NSCLC and melanoma (R16-5545, R15-3696, R16-5544).
Unfortunately, the improved efficacy of combined nivolumab and ipilimumab was associated 
with a significant increase in the rate and severity of AEs. Grade 3 and 4 AE rates of 53% to 
55% were reported with the full-dose combination of nivolumab and ipilimumab in patients 
with melanoma (R15-3696, R16-5544) and 33% to 37% with reduced dose and dosing 
frequency of the ipilimumab component in NSCLC compared to approximately 10% for 
nivolumab monotherapy in these populations (R15-3696, R16-5544).
Treatment with BI 754111 and BI 754091 is anticipated to be associated with a similar 
pattern of AEs as nivolumab and ipilimumab. Infusion-related reactions have been reported 
with checkpoint-inhibitor treatments. These reactions occur infrequently and are typically 
managed based on symptoms using treatments ranging from histamine antagonists in mild 
cases to administration of epinephrine when symptoms of anaphylaxis are detected. Detailed 
irAE management guidelines are presented in Appendix 10.2.
BI 754091 combined with BI 754111 should be permanently discontinued (and withheld at 
least temporarily until recovery in the case of some lower grade events, e.g., pneumonitis) for 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5 Grade 3 or 4 
pneumonitis, Grade 3 or 4 adrenal insufficiency, Grade 3 or 4 or recurrent colitis of any 
grade, Grade 4 diabetes mellitus, Grade 4 hypophysitis, Grade 4 rash, any grade encephalitis, 
any recurrent Grade 3 or 4 AE, transaminase values >5 times the upper limit of normal 
(ULN) or total bilirubin >3 times ULN, inability to taper steroids to 10 mg or less prednisone 

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or equivalent within 12 weeks, or persistent Grade 2 or 3 AEs that do not recover to Grade 1 
or less within 12 weeks. Additional information of management of irAEs is provided 
in Appendix 10.2
Based on these pre-clinical data, as well as clinical data obtained with BI 754091 and other 
anti-PD-1 mAbs, the inhibitory effects of the combination of BI 754111 and BI 754091 may 
translate into clinical benefit in cancer patients. 
Therefore, treatment with BI 754111 and BI 754091 is expected to provide patients with 
clinical benefit at an acceptable risk.
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.
Although rare, the 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 patient safety (refer to the Master protocol).
Infusion-related reactions have been reported in approximately 7% (6/86) of patients treated 
with the combination of BI 754091 and BI 754111, and none were reported with BI 754091 
monotherapy. The majority of the events were reported in patients receiving 240 mg of BI 
754091 in combination with 600 mg of BI 754111, with 2 events reported in patients 
receiving 240 mg of BI 754091 in combination with 20 mg of BI 754111. The majority were 
CTCAE Grade 2. Two events were Grade 3 and led to treatment discontinuation. The 
reported infusion-related reactions occurred during the infusion mostly during Cycle 2 or 
Cycle 3.

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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 
BI 754091 combined with BI 754111 in patients previously exposed to anti-PD-1 or PD-L1 
based therapy and patients who achieved benefit from or failed to respond to the previous 
anti-PD-1or anti-PD-L1 therapy.
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.

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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 754111 administered in 
combination with BI 754091 to patients in one of three cohorts shown below.
Cohort 1 GEC: Locally advanced, unresectable or metastatic gastric adenocarcinoma or gastro-
oesophageal adenocarcinoma with 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 with previously anti-PD-1 or anti-PD-L1 based treatment who progressed 
after achieving benefit (at least SD with a minimum duration of benefit of 6 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). For patients with NSCLC who received anti-PD-1 
or anti-PD-L1 based treatment as a first line regimen, the minimum duration of benefit is 8 months with 
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 (SD <6 months or progressive disease in <6 months while on previous anti-PD-1 or anti PD-L1 
based treatment.
----------------------------------------------------------------------------------------------------------7 
BI or 
Non-BI 
anti-PD-I 
or anti-
PD-Ll 
ba ed 
therapies 
[- --C-o-11-01_1_1 :_G_E_c ____ }---------, ___ 
, ---. 
_ 
n=40 
_ 
Cohort 2: 
Seconda1 resistance to 
anti-PD-1 or anti-PD-L 1 
based therap 
n=30 
Coho1t 3: 
Pri111ary resi tance to 
anti-PD-1 or anti-PD-L 1 
ba ed therap 
n=40 
..... 
..s:::: 
t'""" 
I 
CG 
I 
----------, 
L-----------------------------------------------------------------------------------------------------------

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Patients in this Module of the clinical trial will receive BI 754111 combined with BI 754091 
by i.v. infusion after signing the Master and Module informed consent forms and completing 
the screening processes. Treatment cycles will be administered every 3 weeks (21 days). 
Safety laboratory assessments will be performed locally according to the Flow Chart (See
Module A flow chart).
Tumour assessments will be done using Response Evaluation Criteria in Solid Tumours 
RECIST v1.1 and/or Immune-Related Response Evaluation Criteria in Solid Tumours 
(iRECIST) at screening and reassessed every 2 cycles (6 weeks ±3 days) for the first 6 
months, then every 9 weeks using the same radiographic procedure. Pharmacokinetic and 
biomarker samples will be collected throughout the study as described in Section 10.4
and Section 10.4.1. 
Patients will continue study treatment until disease progression (PD) according to RECIST 
v1.1 or iRECIST, withdrawal of patient consent, or an unacceptable toxicity occurs, 
whichever occurs first; maximum treatment duration is 1 year. 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 treatment beyond 1 year 
on a case-by-case basis after discussion with the Medical Monitor and the sponsor. The 
patient will be required to sign a new ICF to continue treatment.
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 (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 item number 2, Section 3.3.2.

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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.
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 gastro-oesophageal adenocarcinoma (GEC) (defined as 
primary tumour localisation below the gastro-oesophageal junction (GEJ) with 
prior anti-PD-1 or anti-PD-L1 based treated tumour. 
-
Must have had ≥1 line of prior treatment; only 1 prior anti-PD-1/PD-L1
based therapy with the exception of BI PD-1 investigational agent allowed 
(prior chemotherapy plus anti-PD-L1 combination is allowed).
-
Previous anti-PD-1 or anti-PD-L1 based therapy in a clinical trial setting is 
allowed as long as it is confirmed that the patient did receive anti-PD-1 or 
anti-PD-L1 based therapy in the trial (i.e., not placebo).

Cohort 2 Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based 
therapy: Any advanced or metastatic solid tumour with previously anti-PD-1 or 
anti-PD-L1 based treatment who progressed after achieving benefit 
-
Must have had ≥1 line of prior 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 6 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. For patients with NSCLC who received anti-PD-1 or 
anti-PD-L1 based treatment as a first line regimen, the minimum duration 
of benefit is 8 months with 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 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 6 months or progressive disease in less 
than 6 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 

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o
Other gastrointestinal (GI) cancers: hepatocellular carcinoma 
(HCC), biliary tract
o
Other thoracic cancers: small-cell lung cancer (SCLC) and 
mesothelioma  
o
Other tumour types for whom no therapy of proven efficacy exists, 
or who are not amenable to standard therapies and where anti-PD-
1/PD-L1 therapy may be considered exceptional cases upon 
discussion with the Medical Monitor.
3.
All patients must have measurable lesions according to RECIST v1.1
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. If the patient does not have an archival tumour tissue 
sample and is not biopsiable 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.
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. Previous treatment with an anti-LAG-3 agent
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.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
4.1.1.1
BI 754111
Details of the drug product, BI 754111, are presented in Table 4.1.1.1: 1 Additional details 
are presented in the BI 754111 IB and the Module A Pharmacy Manual.
Table 4.1.1.1: 1
BI 754111
Substance:
BI 754111
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & 
Co. KG
Unit strength:
20 mg/mL
Posology:
Infusion on Day 1 of each 3-week cycle
Route of administration:
I.V. infusion
4.1.1.2
BI 754091
Details of the drug product BI 754091 are presented in Table 4.1.1.2: 1.  Additional details 
are presented in the BI 754091 IB and the Module A Pharmacy Manual.
Table 4.1.1.2: 1
BI 754091
Substance:
BI 754091
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg/mL
Posology:
Infusion on Day 1 of each 3-week cycle
Route of administration:
I.V. infusion

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4.2
SELECTION OF DOSES IN THE TRIAL
BI 754111 and BI 754091 will be diluted and administered via i.v. infusion once every three 
weeks according to the details in the Module A Pharmacy Manual.
4.2.1
BI 754111
The selected dose of BI 754111 to be used in combination with 240 mg BI 754091 is 600 mg
administered via i.v. infusion once every 3 weeks. This dose of BI 754111 in combination 
with the selected dose of BI 754091 240 mg was selected based on the dose escalation data 
obtained in the ongoing trial 1381.2 (refer to the BI 754091 Investigator’s Brochure (IB) and 
the BI 754111 IB).
4.2.2
BI 754091
The selected dose of BI 754091 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 1381.1, administering BI 754091 monotherapy to patients with advanced solid 
tumours.  PK data were collected and clinical response was observed during the conduct of 
trial 1381.1, providing a basis to investigate a combination approach (BI 754091 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 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.

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4.2.8
Dose modifications
Dose reductions or escalations of BI 754111 or BI 754091 are not permitted in any one 
patient. Treatment administration may be delayed for a patient for one cycle, plus an 
additional 3 weeks, because of AEs, following discussion with the Medical Monitor.
If treatment is held or discontinued due to an AE(s), both BI 754091 and BI 754111 will be 
held or discontinued together. If treatment is to be restarted after resolution (≤ Grade 1) of the 
AE(s), both BI 754091 and BI 754111 must be restarted together.
The study drug(s) should be permanently discontinued for Grade 3 to 4 pneumonitis (for 
Grade 2 pneumonitis interrupt study drugs until resolution), Grade 3 to 4 adrenal 
insufficiency, Grade 4 diabetes mellitus, any grade encephalitis, Grade 4 hypophysitis, Grade 
4 rash, Grade 3 to 4 colitis or recurrent colitis of any grade, any recurrent Grade 3 to 4 AE, 
transaminase increases >5 times ULN or total bilirubin >3 times ULN (unless unequivocally 
attributed to another cause), inability to taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2 to 3 AEs that do not recover to Grade 1 or 
less within 12 weeks. Study drug(s) should also be permanently discontinued for Grade 3 to 4 
AEs that are classified as immune-related by the Investigator that are not listed in 
Appendix 10.1. Study drug(s) should be discontinued if ≥ Grade 4 drug-related AEs are 
reported. Please see Appendix 10.2 for guidelines for management of immune-related 
adverse events.
To reduce the risk of infusion-related reactions, patients are to 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. 
In the event of an infusion-related reaction ≤ Grade 2, treat the symptoms accordingly with 
antihistamine or corticosteroids if needed. 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.
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 
can be found in Appendix 10.2.

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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.
4.3.2.2
Permitted concomitant medications

If medically feasible, patients taking regular medication should be maintained on it 
throughout the trial.

Pre-medication will not be required, but may be utilised following the first dose of BI 
754111 or 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.

Blood transfusions are allowed at any time during 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 
first 3 weeks of any cohort, but may be started thereafter. Immunosuppressive 
medications including, but not limited to systemic corticosteroids at doses exceeding 
10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumour 
necrosis factor-alpha blockers are prohibited. Use of immunosuppressive medications 
for the management of investigational product-related AEs or in patients with contrast 
allergies is acceptable, and does not necessarily warrant immediate treatment 
discontinuation. In addition, use of inhaled, topical, intranasal corticosteroids or local 
steroid injections (e.g., intra-articular injection) is permitted. Temporary uses of 
corticosteroids for concurrent illnesses (e.g., food allergies, computed tomography 
(CT) scan contrast hypersensitivity) are acceptable upon discussion with the Medical 
Monitor.

To reduce the risk of infusion related reactions, patients are to 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.

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4.3.2.3
Prohibited concomitant medications

Live attenuated vaccines are prohibited during the trial through 30 days after the last 
dose of investigational product.

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.

Granulocyte colony stimulating factors should not be used prophylactically during the 
first 3 weeks treatment. Thereafter, prophylactic colony stimulating factors may be 
used according to institutional standards.

Palliative radiotherapy is not allowed during the first cycle. 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 to diet or life style have been identified for BI 754091 or BI 754111.
4.3.2.5
Contraception requirements
Refer to the Master protocol Section 4.2.2.3).
4.4
TREATMENT COMPLIANCE
Refer to the Master protocol Section 4.3).
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
To review the section on assessing efficacy according to RECIST v1.1 (R09-0262) and 
iRECIST (R15-2005) refer to the Master protocol. 
5.2
ASSESSMENT OF SAFETY
The safety of BI 754091 and BI 754111 will be assessed by a descriptive analysis of 
incidence and severity of AEs graded according to CTCAE (Version 5), 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, 
vital signs, laboratory parameters, and electrocardiogram).

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5.2.1
Other safety parameters
Not applicable.
5.2.2
Assessment of adverse events
Refer to the Master protocol for assessment of adverse events.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood for pharmacokinetic analysis of BI 754091 and BI 754111 will be collected at the 
visits specified in the Module A flow chart and in Appendix 10.4.
Pre-dose plasma concentrations shortly before the next infusion and the plasma 
concentrations after end of infusion of BI 754091 and BI 754111 will be evaluated 
descriptively according to BI internal Standard Operating Procedure (SOP) (001-MCS-36-
472_RD-01 [2.0] and 
 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 sample 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 BI 754091 
and BI 754111 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 ADA or biomarker for PK if sample 
volume allowed). The trial samples will be discarded after completion of the additional 
investigations.
Details on sample collection for BI 754111 and BI 754091 characteristics, processing, 
handling, and shipment are provided in the Module A Laboratory Manual. 

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5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a PK/PD relationship is planned.
5.4.1
Methods of sample collection
Pre-treatment and on-treatment tumour biopsy collections for biomarker and PD analyses will 
be mandatory from all patients in the trial. If the patient is not biopsiable because of a safety 
concern the patient could be considered for study after discussion with the Medical Monitor 

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to allow for a tumour type of interest. Patients enrolling in a 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. If the patient enters another 
module, this biopsy could be considered a pre-treatment sample. All samples must be 
adequately labelled by the trial site personnel. Details about tumour tissue and blood sample 
collection, plasma/serum preparation, required tubes, labelling of tubes, storage and shipment 
(frequency and addresses) will be provided in the ISF.

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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.

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
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 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 A Section 5.4.2.4 may be banked.
5.7
APPROPRIATENESS OF MEASUREMENTS
All assessments have been planned in accordance with traditional oncology Phase II trial 
methodology.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and exclusion criteria for the Master and the Module A and 
who have signed a written ICF (Master and Module A), are eligible for participation in this 
Module. Patients will visit the clinical site at the time points specified in the flow chart (see
Module A 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 for any reason is made for a patient to stop the treatment with the 
combination of BI 754111 plus BI 754091, 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.
Additional PFS follow-up visits after the 30-day safety follow-up visit will only be performed 
for patients who did not progress on treatment. These will be performed once every 12 weeks 
at least until PD, introduction of a new anti-cancer treatment, death, loss to follow-up, 
withdrawal of consent, or end of the whole trial.
The trial will be conducted according to the principles of 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 
relevant flow charts of this protocol (Module A flow chart). The key procedures required 
include:

Reporting of all AEs occurring from signing the ICF onwards until end of residual 
effect period (REP).

Baseline and on-treatment blood biomarker and immunogenicity assessments

Tumour assessments (based on CT/PET and/or MRI scan) according to RECIST v1.1 
and iRECIST must be performed once every 2 cycles (meaning every 6 weeks if there 
are no delays in cycles but as close as possible to the end of the second of the 2 cycles 
of treatment if there was a delay) after the start of BI 754111 for the first 6 months, 
and then every 3 cycles (9 weeks) thereafter.
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 754111 and BI 754091). For the detailed description of the tests to be 
performed during this period and their timing, please refer to the appropriate flow chart.

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6.2.2
Treatment period
Please refer to the Module A 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.
6.2.3.2
30-day post-treatment safety visit
The safety follow-up visit is performed 30 (+2) days after discontinuation of 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.
6.2.3.3
Progression-free survival visits
Additional follow-up visits after the 30-day safety follow-up visit will only be performed for 
patients who did not progress on treatment. These will be performed once every 12 weeks at 
least until PD, introduction of a new anti-cancer treatment, death, loss to follow-up, or end of 
July 2021. Sites may conduct one final PFS visit for each patient that had been followed until 
July 2021. For patients who remain on treatment after July 2021, no separate PFS visits will 
be done (the 30-day post treatment safety visit will be their last study visit).
6.2.3.4
Overall survival visits
These will be performed once every 12 weeks at least on the same schedule as PFS survival 
visits until death, loss to follow-up, or end ofuly 2021. As of July 2021, no further OS data 
needs to be collected. Sites may collect one final OS visit for each patient they had been 
following. For patients who remain on treatment after July 2021, no separate OS visit will be 
done (the 30-day post treatment safety visit will be their last study visit).

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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, 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. Until any 
decision from the futility analysis is done, 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 20th patient in cohort 1 and 3 or 15th patient in cohort 2 has completed 
the third on-treatment imaging assessment (i.e. end of cycle 6).
If the 20th patient in cohort 1 and 3 or 15th patient in cohort 2 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.
In addition, interim analyses may be performed as each cohort is finished.
7.5
HANDLING OF MISSING DATA
Refer to the Master protocol.
7.6
RANDOMISATION
For general aspects please refer to the Master protocol. If at a later time-point there is more 
than one treatment option available, the respective randomisation procedure will be described 
in the related Module.

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7.7
DETERMINATION OF SAMPLE SIZE
For all three cohorts, 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% (cohorts 
1 and 2) and 0% (cohort 3) respectively with anti-PD-1 antibody monotherapy.
The futility boundary and early stopping probability for each cohort is described in
Table 7.7: 1.
About 40 patients each will be included in Cohorts 1 and 3, and 30 patients will be included 
in Cohort 2. The target response ’s are 20%, 20% and 10% respectively. Different 
homogeneous scenarios and heterogeneous scenarios are considered in the simulations to 
assess the frequentist operating characteristics of the BHM approach. The simulation results 
as shown in Table 7.7: 1 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.

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Table 7.7: 1
Operating characteristics of the Bayesian Hierarchical Modelling 
approach for final analysis under different scenarios with interim 
analysis based on observed ORR 
Scenario (ORR
(%) in each 
patient cohort)
Early stopping 
criterion 
(observed 
ORR)
Early stopping 
probability
Probability of 
shrinkage estimator 
of the ORR > 
(20%, 20%, 10%)
in at least one 
cohort at final
Probability of 
shrinkage estimator 
of the ORR > (20%, 
20%, 10%) in each 
cohort at final
(25, 25, 15)
(<10%, 
<10%, <5%)
8% / 9% / 17%
96%
83% / 80% / 81%
(15, 15, 7.5)
(<10%, 
<10%, <5%)
41% / 33% / 
56%
32%
13% / 14% / 19%
(5, 5, 0)
(<10%, 
<10%, <5%)
90% / 86% / 
100%
0%
0% / 0% / 0%
(5, 25, 15)
(<10%, 
<10%, <5%)
92% / 7% / 19%
86%
0% / 67% / 74%
(25, 25, 0)
(<10%, 
<10%, <5%)
9% /7% / 100%
86%
74% / 73% / 0%
(25, 5, 0)
(<10%, 
<10%, <5%)
9% / 83% / 
100%
64%
64% / 0% / 0%
(5, 5, 15)
(<10%, 
<10%, <5%)
92% / 83% / 
17%
67%
0% / 0% / 67%
Number of simulations = 1000
Therefore, a total sample size of approximately 110 patients is expected.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
Refer Section 8 in the Master protocol for this information.
8.1
TRIAL APPROVAL, PATIENT INFORMATION INFORMED CONSENT
Refer to the Master protocol.
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 CONFIDENTIALIT 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.
R15-2005
Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response 
criteria: irRECIST. 39th Ann Cong of the European Society for Medical
Oncology (ESMO), Madrid, 26-30 Sep 2014 (Poster).
R15-3588
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, 
et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. 
N Engl J Med. 2012;366(26):2443-54.
R15-3696
Larkin J, Chiarion- Sileni V, Gonzalez R, Grobb JJ, Cowey CL, Lao CD, et al. 
Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. 
N Engl J Med. 2015;373(1):23–34.
R15-3778
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-
programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-
refractory advanced melanoma: a randomised dose-comparison cohort of a 
phase 1 trial. Lancet. 2014;384:1109-17.
R16-0852
Woo SR, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically 
regulate T cell function to promote tumoral immune escape. Cancer Res. 
2012;72(4):917-27.
R16-0868
Koyama S, et al. Adaptive resistance to therapeutic PD-1 blockade is with 
upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.
R16-0876
Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, 
advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet. 2016;387(10027):1540-50.
R16-0881
Matsuzaki J; Gnjatic S; Mhawech-Fauceglia P; Beck A; Miller A; Tsuji T, et 
al. Tumor infiltrating NY-ESO-1-specific CD8+ T cells are negatively 
regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci 
USA. 2010;107(17):7875-80.
R16-2707
Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, et al. Nivolumab 
alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer 
(CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 
2016.
R16-5204
Lipson EJ, Gopal AK, Neelapu SS, Armand P, Spurgeon S, Leonard JP, et al. 
Initial Experience Administering BMS-986016, a Monoclonal Antibody That 
Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination 
With Nivolumab to Patients With Hematologic and Solid Malignancies. 31st 
Ann Sci Mtg of the Society of Immunotherapy of Cancer (SITC), National 
Harbor, 9-13 Nov 2016 (Abstract).
R16-5218
Lipson EJ, Gopal AK, Neelapu SS, Armand P, Spurgeon S, Leonard JP, et al. 
Initial Experience Administering BMS-986016, a Monoclonal Antibody That 
Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination 
With Nivolumab to Patients With Hematologic and Solid Malignancies. 31st 

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Ann Sci Mtg of the Society of Immunotherapy of Cancer (SITC), National 
Harbor, 9-13 Nov 2016 (Poster).
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Huang RY, Francois A, McGray AJR, Miliotto A, Odunsi K. Compensatory 
upregulation of PD-1, LAG-3 and CTLA-4 limits the efficacy of single agent 
checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 
2016;6(1):e1249561.
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Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of 
LAG-3 in regulatory T cells. Immunity 2014;21:503-13.
R16-5356
Workman CJ, Vignali DAA. Negative regulation of T cell homeostasis by 
lymphocyte activation gene-3 (CD223). J Immunol. 2005;174(2):688-95.
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Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-
Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related 
to CD4. J Exp Med. 1990;171(5):1393–1405.
R16-5358
Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. 
Characterization of the major histocompatibility complex class II binding site 
on LAG-3 protein. Proc Natl Acad Sci USA. 1997;94:5744-49.
R16-5359
Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali 
DAA. Lymphocyte activation gene-3 (CD223) regulates the size of the 
expanding T cell population following antigen activation in vivo. J Immunol.
2004;172(9):5450-5.
R16-5544
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, 
et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 
2013;369(2):122-33.
R16-5545
Hellmann MD, Gettinger SN, Goldman JW, Brahmer JR, Borghaei H, Chow 
LQ, et al. CheckMate 012: safety and efficacy of first-line (1L) nivolumab 
(nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 
2016;34(Suppl), Abstr 3001.
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Berry SM, Broglio KR, Groshen S, Berry DA. Bayesian hierarchical 
modelling of patient subpopulations: efficient designs of Phase II oncology 
clinical trials. Clin Trials. 2013:10:720-34.

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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.

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10.3
PHARMACOKINETIC METHODS AND ANALYSES 
Not applicable.
10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD SAMPLING
10.4.1
Schedules for PK, 
 blood sampling 
Protocol Version 3 or later: As of 01 July 2021, PK, 
 samples are no longer 
collected, including the End of Treatment, or the 30-day follow-up.
Table 10.4.1:1
Time schedule for PK, 
 blood sampling in Cycle 1
Treatment
Cycle
Day
Time Point 
Description
CRF Time 
(= Planned 
Time, PTM) 
[hh:mm]
PK 
BI 754091
PK 
BI 754111
1
1
Before 
start of 
infusion
-0:05
X
X
X
X
X
X
X
X
Start 
of infusion
0:00
2 h after 
start of 
infusion
2:00
X
X
2
24 h after 
start of 
infusion
24:00
X
X
X
X

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Treatment
Cycle
Day
Time Point 
Description
CRF Time 
(= Planned 
Time, PTM) 
[hh:mm]
PK 
BI 754091
PK 
BI 754111
8
168 h after 
start of 
infusion
168:00
X
X
X
15
336 h after 
start of 
infusion
336:00
X
X
X
X
X
X
X
; EOT = end of treatment; FU 
= Follow-up; 
; PK = Pharmacokinetics; 
 
The planned infusion duration is 1 hour. Actual date and clock time of start of infusion, end of infusion and blood draws have to be recorded.
The following time windows are specified for PK sampling for procedural reasons:

Predose (PTM -0:05): within 1 hour before next drug infusion

2 hours post start of infusion (PTM 2:00): anytime from the end of drug infusion up to 4 hours post-infusion

24 hours post start of infusion (PTM 24:00): ±2 hour

168 hours post start of infusion (PTM 168:00): ±1 day

336 hours post start of infusion (PTM 336:00): ±1 day

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Table 10.4.1: 2  
Time schedule for PK, 
blood sampling from Cycle 2 onwards
Treatment
Cycle
Day
Time Point 
Description
CRF Time 
(= Planned 
Time, PTM) 
[hh:mm]
PK 
BI 754091
PK 
BI 754111
2, 4, 8
1
Before
start of infusion
-0:05
X
X
X (C4 & C8)
X (C4 & 
C8)
X (C2)
X (C2)
X (C2)
Start 
of infusion
0:00
2 h after 
start of infusion
2:00
X
X
3, 5, 6
1
Before 
start of infusion
-0:05
X
X
X (C3 only)
X (C3 
only)
X (C3)
12, 16
1
Before 
start of infusion
-0:05
X
X
X
X
EOT
X
X
X
X
X
X
X
X
30-days 
FU
X
X
X
X
; CRF = Case Report Form; EOT = end of treatment; FU 
= Follow-up; 
; PK = Pharmacokinetics; VEGF = Vascular Endothelial Growth 
Factor
The planned infusion duration is 1 hour. Patients will be requested to provide samples of blood prior to their first treatment, on-treatment (Cycle 3 Day 1), and at disease 
progression or EOT.Actual date and clock time of start of infusion, end of infusion and blood draws have to be recorded.
The following time windows are specified for PK sampling for procedural reasons:

Predose (PTM -0:05): within 1 hour before next drug infusion

2 hours post start of infusion (PTM 2:00): anytime from the end of drug infusion up to 4 hours post-infusion

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10.4.2
Stability testing
Additional blood sample for stability testing:
In order to assess the stability of BI 754091 and BI 754111 in whole blood, one additional 
blood sample per analyte will be taken from 3 subjects at one pre-selected site. Please refer to 
the lab manual for details. The results of the analysis of these samples will not be reported 
within the clinical trial report but will be used for bioanalytical assay validation and therefore 
included in the corresponding method validation report.

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10.5
TRIAL BIOMARKER PLAN
Biomarker collections are included in Appendix 10.4.1.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
07 May 2019
EudraCT number
EU number
2018-002344-81
BI Trial number
1381-0009
BI Investigational 
Medicinal Product(s)
BI 754091 (anti-PD-1)
BI 754111 (anti-LAG3)
Title of protocol
An open-label, Phase II trial evaluating the safety and 
efficacy of BI 754111 in combination with BI 754091 in 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
Synopsis Main in- and exclusion criteria
Description of change
Abbreviated Exclusion Criteria 
1.
Any exclusion criteria listed in the Master protocol.
2.
Previous treatment with an anti-LAG-3 agent
3.
The use of systemic steroids
4.
Autoimmune disease
Rationale for change
Both exclusion criteria were removed from Module A 
since they were both in the Master.
Section to be changed
Flow Chart MODULE A BI 1381.9
Description of change
A new row “Administration of Pre-Treatment 
Medicationn “and footnote “n- Pre-treatment 
medications (antihistamine and acetaminophen or 
paracetamol) should be administered at sufficient time 
prior to initiation of infusion to allow the agents to 
exert their influence.” were added. 
Rationale for change
Pre-treatment medication have been added to the study 
prior to administration of the study treatment in order to 
reduce the risk of infusion-related reactions.
Section to be changed
Flow Chart MODULE A BI 1381.9

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Description of change
d
… Baseline PD-L1 expression level, 
microsatellite instability (MSI), and tumour mutation 
burden (TMB) information will be collected in the 
eCRF, if locally available….
Rationale for change
Additional baseline data for a deeper analysis was added. 
Section to be changed
Flow Chart MODULE A BI 1381.9 Blood Samples for 
Description of change
X (C3 & C4 only)
Rationale for change
An additional blood collection was added on C3D1to 
better track 
 
Section to be changed
Flow Chart MODULE A BI 1381.9 footnote m
Description of change
Another mandatory biopsy will be collected at C3D1 (±5 
days).
Rationale for change
A 5 day window was added to allow for flexibility in the 
collection of the C3D1 biopsy tissue. 
Section to be changed
Section 1.4 BENEFIT – RISK ASSESSMENT
Description of change
Infusion-related reactions have been reported in 
approximately 7% (6/86) of patients treated with the 
combination of BI 754091 and BI 754111, and none 
were reported with BI 754091 monotherapy. The 
majority of the events were reported in patients 
receiving 240 mg of BI 754091 in combination with 600 
mg of BI 754111, with 2 events reported in patients 
receiving 240 mg of BI 754091 in combination with 20 
mg of BI 754111. The majority were CTCAE Grade 2. 
Two events were Grade 3 and led to treatment 
discontinuation. The reported infusion-related 
reactions occurred during the infusion mostly during
Cycle 2 or Cycle 3.
Rationale for change
The risk of infusion-related reactions has been described 
based on the most recent safety information. 
Section to be changed
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING 
THE CHOICE OF CONTROL GROUPS
Description of change
Not applicable
Rationale for change
To clarify the text. 
Section to be changed
3.3.2 Inclusion criteria
Description of change
2.
Histologically confirmed diagnosis of one of the 
following cohorts:

Cohort 1 GEC - Locally advanced, unresectable or 
metastatic gastric adenocarcinoma or gastro-
oesophageal adenocarcinoma (GEC) (defined as 

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primary tumour localisation below the gastro-
oesophageal junction (GEJ) with prior anti-PD-1 or 
anti-PD-L1 based treated tumour. 
-
Must have had ≥1 line of prior treatment; only 1 
prior anti-PD-1/PD-L1 based therapy with the 
exception of BI PD-1 investigational agent
allowed (prior chemotherapy plus anti-PD-L1 
combination is allowed).
-
Previous anti-PD-1 or anti-PD-L1 based therapy 
in a clinical trial setting is allowed as long as it is 
confirmed that the patient did receive revive
anti-PD-1 or anti-PD-L1 based therapy in the 
trial (i.e not placebo).

Cohort 2 Patients with secondary resistance to anti-
PD-1 or anti-PD-L1 based therapy: Any advanced 
or metastatic solid tumour with previously anti-PD-
1 or anti-PD-L1 based treatment who progressed 
after achieving benefit 
-
Must have had ≥1 line of prior 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 6 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. For patients with 
NSCLC who received anti-PD-1 or anti-PD-L1 
based treatment as a first line regimen, the 
minimum duration of benefit is 8 months with 
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 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) 

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less than 6 months or progressive disease in less 
than 6 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: 
hepatocellular carcinoma (HCC), biliary tract
o
Other thoracic cancers: small-cell lung cancer 
(SCLC) and mesothelioma  
o
Other tumour types for whom no therapy of 
proven efficacy exists, or who are not 
amenable to standard therapies and where 
anti-PD-1/PD-L1 therapy may be considered 
exceptional cases upon discussion with the 
Medical Monitor.
Rationale for change
Additional text has been added to clarify that prior use of 
PD-1 investigational agents is not exclusionary.
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
3
The use of systemic steroids
4
Autoimmune disease
Rationale for change
Both exclusion criteria were removed from Module A 
since they were both in the Master. 
Section to be changed
4.2.8
Dose modification
Description of change
To reduce the risk of infusion-related reactions, 
patients are to 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. 
In the event of an infusion-related reaction ≤Grade 2, 
treat the symptoms accordingly with antihistamine or 
corticosteroids if needed. Tthe 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 

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safety section in the Master protocol) and adequate 
therapy should be initiated to treat the AE.
Rationale for change
Pre-treatment medication has been added to the study prior 
to administration of the study treatment in order to reduce 
the risk of infusion related reactions.
Section to be changed
4.3.2.2 Permitted concomitant medications
Description of change

To reduce the risk of infusion related reactions, 
patients are to 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.
Rationale for change
Pre-treatment medication has been added to the study prior 
to administration of the study treatment in order to reduce 
the risk of infusion-related reactions.
Section to be changed
Section 5.3.2 Methods of sample collection
Description of change
The trial samples will be discarded after completion of the 
additional investigations.but not later than 5 years after the 
final trial report has been signed. 
Rationale for change
The 5 year limit on holding trial samples has been 
removed to allow for more flexibility. 
Section to be changed
Description of change
Rationale for change
 
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 6.2 DETAILS OF TRIAL PROCEDURES AT 
SELECTED VISITS
Description of change
Reporting of all AEs ocuring from signing the ICF 
onwards until end of residual effect period (REP). 
Rationale for change
To clarify that AEs will be reported through the entirety of 
the REP. 
Section to be changed
7.4 INTERIM ANALYSES

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Description of change
An interim futility analysis will be performed for each 
cohort in the Module. Until any decision from the 
futility analysis is done, the enrolment of next patient 
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 20th patient in cohort 1 and 3 or 
15th patient in cohort 2 has completed the 
third on-treatment imaging assessment (i.e. 
end of cycle 6).
If the 20th patient in cohort 1 and 3 or 15th patient in 
cohort 2 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.
In addition, interim analyses analysis may be performed as 
each cohort is finished. 
Rationale for change
An interim futility analysis has been added to the study. 
Section to be changed
7.7 DETERMINATION OF SAMPLE SIZE
Description of change
For all three cohorts, no literature is available for the 
target patients. As there are no treatments of proven 
efficacy for this population, it is assumed around 5% 
(cohorts 1 and 2) and 0% (cohort 3) respectively with 
anti-PD-1 antibody monotherapy.
The futility boundary and early stopping probability 
for each cohort is described in Table 7.7: 1.
About 40 patients each will be included in Cohorts 1 and 
32, and 30 patients will be included in Cohort 2. The target 
response ’s are 2035%, 20% and 10% respectively
Rationale for change
The text was added to provide more detail about the target 
patient enrollment sizes. 
Section to be changed
10.3
PHARMACOKINETIC METHODS AND 
ANALYSES
Description of change
Not applicable
Rationale for change
To clarify the text. 
Section to be changed
10.4.1 Schedule for PK, 
 
sampling

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Description of change
Table 7.7: 1
Operating characteristics of the 
Bayesian Hierarchical Modelling 
approach for final analysis under 
different scenarios with interim 
analysis based on observed ORR
Operationg cheacteristics of the 
Baysean Hierarchical Modeling 
approach under different scenarios
Scenario 
(ORR 
(%) in 
each 
patient 
cohort)
Early 
stopping 
criterion 
(observed 
ORR)
Early 
stopping 
probability
Probability 
of 
shrinkage 
estimator 
of the 
ORR > 
(20%, 
20%, 10%) 
in at least 
one cohort 
at final
Probability 
of 
shrinkage 
estimator 
of the 
ORR > 
(20%, 
20%, 10%) 
in each 
cohort at 
final
(25, 25, 
15)
(<10%, 
<10%, 
<5%)
8% / 9% / 
17%
96%
83% / 80% 
/ 81%
(15, 15, 
7.5)
(<10%, 
<10%, 
<5%)
41% / 
33% / 
56%
32%
13% / 14% 
/ 19%
(5, 5, 0)
(<10%, 
<10%, 
<5%)
90% / 
86% / 
100%
0%
0% / 0% / 
0%
(5, 25, 
15)
(<10%, 
<10%,
<5%)
92% / 7% 
/ 19%
86%
0% / 67% / 
74%
(25, 25, 
0)
(<10%, 
<10%, 
<5%)
9% /7% / 
100%
86%
74% / 73% 
/ 0%
(25, 5, 0)
(<10%, 
<10%, 
<5%)
9% / 83% 
/ 100%
64%
64% / 0% / 
0%
(5, 5, 15)
(<10%, 
<10%, 
<5%)
92% / 
83% / 
17%
67%
0% / 0% / 
67%

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Scenario 
(objective 
response rate 
(%) in each 
patient cohort)
Probability of 
shrinkage estimator 
of the objective 
response rate > 
(35%, 20%, 10%) 
in at least one 
cohort
Probability of 
shrinkage estimator 
of the objective 
response rate > 
(35%, 20%, 10%) in 
each cohort
(40, 25, 
15)
97%
79% / 83% / 
93%
(30, 15, 
7.5)
40%
17% / 15% / 
27%
(15, 5, 
0)
0%
0% / 0% / 
0%
(15, 25, 
15)
84%
0% / 60% / 
74%
(40, 25, 
0)
84%
68% / 70% / 
10%
(40, 5, 
0)
58%
58% / 0% / 
0%
(15, 5, 
15)
58%
0% / 0% / 
58%
Rationale for change
Updated Baysean Hierarchical Modelling parameters were 
updated based in updated projected ORR. 
Section to be changed
Table 10.4.1: 2 Time schedule for PK, 
 
 blood sampling from Cycle 2 onwards
Description of change
X (C3 only)
Rationale for change
An additional blood collection was added on C3D1to 
better track 
.
Section to be changed
10.5
TRIAL BIOMARKER PLAN
Description of change
 collections are included in Appendix 10.4.1. 
Appendix 10.1 and Appendix 10.2
Rationale for change
The text has been corrected to right appendix number. 

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11.10
GLOBAL AMENDMENT 2
Number of global 
amendment
2
Date of CTP revision
14 Jul 2021
EudraCT number
EU number
2018-002344-81
BI Trial number
1381-0009
BI Investigational 
Medicinal Product(s)
BI 754091 (anti-PD-1)
BI 754111 (anti-LAG3)
Title of protocol
An open-label, Phase II trial evaluating the safety and 
efficacy of BI 754111 in combination with BI 754091 in 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
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts 
of sections with changes are presented. Please note that formatting changes and minor 
changes to punctuation, spelling, and abbreviations that do not affect meaning are not 
noted in this summary.

Boehringer Ingelheim
14 JUL 2021
BI Trial No.: 1381-0009
c25025479-03
Clinical Trial Protocol Module  A
Page 58 of 60
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001-MCS-40-106-RD-03 (15.0) / Saved on: 30. Nov 2017
Section to be changed
Coordinating Investigator
Description of change
, 
Rationale for change
 
will replace 
 as the coordinating 
investigator.
Section to be changed
Flowchart and footnote f
Description of change
On study electrocardiograms were removed from the 
flowchart until the EOT visit, and footnote f was changed to . 
Single digitalised ECGs must 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
Rationale for change
Electrocardiograms are no longer required until the EOT visit 
unless 
Section to be changed
Flowchart: footnote h 
Description of change
Additional progression-free survival (PFS) follow-up visits 
after the 30-day safety follow-up visit will only be performed 
for patients who did not progress on treatment. These will be 
performed once every 12 weeks at least until PD, introduction 
of a new anti-cancer treatment, death, loss to follow-up, 
withdrawal of consent, or end of July 2021. As of July 2021, 
sites may conduct one final PFS visit for each patient that 
is being followed. For patients who remain on treatment 
after July 2021, no separate PFS visits will be done (the 
30-day post treatment safety visit will be their last study 
visit). the whole trial.
Rationale for change
The sponsor has determined that sufficient PFS and OS data 
has been collected and very few patients remain on study 
drug.
Section to be changed
Flowchart: footnote o
Description of change
As of 01 July 2021, PK, 
 
 samples are no longer 
collected, including the End of Treatment, or the 30-day 
follow-up.
Rationale for changes
As of July 2021, sufficient PK, 
 
 samples have been collected 
and analyzed.  The additional collection of samples will not 

Boehringer Ingelheim
14 JUL 2021
BI Trial No.: 1381-0009
c25025479-03
Clinical Trial Protocol Module  A
Page 59 of 60
Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (15.0) / Saved on: 30. Nov 2017
contribute to a better understanding of the characteristics of 
the molecule. In order to reduce the burden of collection of 
further samples from patients, PK, 
 
samples no 
longer need to be collected.
Section to be changed
6.2.3.3
Progression-free survival visits
Description of change
Additional follow-up visits after the 30-day safety follow-up 
visit will only be performed for patients who did not progress 
on treatment. These will be performed once every 12 weeks 
at least until PD, introduction of a new anti-cancer treatment, 
death, loss to follow-up, or end of July 2021the whole trial. 
Sites may conduct one final PFS visit for each patient that 
had been followed until July 2021. For patients who 
remain on treatment after July 2021, no separate PFS 
visits will be done (the 30-day post treatment safety visit 
will be their last study visit).
Rationale for changes
The sponsor has determined that sufficient PFS data has been 
collected and very few patients remain on study drug.
Section to be changed
6.2.3.4
Overall survival visits
Description of change
These will be performed once every 12 weeks at least on the 
same schedule as PFS survival visits until death, loss to 
follow-up, or end of July 2021the whole trial as in the safety 
and efficacy sections in the Master. As of July 2021, no 
further OS data needs to be collected. Sites may collect 
one final OS visit for each patient they had been 
following. For patients who remain on treatment after 
July 2021, no separate OS visit will be done (the 30-day 
post treatment safety visit will be their last study visit).
If the sponsor determines that enough OS data has been 
collected from select cohorts, sites could be instructed to 
discontinue OS visits for those cohorts.
Rationale for changes
The sponsor has determined that sufficient OS data has been 
collected and very few patients remain on study drug.
Section to be changed
10.4.1
Schedule for PK, 
 
 blood sampling
Description of change
As of 01 July 2021, PK, 
 
 samples are no longer 

Boehringer Ingelheim
14 JUL 2021
BI Trial No.: 1381-0009
c25025479-03
Clinical Trial Protocol Module  A
Page 60 of 60
Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (15.0) / Saved on: 30. Nov 2017
collected, including the End of Treatment, or the 30-day 
follow-up.
Rationale for changes
As of July 2021, sufficient PK, 
 
 samples have been collected 
and analyzed.  The additional collection of samples will not 
contribute to a better understanding of the characteristics of 
the molecule. In order to reduce the burden of collection of 
further samples from patients, PK, 
 
samples no 
longer need to be collected.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25025479
3.0
clinical-trial-protocol-version-03-module-a
An open-label, Phase II trial evaluating the safety and efficacy of BI 754111 in
combination with BI 754091 in PD-(L)1 naive 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
15 Jul 2021 05:04 CEST
Author-Trial Clinical
Pharmacokineticist
15 Jul 2021 07:48 CEST
Author-Trial Statistician
15 Jul 2021 16:03 CEST
Approval-Therapeutic Area
15 Jul 2021 17:52 CEST
Approval-Translational Medicine
Expert
15 Jul 2021 18:56 CEST
Approval-Team Member Medicine
16 Jul 2021 15:54 CEST
Verification-Paper Signature
Completion
26 Jul 2021 03:12 CEST
Boehringer 
~11111~ lngelhein1 

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c25025479
3.0