An Open Label Phase I PET Imaging Study to Investigate the Bio-distribution and Tumor Uptake of [89Zr]Zr-BI 754111 in Patients With Advanced Non-small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma Treated With BI 754111 in Combination With BI 754091
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung, Head and Neck Neoplasms
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-03 (15.0) / Saved on: 30 November 2017
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21115267-03
EudraCT No.:
2017-005046-30
BI Trial No.:
1381-0003
BI Investigational 
Product(s):
[89Zr]Zr-BI 754111, BI 754091 and BI 754111
Title:
An open label Phase I PET imaging study to investigate the bio-
distribution and tumor uptake of [89Zr]Zr-BI 754111 in patients 
with advanced non-small cell lung cancer and head and neck 
squamous cell carcinoma treated with BI 754111 in combination 
with BI 754091
Lay Title:
This study tests how BI 754111 is distributed in patients with 
advanced non-small cell lung cancer or patients with head and 
neck cancer who are treated with BI 754091
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Phone: 
Fax: 
Principal / 
Coordinating 
Investigators:
PO box
Phone: 
Fax: 
PO box
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 27 Jan 2020
Page 1 of 95
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in Part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name:
Boehringer Ingelheim 
Finished product name:
N/A
Active ingredient name:
[89Zr]Zr-BI 754111, BI 754111 and BI 754091
Protocol date:
01 August 2018
Revision date:
27 January 2020
Trial number:
1381-0003
Title of trial:
An open label Phase I PET imaging study to investigate the bio-distribution and 
tumor uptake of [89Zr]Zr-BI 754111 in patients with advanced non-small cell lung 
cancer and head and neck squamous cell carcinoma treated with BI 754111 in 
combination with BI 754091
Principal Investigators:
PO box 
 
Tel: 
Fax:
PO box 
 
Tel: 
Fax: 
 
Trial site(s):
PO box
Clinical phase:
I
Trial rationale:
This trial will use a non-invasive method to determine tumor and tissue drug 
concentration and support Pharmacokinetics (PK) modelling. It will be evaluated 
whether [89Zr]Zr-BI 754111 uptake may serve as a Positron Emission Tomography
(PET) imaging based selection biomarker for Lymphocyte-Activation Gene 3
(LAG-3) overexpression within tumors as a potential resistance mechanism for 
preceding checkpoint inhibitor treatment
Trial objective(s):
The main objective of this study is to determine the biodistribution and intra-tumor 
accumulation of [89Zr]Zr-BI 754111 at baseline and its change upon treatment
Trial endpoint(s):
Primary endpoint:
Standardized uptake values (SUVs) of [89Zr]Zr-BI 754111 for tumor uptake at 
baseline and post BI 754111 dose
Trial design:
This is an open-label, non-randomised study divided into two Parts

Part 1: dosimetry and feasibility assessment of [89Zr]Zr-BI 754111 PET/
Computed Tomography (CT)

Part 2: assessment of tumor uptake of [89Zr]Zr-BI 754111 at various doses 
of BI754111 treatment

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Both Parts include a baseline assessment and an on-treatment assessment of 
[89Zr]Zr-BI 754111 tumor uptake. During the on-treatment assessment, it is 
planned to explore at least 2 doses of BI 754111.
The study will be performed in a staggered approach. 
Part 2 will commence based on Study Monitoring Committee (SMC) decision after 
review of all available data from Part 1. 
Total number of patients
entered: 
Up to 40 patients are planned to be entered in this trial
Number of patients on 
each treatment:
Part 1: up to 5 patients 
Part 2: up to 35 patients
Diagnosis:

Patients with advanced or metastatic non small cell lung cancer (NSCLC) 
who have failed on or after preceding anti-programmed cell death protein-
1 (PD-1) or anti-programmed death ligand-1 (PD-L1) based treatment with 
at least 3 months stable disease before progression

Patients with recurrent and metastatic head and neck squamous cell 
carcinoma (HNSCC) who have been treated with at least one previous 
systemic chemotherapy or are chemotherapy intolerant/unresponsive. 
Previous treatment with an anti PD-1/PD-L1 is allowed
Main criteria for
inclusion:

Adult patients of legal age with no active use of systemic steroids, no 
active auto-immune disease, and a life expectancy of at least 12 weeks

Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Must have at least one PET imageable and evaluable lesion of 20mm 

Must have at least one tumor lesion amenable to biopsy. This lesion should 
be PET imageable and evaluable as defined above and the biopsy should 
be obtained before the first BI 754091 administration, unless medically 
contra-indicated. In the latter case, 25 4µm-sections from an archival 
biopsy taken at relapse after the previous treatment are acceptable

Must have evaluable lesion(s) according to Revised Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 and for cancer 
immunology trials (iRECIST)
Patients with NSCLC:

must have histologically confirmed NSCLC

must have received anti-PD-1 or anti-PD-L1 as Part of last treatment with 
at least 3 months stable disease and are progressing on this anti-PD1/PD-
L1 based treatment.
Patients with HNSCC.

must have histologically confirmed, recurrent metastatic HNSCC

must have progressed after previous systemic chemotherapy, or not 
eligible for receiving standard (radio) chemotherapy. Previous treatment 
with an anti PD-1/PD-L1 is allowed.
Main criteria for 
exclusion:
No previous treatment with anti-lymphocyte-activation gene 3 (LAG-3; CD223) 
agents.
Test product(s):
[89Zr]Zr-BI 754111, BI 754111 and BI 754091
dose:

[89Zr]Zr-BI 754111: Approximately 4mg - 37MBq
other mass doses of BI 754111 may be explored to 
achieve optimal tumor uptake

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
BI 754111:
Recommended dose for the expansion phase of trial 
1381-0002. Other doses, in the range of the doses
tested in the dose escalation Part of trial 1381-0002,
may be applied at Cycle2.

BI 754091:
240mg
Doses administration at Cycle1 (baseline assessment phase):

Cycle1 Day1: 1st administration of BI 754091

No later than day8: 1st administration of [89Zr]Zr-BI 754111
Doses administration at cycle 2 (on-treatment phase) and further cycles: 

Cycle 2 Day1: 1st administration of BI 754111 treatment in combination 
with BI 754091 followed by the 2nd administration of [89Zr]Zr-BI 754111

In Part 2 during Cycle2, at least 2 different BI 754111 treatment doses in
combination with BI 754091 will be assessed in patients tested positive for 
tumor LAG-3 expression

Cycle3 Day1 and further cycles: administration of the recommended 
expansion dose of BI 754111 treatment in combination with BI 754091
method and route of 
administration:
Intravenous infusion for BI 754111 and BI 754091 - once every 3 weeks
Intravenous infusion for [89Zr]Zr-BI 754111 - once at Cycle1 and, if applicable,
once at Cycle2
Duration of treatment:
Administration will continue until progression of disease (PD), unacceptable 
toxicity, or a maximum treatment duration of 1 year. If the patient is benefiting 
clinically at 1 year, he/she may continue on treatment after a case-by-case review 
with the sponsor
Statistical methods:
For both Parts of the study (Part 1 and Part 2) endpoints will be analysed by 
descriptive statistics. 
In Part 2, an exploratory analysis might be performed to model the association
between BI 754111 treatment dose vs tumor uptake values (SUVs). These 
evaluations will be performed only if at least 3 different BI 754111 doses are 
investigated with a sufficient number of patients per dose (minimum of 3 patients 
per dose cohort).
Association between tumor uptake and other imaging/efficacy or biomarker 
assessments will be investigated using generalized linear models. In addition, 
parameter-free correlation techniques, e.g. Kendall tau, will be provided where 
applicable. These analyses will be based on all data collected in the study.

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FLOW CHART
Trial Periods
Screening 
Period
Dosimetry and feasibility/specificity
Treatment Period
End of 
treatment
End of trial
Cycle 1(*):
Baseline assessment phase
Cycle 2(*):
On-treatment assessment phase
Cycle 3 and 
further
Treatment 
stop
30-Day safety 
FU
Visit
Screening
C1V1
C1V2 C1V3 C1V4
C1V513
C2V1
C2V2
C2V3
C2V413
C3V1+
EOT
30dFU
Days
-15
Day 1
1
(***)
+30
Time window for visits
(±2)
(within 7days)
(+2)
Informed consent(s)(**) 
x
Demographics
x
Medical history (including 
documentation of disease 
x
Physical examination1
x
x
x
x
x
x
x
Vital signs1
x
x
x
x
x
x
x
ECOG performance status
x
x
x
x
x
x
Laboratory tests: hemato, 
x
x2
x
x
x
x
Urinalysis
x
x2
x
x
x
Pregnancy test for women of child-
bearing potential (HCG)
x
x2
x
x
x
12 lead-ECG
x
x2
x
x10
Review of in-/exclusion criteria
x
FDG PET/CT 
x3-9
Administration of Pre-treatment 
medication12
x
x
Infusion BI754091 treatment
x
x
x
Infusion BI754111 treatment
x
x
PK BI754111 blood sampling
x
x
x
x
x
x
x
x
x
x6
x

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Trial Periods
Screening 
Period
Dosimetry and feasibility/specificity
Treatment Period
End of 
treatment
End of trial
Cycle 1(*):
Baseline assessment phase
Cycle 2(*):
On-treatment assessment phase
Cycle 3 and 
further
Treatment 
stop
30-Day safety 
FU
Visit
Screening
C1V1
C1V2 C1V3 C1V4
C1V513
C2V1
C2V2
C2V3
C2V413
C3V1+
EOT
30dFU
Days
-15
Day 1
1
(***)
+30
ADA BI754111 blood sampling
x
x
x11
x
Tumor biopsy
x4
x4
BM blood sample 
Immunophenotyping
x
x
x
x5
x5
x
Infusion [89Zr]Zr-BI 754111 
x7
x8
PK radioactivity blood sampling
x7
x7
x7
x7
x8
x8
x8
[89Zr]Zr-BI 754111 PET + low 
dose CT scans
(x7)
x7
x7
x7
x8
x8
x8
CT-scan for tumor assessment9
within 28 days prior to 1st BI754111
Every 6 weeks for 6 months (then every 9 weeks)---
Adverse events/SAEs/AESIs 
x
Concomitant therapy
x
Completion of patient Participation 
x
Vital status collection (*****)
x
(*)
All cycles will last for 21 days. Cycle1 starts with the first administration of anti-PD-1 treatment BI 754091. Specific PET scan procedures will take place only during Cycle1 (baseline 
assessment) and Cycle2 (on-treatment assessment). 
(**)
The informed consent for trial Participation should be signed prior to any trial procedure. Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. A separate informed consent should be signed for biobanking if agreed by the patient.
(***)
When a decision is taken to discontinue all treatment drugs, the EOT visit should be done instead of the scheduled visit.
(****)
After the individual patient’s end of the trial the investigator should report only any occurrence of cancer of new histology, related SAEs and related AESIs of which the investigator 
may become aware of and only via the SAE form, please see Section 5.2.6.2.1.
(*****)
Completion of patient Participation and vital status collection should also be completed if the patient withdraws prematurely following treatment start (see Section 3.3.3).
1.
At days of any drug administration (incl. [89Zr]Zr-BI 754111), a physical examination and vital signs (pre- and post infusions) are required.
2.
Laboratory assessments (hemato, chemistry, urinalysis and pregnancy test) and 12-lead Electrocardiogram (ECG) do not need to be repeated at Day1 if performed at screening within 
72 hours prior to first administration of anti-PD-1 treatment BI 754091.

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3.
Standard static diagnostic Fluorodeoxyglucose –Positron Emission Tomography (FDG-PET)/CT should be done at screening prior to first administration of anti-PD-1 treatment 
BI 754091. In case FDG-PET is coupled with the baseline tumor assessment, it should be done within 7 days prior to first BI 754091 administration.
4.
Tumor biopsy: 2 core needle tumor biopsies (or equivalent) are to be taken from an imageable and evaluable lesion prior to first BI 754091 administration, unless medically contra-
indicated. In the latter case, 25 4µm-sections from an archival biopsy taken at relapse after the previous treatment are acceptable. For PD-1/PD-L1 pre-treated patients, if available, 
5 sections of an archived tumor biopsy taken prior to the anti-PD-1/PD-L1 treatment should be obtained. Optional: one, if feasible, two biopsies (2 core needle biopsies each) are to be 
taken for autoradiography and Flow cytometry analysis within 48h after the last 89Zr-BI 754111 PET scan of C1. The biopsies are to be taken from two different lesions based on the 
results of the PET scans: one lesion with tracer uptake ( = positive) and one lesions without visible tracer uptake (= negative). See Section 5.4.1 for details.
5.
Biomarker (BM) blood sampling for immunophenotyping is to be done at Cycle1 Day1 and Day7±1 day post [89Zr]Zr-BI 754111 , at Cycle2 Day1 (prior to BI 754111 treatment 
infusion) and Day 7± 1day post [89Zr]Zr-BI 754111 (=Cycle 2 Day7± 1day for LAG-3 negative patients), Cycle3 Day1 and EOT. See Blood Sample Flow Chart for time schedule.
6.
Blood sampling for BI 754111 PK concentration will be performed at Cycle1 “baseline assessment phase” (before [89Zr]Zr-BI 754111 infusion, after [89Zr]Zr-BI 754111 infusion and 
during the first and each subsequent PET scan procedure, at Cycle2 “on-treatment assessment phase” (pre-treatment, after [89Zr]Zr-BI 754111 infusion and at each PET scans
procedures, at Cycles 3, 4, 7 (prior to BI 754111 treatment infusion) and at the EOT visit. See Blood Sample Flow Chart for a more detailed time schedule.
7.
Timing of baseline assessment procedures for [89Zr]Zr-BI 754111 PET scanning: 

[89Zr]Zr-BI 754111 is to be administered no later than day 8 (within day 1 to 8)

Only for patient in Part 1: PET/CT scan for dosimetry is to be done 1-2 hours after [89Zr]Zr-BI 754111 administration 

[89Zr]Zr-BI 754111 PET for LAG-3 combined with low dose CT scan for tumor volume: 2 (before CTP 3.0)-3(after CTP 3.0) scans between 24 h and up to 7 days post 
[89Zr]Zr-B I754111 injection

Blood sampling for radioactivity concentration: samples will be taken post [89Zr]Zr-BI 754111 injection and at each [89Zr]Zr-BI 754111 PET scanning. See Blood Sample 
Flow Chart for detailed time schedule.
8.
Timing of on-treatment assessement procedures for [89Zr]Zr-BI 754111 PET scanning:

[89Zr]Zr-BI 754111 administration is to be done at day 1 following the administration of BI 754111/BI 754091 combined treatment 

[89Zr]Zr-BI 754111 PET for LAG-3 combined with low dose CT scan for tumor volume: 2 (before CTP 3.0)-3(after CTP3.0) scans between 24 h and up to 7 days post 
[89Zr]Zr-BI 754111 administration

Blood sampling for radioactivity concentrations: samples will be taken post [89Zr]Zr-BI754111 injection and at each [89Zr]Zr-BI 754111 PET scanning. See Blood Sample 
Flow Chart for time schedule
9.
Tumor assessment should be done according to RECIST 1.1 and iRECIST using CT-scan/MRI/PET. The baseline tumor assessment should be done within 28days prior to first 
administration of the anti-LAG-3 treatment BI754111. 

If done at screening, the baseline RECIST/iRECIST tumor assessment should be performed within 7 days prior to first administration of anti-PD-1 treatment BI 754091 and 
can be combined with FDG-PET/CT

If done at C1, the baseline RECIST/iRECIST tumor assessment can be performed after the administration of [89Zr]Zr-B I754111 in combination with a PET/CT scan 
assessment 
Thereafter, tumor assessment will be repeated every 6 weeks (+/-3 days) during the first 6 months and every 9 weeks (+/-3 days) thereafter. A tumor assessment should be 
done at EOT to confirm disease progression if not done earlier
10. 12-lead ECG is to be done at each Cycle until Cycle6 and every other Cycle thereafter (i.e at Cycle8, Cycle10…). It can be repeated when investigator deems it necessary.

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11. Blood sampling for BI 754111 immunogenicity assessment (i.e. ADA determination) will be performed at Cycle1 “baseline assessment phase” within 1 week before [89Zr]Zr-
BI 754111 infusion, at cycle 2, at Cycle4 and Cycle7 (prior to BI 754111 treatment infusion) and at the EOT visit. See Blood Sample Flow Chart for time schedule.
12. Pre-treatment (antihistamine and acetaminophen or paracetamol) should be administered at sufficient time prior to initiation of infusion to allow the agents to exert their influence
13. Visits only applicable after CTP v 3.0
For further details on procedures, please refer to specific sections in the protocol.

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BLOOD SAMPLE FLOW CHART
Table 1
Time schedule for PK, ADA and biomarker blood sampling in Cycle 
1 (before CTP amendment 2.0)
Treatment
Cycle
Visit
Time Point Description
PK 
BI 754111
ADA
BI 754111
BM
Immuno-
pheno-typing
PK 
Radioactivity
1
1
Day 1, 
within 1 hour prior to 
BI 754091 infusion
x
x
x
BI 754091 infusion
2
within 8 days after
BI 754091 infusion:
[89Zr]Zr-BI 754111 
infusion
1 hour after 
[89Zr]Zr-BI 754111
infusion
x
within 30 min 
before 
Dosimetry PET scan*
x*
1-2 hours after
[89Zr]Zr-BI 754111
infusion:
Dosimetry PET scan*
3
within 30 min 
before PET scan 1
x
x
≥24hours post
[89Zr]Zr-BI 754111
PET scan 1
4
within 30 min 
before PET scan 2
x
x
≤ 7 days post
[89Zr]Zr-BI 754111
PET scan 2
* Only for patients in Part 1, not applicable in Part 2
ADA = anti-drug antibodies; PK = Pharmacokinetics; EOT = end of treatment

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Table 2
Time schedule for PK, ADA and biomarker blood sampling in Cycle 
2 and onwards (before CTP amendment 2.0)
Treatment
Cycle
Visit
Time Point Description
PK 
BI 754111
ADA
BI 754111
BM
Immuno-
pheno-typing
PK 
Radioactivity
2
1
Day 1, 
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
BI 754091 + BI 754111 
infusion
after BI 754091 + 
BI 754111 infusion:
[89Zr]Zr-BI 754111 
infusion**
1 hour after 
[89Zr]Zr-BI 754111
Infusion**
x**
2
within 30 min 
before PET scan 1
x**
x**
≥24hours post
[89Zr]Zr-BI 754111
PET scan 1
3
within 30 min 
before PET scan 2**
x**
x**
x**
≤ 7 days post
[89Zr]Zr-BI 754111
PET scan 2**
3
1
Day 1,
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
4
1
Day 1,
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
x
7
1
Day 1,
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
x
EOT
EOT
at treatment discontinuation
x
x
x
**
These procedures are not applicable in Part 2 for patients with tumor tested negative for LAG-3 expression except the 
sample for immunophenotyping that should be taken at day7 (± 1day)

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Table 3
Time schedule for PK, ADA and biomarker blood sampling in Cycle 
1 (after CTP amendment 2.0)
Treatment
Cycle
Visit
Time Point Description
PK 
BI 754111
ADA
BI 754111
BM
Immuno-
pheno-typing
PK 
Radioactivity
1
1
within 3 hours prior to 
BI 754091 infusion
x
x
x
BI 754091 infusion
2
within 8 days after
BI 754091 infusion:
[89Zr]Zr-BI 754111 infusion
+5 min post end of [89Zr]Zr-
BI 754111 infusion
x
x
+ 30 min post end of 
[89Zr]Zr-BI 754111 infusion
x
x
+ 60 min post end of 
[89Zr]Zr-BI 754111 infusion
x
x
+ 120 min post end of
[89Zr]Zr-BI 754111 infusion 
x
x
3
Planned time +24hs (within 
1 to 2 days) post
[89Zr]Zr-BI 754111
PET scan 1
within 30 min 
after PET scan 1
x
x
4
Planned time+48hours 
(within 2 to 4 days) post
[89Zr]Zr-BI 754111
PET scan 2
within 30 min 
after PET scan 2
x
x
5
Planned time+96 hours 
(within 4 to 7 days) post
[89Zr]Zr-BI 754111
PET scan 3
within 30 min 
after PET scan 3
x
x
At day 7± 1day
x
ADA = anti-drug antibodies; PK = Pharmacokinetics; EOT = end of treatment

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Table 4
Time schedule for PK, ADA and biomarker blood sampling in Cycle 
2 and onwards (after CTP amendment 2.0)
Treatment
Cycle
Visit
Time Point Description
PK 
BI 754111
ADA
BI 754111
BM
Immuno-
pheno-typing
PK 
Radioactivity
2
1
within 3 hour prior to 
BI 754091 + BI 754111 
infusion
x
x
x
BI 754091 + BI 754111 
infusion
after BI 754091 + 
BI 754111 infusion:
[89Zr]Zr-BI 754111 
infusion**
+5 min post [89Zr]Zr-
BI 754111 infusion**
x**
x**
+30 min post [89Zr]Zr-
BI 754111 infusion**
x**
x**
+60 min post [89Zr]Zr-
BI 754111 infusion**
x**
x**
+120 min post [89Zr]Zr-
BI 754111 infusion**
x**
x**
2**
Planned time +24hs 
(within 1 to 2 days) post
[89Zr]Zr-BI 754111
PET scan 1**
within 30 min 
after PET scan 1**
x**
x**
3**
Planned time+48hours 
(within 2 to 4 days) post
[89Zr]Zr-BI 754111
PET scan 2**
within 30 min 
after PET scan 2**
x**
x**
4**
Planned time+96 hours 
(within 4 to 7 days) post
[89Zr]Zr-BI 754111
PET scan 3**
within 30 min 
after PET scan 3**
x**
x**
At day 7± 1day
x 

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Table 4
Time schedule for PK, ADA and biomarker blood sampling in Cycle 
2 and onwards (after CTP amendment 2.0) (cont.)
Treatment
Cycle
Visit
Time Point Description
PK 
BI 754111
ADA
BI 754111
BM
Immuno-
pheno-typing
PK 
Radioactivity
3
1
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
x
4
1
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
x
7
1
within 1 hour prior to 
BI 754091 + BI 754111 
infusion
x
x
EOT
EOT
at treatment discontinuation
x
x
x
**
These visits and procedures are not applicable in Part 2 for patients with tumor tested negative for LAG-3 
expression except the sample for immunophenotyping that should be taken at day7 (± 1day)

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TABLE OF CONTENTS
TITLE PAGE .......................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .................................................................2
FLOW CHART....................................................................................................................5
BLOOD SAMPLE FLOW CHART...................................................................................9
TABLE OF CONTENTS ..................................................................................................14
ABBREVIATIONS............................................................................................................18
1.
INTRODUCTION...........................................................................................21
1.1
MEDICAL BACKGROUND.........................................................................21
1.2
DRUG PROFILE............................................................................................23
1.2.1
BI 754111 .........................................................................................................23
1.2.2
[89Zr]Zr-BI 754111.........................................................................................23
1.2.3
BI 754091 .........................................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.....................................23
1.4
BENEFIT - RISK ASSESSMENT.................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS..................................................29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS....29
2.1.1
Main objective(s).............................................................................................29
2.1.2
Primary endpoint(s)........................................................................................29
2.1.3
Secondary endpoint(s) ....................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.....................31
3.1
OVERALL TRIAL DESIGN AND PLAN ...................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)..................................................................................33
3.3
SELECTION OF TRIAL POPULATION ...................................................34
3.3.1
Main diagnosis for trial entry ........................................................................34
3.3.2
Inclusion criteria .............................................................................................34
3.3.3
Exclusion criteria ............................................................................................35
3.3.4
Withdrawal of patients from therapy or assessments .................................37
3.3.4.1
Withdrawal from trial treatment .......................................................................37
3.3.4.2
Withdrawal of consent for trial Participation....................................................38
3.3.4.3
Discontinuation of the trial by the sponsor.......................................................38
4.
TREATMENTS...............................................................................................39
4.1
INVESTIGATIONAL TREATMENTS .......................................................39
4.1.1
Identity of the Investigational Medicinal Products......................................39
4.1.1.1
BI 754111..........................................................................................................39
4.1.1.2
[89Zr]Zr-BI 754111 ...........................................................................................39

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4.1.1.3
BI 754091..........................................................................................................40
4.1.2
Selection of doses in the trial and dose modifications..................................40
4.1.2.1
[89Zr]Zr-BI 754111 ...........................................................................................40
4.1.2.2
BI 754111..........................................................................................................40
4.1.2.3
BI 754091..........................................................................................................41
4.1.2.4
Dose modification for BI 754111 and BI 754091 treatments...........................41
4.1.3
Method of assigning patients to treatment groups.......................................41
4.1.4
Drug assignment and administration of doses for each patient..................42
4.1.5
Blinding and procedures for unblinding.......................................................43
4.1.5.1
Blinding.............................................................................................................43
4.1.5.2
Unblinding and breaking the code ....................................................................43
4.1.6
Packaging, labelling, and re-supply...............................................................43
4.1.7
Storage conditions...........................................................................................43
4.1.8
Drug accountability.........................................................................................44
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ............................................................................................44
4.2.1
Other treatments and emergency procedures..............................................44
4.2.2
Restrictions ......................................................................................................45
4.2.2.1
Restrictions regarding concomitant treatment ..................................................45
4.2.2.2
Restrictions on diet and life style......................................................................46
4.2.2.3
Contraception requirements..............................................................................46
4.3
TREATMENT COMPLIANCE....................................................................47
5.
ASSESSMENTS..............................................................................................48
5.1
ASSESSMENT OF EFFICACY....................................................................48
5.2
ASSESSMENT OF SAFETY.........................................................................48
5.2.1
Physical examination ......................................................................................48
5.2.2
Vital signs.........................................................................................................48
5.2.3
Safety laboratory parameters ........................................................................49
5.2.4
Electrocardiogram ..........................................................................................51
5.2.5
Other safety parameters.................................................................................51
5.2.6
Assessment of adverse events.........................................................................51
5.2.6.1
Definitions of AEs ............................................................................................51
5.2.6.1.1
Adverse event....................................................................................................51
5.2.6.1.2
Serious adverse event........................................................................................51
5.2.6.1.3
AEs considered “Always Serious”....................................................................52
5.2.6.1.4
Adverse events of special interest (AESIs).......................................................52
5.2.6.1.5
Intensity (severity) of AEs................................................................................55
5.2.6.1.6
Causal relationship of AEs................................................................................55
5.2.6.2
Adverse event collection and reporting ............................................................56
5.2.6.2.1
AE Collection....................................................................................................56
5.2.6.2.2
AE reporting to sponsor and timelines..............................................................56
5.2.6.2.3
Information required .........................................................................................56
5.2.6.2.4
Pregnancy..........................................................................................................57
5.2.6.2.5
Exemptions to SAE reporting ...........................................................................57
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...............................................................................58

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5.3.1
Assessment of pharmacokinetics ...................................................................58
5.3.2
Methods of sample collection .........................................................................58
5.3.4
Pharmacokinetic – pharmacodynamic relationship....................................58
5.6
OTHER ASSESSMENTS...............................................................................60
5.6.1
FDG-PET/CT procedure................................................................................60
5.6.2
[89Zr]Zr-BI 754111 PET scan procedure......................................................60
5.6.3
Assessment of anti-drug antibodies (ADAs).................................................61
5.7
APPROPRIATENESS OF MEASUREMENTS..........................................61
6.
INVESTIGATIONAL PLAN.........................................................................62
6.1
VISIT SCHEDULE.........................................................................................62
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .............62
6.2.1
Screening period..............................................................................................63
6.2.1.1
Baseline Conditions ..........................................................................................63
6.2.1.2
Medical History.................................................................................................63
6.2.1.2.1
Medical history of cancer..................................................................................63
6.2.1.2.2
Other medical history........................................................................................63
6.2.1.3
Concomitant medications..................................................................................64
6.2.2
Treatment period(s)........................................................................................64
6.2.3
Follow up period and trial completion..........................................................64
6.2.3.1
End-of-treatment visit .......................................................................................64
6.2.3.2
30-day safety follow-up visit ............................................................................64
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...........................................................................................................................65
7.1
STATISTICAL DESIGN - MODEL.............................................................65
7.2
NULL AND ALTERNATIVE HYPOTHESES ...........................................65
7.3
PLANNED ANALYSES.................................................................................65
7.3.1
Primary endpoint analyses.............................................................................65
7.3.3
Safety analyses.................................................................................................66
7.3.4
Pharmacokinetic and pharmacodynamic analyses......................................66
7.4
INTERIM ANALYSES ..................................................................................67
7.5
HANDLING OF MISSING DATA ...............................................................67
7.6
RANDOMISATION .......................................................................................67
7.7
DETERMINATION OF SAMPLE SIZE .....................................................67
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ....69
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .......................................................................................................69
8.2
DATA QUALITY ASSURANCE ..................................................................70
8.3
RECORDS.......................................................................................................70

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8.3.1
Source documents ...........................................................................................70
8.3.2
Direct access to source data and documents.................................................71
8.3.3
Storage period of records ...............................................................................72
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..............................72
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY....72
8.5.1
Collection, storage and future use of biological samples and corresponding 
data...................................................................................................................72
8.6
TRIAL MILESTONES...................................................................................73
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...............................73
9.
REFERENCES................................................................................................75
9.1
PUBLISHED REFERENCES........................................................................75
9.2
UNPUBLISHED REFERENCES..................................................................80
10.
APPENDICES.................................................................................................81
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .81
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS..........84
10.3
IRECIST ..........................................................................................................87
10.4
SPECIFIC COUNTRY ADAPTIONS ..........................................................91
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .....................................92
11.1
GLOBAL AMENDMENT 1 ..........................................................................92
11.2
GLOBAL AMENDMENT 2 ..........................................................................93

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ABBREVIATIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase
AST
AsPartate aminotransferase
AUC
Area under the Curve
β-hCG
Beta human chorionic gonadotropin
BI
Boehringer Ingelheim
BM
Biomarker
BOR
Best Overall Response
Bx
Tumor Biopsy
C
Cycle
CA
Competent Authority
CCMO
Centrale Commissie Mensgebonden Onderzoek
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology
CL
Total clearance of the analyte in plasma following intravascular 
administration
CML
Clinical Monitor Local
CPK
Creatinine Phosphokinase
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electrocic (sometimes referred to as “eCRF”)
CT scan
Computed Tomography scan
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
D
Day
DHEA
Dehydroepiandrosterone
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicities
EANM
European Association of Nuclear Medicine
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
Electronic Data Capture
e.g.
for example
eGFR
estimated Glomerular Filtration Rate
EOT
End Of Treatment
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FC
Flow Chart

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FDG-PET
Fluorodeoxyglucose –Positron Emission Tomography
FFPE
Formalin Fixed Paraffin Embedded
FU
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GI
Gastro-intestinal
HNSCC
Head and Neck Squamous Cell Carcinoma
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiological Protection’
iCPD
Confirmed Progression as per iRECIST
i.e.
that is
IEC
Independent Ethics Committee
IFN
Interferon
IHC
Immunohistochemistry
IMPD
Investigational Medicinal Product Documentation
INR
International Normalized Ratio
irAEs
immune-related Adverse Events
IRB
Institutional Review Board
IPV
Important Protocol Violation
ISF
Investigator Site File
IUD
Intrauterine Device
iUPD
Unconfirmed Progression as per iRECIST
IUS
Intrauterine hormone-releasing System
i.v.
intravenous
LAG-3
Lymphocyte-Activation Gene 3
LDH
Lactate dehydrogenase
LPDD
Last Patient Drug Discontinuation
mAb
Monoclonal Antibody
MBq
Megabecquerel
MedDRA
Medical Dictionary for Drug Regulatory Activities
MDSC
Myeloid-Derived Suppressor Cell
METc
Medisch-Ethische Toetsingscommissies
MHC-II
Major Histocompatibility Complex Class II
MRI
Magnetic Resonance Imaging
mSv
Millisievert
MTD
Maximum Tolerated Dose
NK
Natural Killer
NLNT
New Lesion-Non-Target
NLT
New Lesions-Target
NSCLC
Non-Small-Cell Lung Cancer
OPU
Operating Unit
OR
Overall Response/Objective Response
ORR
Overall Response Rate/Objective Response Rate
PBPK
Physiologically based pharmacokinetic
PD
Progressive Disease

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PD-1
Programmed cell death protein-1
PD-L1/-L2
Programmed death ligand-1/-2
PET
Positron Emission Tomography
PK
Pharmacokinetics
RPIID
Recommended Phase II Dose
PR
Partial Response
QTc
Corrected QT interval
Q3W
Every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumours
iRECIST
Modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1) for 
cancer immunology trials 
ROI
Regions of Interest
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SD
Stable Disease
SMC
Study Monitoring Committee
SOC
Standard of Care
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
SUVs
Standardized Uptake Values
TCM
Trial Clinical Monitor
TILs
Tumor-infiltrating lymphocytes
TNBC
Triple Negative Breast Cancer
TNM
TNM Classification of Malignant Tumours
TP
Time Point
T-reg
Regulatory T-cell
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid Panel
ULN
Upper Limit of Normal
V
Visit
WHO
World Health Organization
WMA
World Medical Association
WOCBP
Woman of childbearing potential
Zr
Zirconium

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Despite the recent advancements in cancer treatment, cancer remains a leading cause of death 
globally. Approximately 1,685,210 new cancer cases were expected to be diagnosed in 2016 
(excluding carcinoma in situ (noninvasive cancer) of any site except urinary bladder and 
basal cell or squamous cell skin cancers). Approximately 595,690 people in the United States 
were expected to die of cancer in 2016 (R16-4925). In the majority of cases, the disease is 
diagnosed in late stages and the vast majority of patients progress on available treatment and 
succumb to their disease. These statistics clearly highlight the urgent need for novel 
therapeutic agents and treatment strategies to improve the treatment outcome for cancer 
patients.
The normal role of the immune system is to protect the body against the invasion of foreign 
antigens such as bacteria, viruses, and parasites as well as the body’s own malfunctioning 
cells. Once a mounted immune response (adaptive or innate) completes its task of eliminating 
the threat, the immune system deploys the immune-checkpoint program to dampen the 
immune response and minimize collateral immune-mediated damage to healthy tissue.
T-cell activation is a highly regulated process that promotes T-cell proliferation, 
differentiation, survival, and cytokine production. Up-regulation of multiple co-regulatory 
receptors on activated T-cells provides a mechanism of fine tuning the immune response. 
Programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway 
was the first negative immune co-regulatory (immune-checkpoint inhibitor) pathway 
described (R16-2361, R16-2363). Indeed, genetic inactivation of the PD-1/PD-L1 pathway in 
mice resulted in various autoimmune phenotypes (R16-2362, R16-2364). PD-1 expression in 
humans is largely restricted to immune cells (T-cells, B-cells, natural killer T-cells, activated 
monocytes and dendritic cells) and is upregulated upon T-cell activation (R15-6038, R16-
2360), whereas PD-L1 protein is expressed on the surface of a wide range of human cancer 
cells (R16-2371). The physiologic function of the PD-1 pathway is to down-regulate the 
immune response once the antigen that stimulated the response is eliminated, thereby limiting 
collateral tissue damage.
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 (R16-5356, R16-5359). LAG-3 is expressed on activated 
cytotoxic, helper as well as 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).
LAG-3 expression has been reported to be associated with advanced head and neck squamous 
cell carcinoma (HNSCC). Its expression has been found to be upregulated on tumor-
infiltrating lymphocytes (TILs) and was significantly associated with a high pathological 
grade, larger tumor size and positive lymph node status. Increased LAG-3 expression was 

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also found in recurrent HNSCC and metastatic lymph nodes hinting to a function of LAG-3 
in tumor recurrence and metastasis (R18-1377).
Tumors use the immune-checkpoint pathways (such as the PD-1 and LAG-3 pathways) to 
evade anti-tumor immune responses. Tumor-infiltrating lymphocytes frequently express high 
levels of PD-1 in combination with other immune-checkpoint inhibitors including LAG-3 
(R16-0868, R16-5335), while the ligands for these checkpoint inhibitors (i.e. PD-L1/L2 and 
MHC-II, respectively) are expressed within the tumor microenvironment. 
Engagement of the co-inhibitory receptors PD-1 and LAG-3 by their respective ligands 
inhibits T-cell function preventing an anti-tumor 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 antitumor immune response leading to tumor growth inhibition in 
some patients. Treatment of patients with advanced melanoma, non-small-cell lung cancer 
(NSCLC), renal cell carcinoma, and many other tumor types with anti-PD-1 (nivolumab or 
pembrolizumab) or anti-PD-L1 (atezolizumab, durvalumab, and avelumab) monoclonal 
antibodies (mAbs) has resulted in highly durable responses in approximately 15% to 30% of 
patients (R15-3715, R15-3776, R15-3778, R15-6023, R16-0663, R16-0864, R16-0876, R16-
1225, R16-1588, R16-3547)
The therapeutic efficacy of mAbs including those modulating the immune system and the 
cancer immune phenotype do not only depend on the specific target, the avidity and effector 
function of the antibodies but most importantly also on the degree of their uptake and 
distribution within tumor lesion(s). The latter is mainly influenced by the heterogenous nature 
of the tumor tissue, e.g. heterogeneity of tumor blood flow, interstitial flow and pressure, 
hypoxia, necrosis (R18-2174, R18-2173). Positron emission tomography (PET using 
zirconium-89 [89Zr]-labeled mAbs is an attractive non-invasive method to improve the 
understanding of the in vivo behavior and distribution of the monoclonal antibody allowing 
to (1) confirm and quantify tumor uptake of mAbs; (2) learn about uptake in critical normal 
organs to anticipate toxicity; and (3) elucidate the interpatient variations in pharmacokinetics 
and tumor targeting. The PET Center at
has a longstanding experience in performing 89Zr-immuno-PET trials (P18-06060, R18-2168, 
R18-2169, R18-2170, R18-2171).
This is the first study that aims to determine the tissue and tumor distribution of the anti-
LAG-3 mAb BI 754111. BI 754111 has been radio-labelled with Zr-89. [89Zr]Zr-BI 754111 
will be administered during Cycle 1 before any administration of anti-LAG-3 mAb 
(BI 754111) treatment to determine its distribution and tumor uptake. A second 
administration of [89Zr]Zr-BI 754111 will occur at the beginning of Cycle 2 (Cycle2 Day1)
directly following the first administration of a certain dose of anti-LAG-3 mAb BI 754111. 
The tissue distribution of [89Zr]Zr-BI 754111 will be monitored using a PET/CT scanner at 
multiple time points after [89Zr]Zr-BI 754111 and after [89Zr]Zr-BI 754111 + BI 754111 
administration respectively. The data from the study will be used to determine the distribution 
of BI 754111 to the organs in the body and to tumorous tissue(s) in order to support dose 
finding and physiologically based pharmacokinetic (PBPK) modelling of the BI 754111 
treatment. 
The trial is divided into two Parts. After confirmation of the blockade of the [89Zr]Zr-

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BI 754111 uptake by a therapeutic dose of BI 754111, the second Part of the study will be 
performed.
This second Part will assess the tumor uptake of [89Zr]Zr-BI 754111 in combination with 
various treatment doses of BI 754111. Various doses of BI 754111will be used to determine 
the best ratio of [89Zr]Zr-BI 754111/BI 754111 to achieve an optimal tumor penetration. 
Furthermore, it should also explore the relation between tumor uptake of [89Zr]Zr-BI 754111 
at baseline and tumor response after adding a therapeutic dose of BI 754111 to the anti-PD1 
therapy.
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. The BI 754111 molecule has a 
molecular weight of approximately 149 kilodaltons. The antibody is composed of 2 heavy 
chains (448 amino acids each) and 2 light chains (214 amino acids each). The 4 polypeptide 
chains of the antibody are linked together by disulfide bonds. Each heavy chain contains one 
consensus sequence for N-linked glycosylation. 
1.2.2
[89Zr]Zr-BI 754111
BI 754111 has been radiolabeled with Zr-89 using p-isothiocyanatobenzyl-desferrioxamine 
(Df–Bz–NCS) as a chelate. [89Zr]Zr-BI 754111 was prepared according to a standard 
procedure (R18-1541). For a more detailed descriptions of [89Zr]Zr-BI 754111 please refer to 
to the current BI 754111 Investigator’s Brochure (IB) and the related Investigational 
Medicinal Product Documentation (IMPD).
1.2.3
BI 754091
For a more detailed description of the BI 754091 and BI 754111 profiles please refer to the 
current respective Investigator’s Brochures (IBs).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Most patients with locally advanced or metastatic tumors will succumb to their disease, 
justifying the substantial need for novel therapeutic strategies to improve the outcome for 
patients with advanced or metastatic malignancies.

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Immune-checkpoint inhibition has been shown to be a promising therapeutic strategy in a 
subset of patients. 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-
tumor activity and improved clinical outcome in a higher percentage of patients compared to 
checkpoint-inhibitor monotherapy. There is now sufficient evidence that blockage 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-
0852, 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.
Still, some aspects of LAG-3 expression and BI 754111 biodistribution (inside and outside 
the tumor lesions) remain unclear. For example, it is unclear which patients may benefit from 
combining anti-LAG-3 and anti-PD1/anti-PDL1 therapies. Even though tumor LAG-3
expression assessed on biopsies may serve as a predictive biomarker, this has limitations such 
as difficult to reach sites, low yields of tumor cells in the obtained bioptic sample, tumor 
heterogeneity resulting in sampling bias and risks for complications of the bioptic procedure 
(pneumothorax, bleeding). A non-invasive and more comprehensive way to study the 
expression of LAG-3 and the kinetic behavior of BI 754111 is needed. PET using 
radiolabeled BI 754111, i.e. [89Zr]Zr-BI 754111, as tracer may offer a unique way of studying 
the interaction between LAG-3 expression and BI 754111 distribution. This non-invasive and 
repeatable technique may allow for studying the spatial and temporal variations in uptake of 
BI 754111. 
Therefore, the aim of this study is to evaluate [89Zr]Zr-BI 754111 PET imaging as a non-
invasive method to determine the biodistribution of the therapeutic antibody at the site of 
action (i.e. in the tumor) and as a non-invasive method to determine LAG-3 expression at the 
site of action (i.e. in the tumor). These readouts are considered supportive to inform 
BI 754111 dose finding and potentially also for future patient selection.
Another aim of this study is to explore whether an association can be established between the
tumor [89Zr]Zr-BI 754111 uptake at baseline and the anti-tumor efficacy of BI 754111
therapy when combined with the anti-PD-1 BI 754091. It is assumed that [89Zr]Zr-BI 754111 
uptake will be related to LAG-3 expression. In addition, additional markers for the status of 
the immune system before/during therapy will be assessed in biopsies and blood samples to 
allow for better interpretation of the impact of LAG-3 overexpression as determined by LAG-
3 immune PET in the context of other potential mechanisms of resistance. The combination 
of the major resistance mechanisms may vary in each patient. 

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While LAG-3 is not expressed on peripheral T-cells in healthy volunteers or most patients 
with solid tumors, it appears to be expressed on T-cells of patients with HNSCC (R18-1377). 
In NSCLC tumors that responded to anti-PD-1/anti-PD-L1 therapy, increase in LAG-3 
expression may be a mechanism of acquired resistance to anti-PD-1/PD-L1 therapy. 
Therefore, intratumoral expression of LAG-3 may be a good enrichment marker for patient
selection for PD-1/LAG-3 combination therapy. Hence, in this study, we will include patients 
with HNSCC and NSCLC (upon progression after an initial response to anti-PD-1/anti-PD-
L1 therapy) in order to measure LAG-3 receptor occupancy in this patient population.
The therapeutic benefit or specific adverse events in patients cannot always be anticipated 
during the trial setup. Later on there may be new scientific knowledge about biomarkers and 
other factors contributing to diseases or the action of a drug. In order to be able to address 
future scientific questions, patients will be asked to voluntarily donate biospecimens for 
banking (please see Section 5.4). If the patient agrees, banked samples may be used for future
biomarker research and drug development projects, e.g. to identify patients that are more 
likely to benefit from a treatment or experience an adverse event (AE), or to gain a 
mechanistic or genetic understanding of drug effects and thereby better match patients with 
therapies.
1.4
BENEFIT - RISK ASSESSMENT
The role of the immune-checkpoint inhibitors within a normal immune response is to dampen 
the immune response after the trigger (antigen) is resolved minimizing collateral-immune-
mediated damage to healthy tissue. Immune-checkpoint inhibitors also play a major role in 
promoting and maintaining self-tolerance by inactivating auto-reactive T-cells. Therefore, 
manipulation of immune-checkpoint-inhibitor pathways unleashes the immune system and 
comes with a higher risk of inducing immune dysfunction leading to immune-related adverse 
events (irAEs). Indeed, mice deficient in PD-1 or its ligands (PD-Ll and PD-L2) were found 
to be highly prone to development of autoimmune diseases (R16-2362, R16-2364, R16-2968, 
R16-2969, R16-2970).
Data from immune-checkpoint clinical trials show that irAEs occur frequently in patients 
treated with anti Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (90%) and anti-PD-
1 or anti-PD-Ll (70%) mAbs. However, the majority of these AEs are mild in severity (R12-
5176, R15-3588, R15-3715) and occur within the first 4 months of initiating therapy (R15-
3780, R16-0864, R16-0899). The irAEs affect mainly the gastrointestinal tract (including 
diarrhea and, less frequently colitis), skin (including rash/erythema and, less frequently 
vitiligo), endocrine glands (including hypothyroidism, hyperthyroidism, and hypophysitis), 
liver (frequently asymptomatic elevated transaminases), and lung (pneumonitis), but could 
also potentially affect other tissues. Rare fatal cases of colitis and pneumonitis have been 
reported with use of immune-checkpoint inhibitors. The main treatment of irAEs is the 
administration of steroids for 2 to 4 weeks; other immunosuppressive agents (such as 
infliximab, mycophenolate mofetil and cyclosporine) can be used in case of a steroid-
refractory irAE (R16-0763, R16-0899).
As previously mentioned, significant improvement in checkpoint inhibitor effect has been 
achieved with checkpoint inhibitor combination therapy. The combination of nivolumab and 

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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. Immune-related AE management guidance will be provided in the trial 
documentation. 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.
Preliminary efficacy analyses indicate that there are 6 patients with Partial response (PR) and 
20 patients with disease stabilization on BI 754091 monotherapy in the 1381-0001. The PRs 
were reported in 2 patients with triple negative breast cancer, 1 patient with fallopian tube 
cancer, 1 patient with renal cancer, 1 patient with stomach cancer and one patient with 
endometrial cancer. All of these PRs occurred in patients receiving the 240 mg q3w dose of 
BI 754091.
BI 754091 has also been administered in combination with BI 754111 (monoclonal IgG4pro 
antibody targeting the human LAG-3) to 86 patients with advanced/metastatic solid tumors in 
trial 1381.2. Fifty five of these patients have been treated with 240 mg BI 754091 in 
combination with increasing doses of BI 754111 (Q3W). In the dose expansion portion of the 

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study, 31 patients have been treated with 240 mg BI 754091 in combination with 600 mg 
BI 754111 Q3W. 
As of 30 November 2018, the combination treatment has been well tolerated with no DLTs 
occurring during the MTD evaluation period of the dose escalation part of the trial and no 
treatment related deaths have been reported. The most frequently reported AEs in patients 
treated with combination BI 754091 and BI 754111 were nausea (23.3%), fatigue (22.2%), 
diarrhoea (15.1%) and vomiting (15.1%). The majority of AEs were CTCAE Grades 1 and 2. 
Grade 3 and 4 AEs occurred at a frequency of 24.4% and 1.2 %, respectively. Of the grade 3 
AEs, colitis, diarrhea (2 cases), infusion related reaction (2 cases), aseptic meningitis and 
maculopapular rash were reported as possibly related to study drugs. The only Grade 5 event 
was respiratory failure, occurring in the context of AEs pneumonia, sepsis and progressive 
disease. These events (including the fatal event) were unrelated to trial drugs.
Infusion related reactions have been reported in approximately 7% of patients treated with 
the combination of BI 754091 and BI 754111, none 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 of CTCAE Grade 
2. Two events were Grade 3 events and led to treatment discontinuation. The reported 
infusion related reactions occurred during the infusion mostly at cycle 2 or cycle 3.
Preliminary efficacy data show 25 patients have achieved best response of stable disease 
(SD) to date and 3 patients have achieved best response of partial response (PR). PR was 
reported for 1 patient with anal cancer treated with 240 mg BI 754091 in combination with 
200 mg BI 754111, 1 patient with microsatellite stable rectal cancer treated with 240 mg 
BI 754091 in combination with 600 mg BI 754111 and 1 patient with Triple Negative Breast 
Cancer (TNBC) treated with 240 mg BI 754091 in combination with 600 mg BI 754111.
Based on these pre-clinical and clinical data treatment with BI 754111 and BI 754091 is 
expected to provide patients with clinical benefit at an acceptable risk.
Risk linked to radiation burden: A single injection of 37 MBq 89Zr-mAb is expected to result 
in a radiation burden of ~ 20 mSv. In addition, every low dose CT scan adds 3 mSv to the 
radiation burden.
The first 3 patients in part 1 of the study will receive 2 injections of 89Zr-mAb followed by 5 
PET scans (3 after the first and 2 after the second injection). This results in a radiation dose 
of 55 mSv.
The following patients in part 1 (maximum 2) will receive 2 injections of 89Zr-mAb followed 
by 4 PET scans. This results in a radiation dose of 52 mSv.
After administration, no shielding is required, and the subject can go home immediately. It is 
recommended that prolonged physical contact with small children (hugging, holding for more 
than a few hours per day) is avoided in the days following injection of 89Zr-mAb.
In part 2 five LAG-3 negative patients will receive 1 injection of 89Zr-mAb followed by 2
(before CTP 3.0) or 3 (after CTP 3.0) PET scans. This results in a radiation dose of 26 or 29
mSv.

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In part 2 up to 30 LAG-3 positive patients will receive 2 injections of 89Zr-mAb followed by 
4 (before CTP 3.0) or 6 (after CTP 3.0) PET scans. This results in a radiation dose of 52 or 
58 mSv.
All patients in this trial will undergo a diagnostic [18F]FDG-PET with a dose of 200 MBq, 
resulting in a radiation burden of 4 mSv, followed by a low dose CT of 3 mSv. Patients for
whom FDG-PET is not part of standard of care, this will add 7 mSv to the total radiation 
dose related to the study. 
Overall, the total radiation dose will represent 52 to 65 mSv.
Optimalisation of the radiation dose is achieved via splitting of the protocol in two parts. 
Optimal mAb dose for imaging will be established in part 1, whereafter the patients in part 2 
will be imaged at this optimal dose. 
In order to ensure the accuracy of quantitation, 37 MBq is the minimum level of activity that 
can be used per injection.
There are no risk increasing / decreasing factors.
Justification of this study is provided through the intended benefit of mitigating serious 
diseases in the future (category 3b).
In conclusion, the radiation burden for this study has been optimized, is justified and falls 
within the dose limits as discussed in NCS-26/ICRP-62 (R18-2184)
Even so, patients should be advised of the potential risks of side effects from investigational 
trial treatments. 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, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.6, adverse events of special interest (AESI).

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objective(s)
The main objective of this study is to determine the biodistribution and intra-tumor 
accumulation of [89Zr]Zr-BI 754111 at baseline and its change upon treatment.
2.1.2
Primary endpoint(s)
The primary endpoint of this study is:
Standardized uptake values (SUVs) of [89Zr]Zr-BI 754111 for tumor uptake at baseline 
(Cycle1) and post BI 754111 dose (up to Cycle2 Day8)
2.1.3
Secondary endpoint(s)
There is no secondary endpoint in this study.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I open label, non-randomized bio-distribution trial to be conducted in one 
specialized center. The trial is divided in 2 Parts as described below in Figure 3.1:1 and will 
be conducted in a staggered approach.
Recommended exp. dose is the BI 754111 dose recommended for the expansion phase of trial 1381-0002.
Figure 3.1: 1 Overall design

Part 1 is intended to assess the dosimetry of [89Zr]Zr-BI 754111, to optimize the imaging 
time window and the feasibility of [89Zr]Zr-BI 754111 PET to assess tumor distribution 
and uptake of BI 754111. The BI 754111 dose administered in this Part will be the dose 
recommended for the expansion phase of trial 1381-0002. The whole body biodistribution 
of [89Zr]Zr-BI 754111 will be assessed and optimal tumor uptake parameters will be 
developed. See Figure 3.1: 2.

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PD= Progression of Disease
Bx=Tumor Biopsy
Figure 3.1: 2 Part 1: dosimetry and feasibility assessment

Part 2 will be initiated following a positive SMC decision after review of all available 
data from Part 1 in order to assess whether a blockade of [89Zr]Zr-BI 754111 has been 
demonstrated. Patients will be tested for tumor LAG-3 expression at screening. During 
cycle 1, all patients will undergo baseline PET assessments. During cycle 2 (on-treatment 
PET assessment), at least 2 doses levels of BI 754111 treatment will be explored in 
patients tested positive for tumor LAG-3 expression. At least 2 patients should be 
included per dose cohort. See Figure 3.1: 3.
Up to five patients tested negative for LAG-3 expression will be included in Part 2. These 
patients will not be part of dose exploration but will be offered treatment with BI 754111 at 
the dose recommended for the expansion phase of trial 1381-0002. Hence, they will not
undergo the on-treatment PET/CT assessment procedures.
After cycle 2, all patients will be treated at the recommended dose. 
PD= Progression of Disease Bx=tumor biopsy
PET/CT post [89Zr]Zr-BI 754111: 2 before CTP 3.0, 3 after CTP 3.0
Figure 3.1: 3 Part 2: assessment of tumor uptake

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Part 1 will assess the feasibility of the methods. The patients included in Part 1 will have a 
[89Zr]Zr-BI 754111 infusion for a baseline PET assessment (prior to first BI 754111
treatment) at Cycle1 and another [89Zr]Zr-BI 754111 infusion for on-treatment PET
assessment (following first BI 754111 treatment) at Cycle2. The baseline PET assessment 
will include a dosimetry to investigate the tracer ([89Zr]Zr-BI 754111) dose. During the on-
treatment PET assessment, the patients will be administered the dose of BI 754111
recommended for the expansion phase of trial 1381-0002. This dose of BI 754111 treatment 
will be tested first to evaluate whether a blockade of the [89Zr]Zr-BI 754111 is possible. 
It is estimated that up to 5 patients will be included in Part 1.
The data obtained from these patients will be analysed and reviewed on a regular basis by the 
SMC. During the SMC reviews, the mass dose of [89Zr]Zr-BI 754111 might be adapted as 
needed based on all imaging data available. Part 2 will commence based on SMC decision 
after review of all available data from Part 1.
Part 2 will assess the tumor uptake of [89Zr]Zr-BI 754111. The patients will be prospectively 
tested for LAG-3 tumor expression. 
The patient tested positive for LAG-3 tumor expression will be included in different dose-
cohorts, each cohort exploring one dose of BI 754111 treatment during cycle 2. It is planned 
to explore at least 2 doses of BI 754111 treatment in this study. At least 2 patients with LAG-
3 expressing tumor are needed in each dose cohort in order to assess the degree of blockade 
of [89Zr]Zr-BI 754111 uptake upon a certain BI 754111 dose.
A cohort of maximum 5 patients tested negative for LAG-3 expression will be included in 
Part 2. These patients will undergo the baseline PET assessment for [89Zr]Zr-BI 754111 
tumor uptake but they will not be considered for dose exploration and will not proceed for the 
on-treatment PET assessment. 
For each patient in Part 2, the cold dose BI 754091 necessary to optimize [89Zr]Zr-BI 754111,
the dose of BI 754111 treatment to be applied at cycle 2 and the imaging timepoints will be 
confirmed by the SMC with reference to the data available.
Up to 35 patients might need to be included in Part 2.
In both Parts:
At screening, all patients should provide two core needle tumor biopsies for LAG-3 IHC
testing. These two core needle tumor biopsies (or equivalent) are to be taken from a PET-
imageable and evaluable lesion prior to first BI 754091 administration
All patients will be administered the anti-PD-1 treatment BI 754091 alone at day 1 of cycle 1. 
Thereafter, the anti-LAG-3 treatment BI 754111 will be added to BI 754091 at day 1 of cycle 
2 and this combination treatment will be administered on the first day of each cycle.

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3.3
SELECTION OF TRIAL POPULATION
Up to 40 patients will be recruited into this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site 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
This trial will include patients with:

NSCLC: Patients with advanced or metastatic disease who have failed on or after 
preceding anti-PD-1 or anti-PD-L1 based treatment with at least 3 months stable disease 
before progression

HNSCC: Patients with recurrent and metastatic disease who have been treated with at 
least one previous systemic chemotherapy or are chemotherapy intolerant/unresponsive
(previous treatment with anti- PD-1/ PD-L1 is allowed).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
For inclusion in the trial, patients must fulfil all of the following criteria:
1. Provision of signed and dated, written Informed Consent Form (ICF) prior to any trial-
specific procedures, sampling, or analyses
2. Patients of legal age (according to local legislation) at the time of signature of the ICF
3. Patients with histologically confirmed diagnosis of recurrent NSCLC who received anti-
PD-1 or anti-PD-L1 as Part of last treatement with at least 3 months of stable disease 
(i.e.patients with confirmed response (PR or CR) regardless of duration of response or 
stable disease (SD) for a minimum of 3 months) and have become refractory to anti-PD-
1/ anti-PD-L1 based treatment
OR
Patients with histologically confirmed diagnosis of recurrent metastatic HNSCC who
progressed after platinum based therapy or not indicated for receiving standard (radio)
chemotherapy (previous treatment with anti- PD-1/ PD-L1 is allowed)
4. Eastern Cooperative Oncology Group (ECOG, R01-0787) score: 0 to 1
5. Patient must have at least one PET imageable and evaluable tumor lesion of 20mm
6. Patients must have at least one tumor lesion amenable to biopsy. This lesion should be 
PET imageable and evaluable as defined above and the biopsy should be obtained before 
first BI 754091 administration, unless medically contra-indicated. In the latter case, 25 
4µm sections from an archival biopsy taken at relapse after the previous treatment are 
acceptable
7. Must have evaluable lesion(s) according to Revised Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 and iRECIST

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8. Life expectancy of at least 12 weeks after the start of the treatment according to the 
Investigator’s judgement
9. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control per 
International Conference on Harmonisation (ICH) M3 (R2) (that result in a low failure 
rate of less than 1% per year when used consistently and correctly) during trial 
Participation and for at least 6 months after the last administration of trial medication. A 
list of contraception methods meeting these criteria is provided in the patient information.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
Patients must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Not having fully recovered from major surgery before they enter into the trial according
to investigator judgment or planned for major surgery within 12 months after screening, 
e.g. hip replacement
2. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
3. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled
4. Previous treatment in this trial
5. Any investigational or anti-tumor treatment within 4 weeks or within 5 half-life periods 
(whichever is shorter) prior to the initiation of trial treatment. 
6. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of 
starting study treatment with the exception of alopecia and Grade 2 neuropathy due to 
prior platinum-based therapy
7. Prior treatment with anti-LAG-3 agents
8. Presence of other active invasive cancers other than the one treated in this trial, with the 
exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma 
in situ of the cervix, or other local tumors considered cured by local treatment
9. Untreated brain metastasis(es) that may be considered active. Patients with previously 
treated brain metastases may Participate provided they are stable (i.e., without evidence 
of PD by imaging for at least 4 weeks prior to the first dose of trial treatment, and any 
neurologic symptoms have returned to baseline), and there is no evidence of new or 
enlarging brain metastases
10. Inadequate organ function or bone marrow reserve as demonstrated by the laboratory 
values presented in Table 3.3.3: 1.
11. Any of the following cardiac criteria:
o
Mean resting corrected QT interval (QTc) >470 msec
o
Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECGs, e.g., complete left bundle branch block, third degree heart block

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o
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history 
of long QT syndrome or unexplained sudden death under 40 years-of-age, or any 
concomitant medication known to prolong the QT interval
o
Ejection fraction <55% or the lower limit of normal of the institutional standard.
12. History of pneumonitis within the last 5 years
13. History of severe hypersensitivity reactions to other mAbs
14. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 
4 weeks prior to the first dose of study treatment. 
15. Active autoimmune disease or a documented history of autoimmune disease, except 
vitiligo or resolved childhood asthma/atopy
16. Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal 
therapy) at start of treatment in this trial
17. Known history of human immunodeficiency virus infection or an active hepatitis B or C 
virus infection
18. Interstitial lung disease
19. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
him/her an unreliable trial patient or unlikely to complete the trial or unable to comply 
with the protocol procedures
20. Women who are pregnant, nursing, or who plan to become pregnant in the trial

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Table 3.3.3: 1
Laboratory values demonstrating inadequate organ function
Laboratory Parameter
Values 
Absolute neutrophil count
<1.5 x 109/L (<1500/mm3)
Alanine aminotransferase (ALT) 
>2.5 X ULN if no demonstrable liver 
metastases or >5 X ULN in the 
presence of liver metastases
Aspartate aminotransferase (AST) >2.5 X ULN if no demonstrable liver 
metastases or >5 X ULN in the 
presence of liver metastases
Haemoglobin 
<9 g/dL
International Normalized Ratio 
(INR) (only tested if clinically 
indicated)
>1.5 X ULN (If treated with 
anticoagulants, prolonged INR is 
acceptable)
Platelet count
<100 x 109/L
Serum Creatinine
>1.5 X ULN or estimated glomerular 
filtration rate (eGFR) <30 
mL/min/1.73 m2 (Chronic Kidney 
Disease Epidemiology (CKD-EPI)
Collaboration equation); 
confirmation of eGFR is only 
required when creatinine is >1.5 X 
ULN.
Total bilirubin
>1.5 X ULN, except for patients with 
Gilbert's syndrome who are excluded 
if total bilirubin >3.0 X ULN or 
direct bilirubin >1.5 X ULN
ULN = Upper Limit of Normal
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to study entry, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and CRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

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
The patient needs to take concomitant medication that interferes with the investigational 
product or other trial medication (see Section 4.2.2.1)

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy) (see Section 4.1.2.4).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
Even if the trial treatment is discontinued, the patient remains in the trial and, given his/her
agreement, the patient will undergo the procedures for the EOT visit and the safety follow up 
as outlined in the Flow Chart (FC) and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported.
If a patient should become pregnant during the trial, the treatment with BI 754111 or 
[89Zr]Zr-BI 754111 and BI 754091 (where applicable) must immediately be stopped. The 
patient will be followed up until delivery or termination of pregnancy (see Section 5.2.6.2.4
for information on pregnancy forms). The data of the patient will be collected and reported in 
the eCRF until the last patient’s last visit and any events occurring thereafter will be reported 
in the BI drug safety database.
3.3.4.2
Withdrawal of consent for trial Participation
Patients may withdraw their consent for trial Participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
and explain the difference between treatment withdrawal and withdrawal of consent for trial 
Participation, as well as explain the options for continued follow up after withdrawal from 
trial treatment, please see Section 3.3.4.1.
3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a Particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a Particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the trial protocol, or the contract impairing 
the appropriate conduct of the trial
The investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
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 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 Day1 of each 3-week Cycle
Method and route of administration:
I.V. infusion
4.1.1.2
[89Zr]Zr-BI 754111
Details of the drug product, [89Zr]Zr-BI 754111, are presented in Table 4.1.1.2: 1. Additional 
details are presented in the [89Zr]Zr-BI 754111 IMPD
Table 4.1.1.2: 1
[89Zr]Zr-BI 754111
Substance:
[89Zr]Zr-BI 754111
Pharmaceutical formulation:
Solution for infusion
Source:
 
Unit strength:
0.2 mg/mL
Posology:
Up to 2 administrations
Method and route of administration:
I.V. infusion via a pump in 10 min

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4.1.1.3
BI 754091
Details of the drug product, BI 754091, are presented in Table 4.1.1.3: 1. Additional details 
are presented in the BI 754091 IB and Pharmacy Manual.
Table 4.1.1.3: 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 Day1 of each 3-week Cycle
Method and route of administration:
I.V. infusion
4.1.2
Selection of doses in the trial and dose modifications
4.1.2.1
[89Zr]Zr-BI 754111
The tracer dose will consist of 4mg BI 754111 and 37 MBq Zr-89 in a total volume of 20mL. 
This dose is based on the lowest dose of BI 754111 tested in the dose escalation Part of trial 
1381-0002.
4.1.2.2
BI 754111
BI 754111 treatment will be administered at doses expected to be therapeutically active based 
on non-clinical and clinical data.
The first dose to be investigated is the dose recommended for the expansion phase of trial 
1381-0002. This dose was selected based on the data obtained in 1381-0002 dose-escalation 
cohorts, where 3 to 9 patients each received BI 754111 at dose levels of 4, 20, 80, 200, 400 
and 600mg in combination with a flat dose of 240mg BI 754091. No DLTs or AESIs were 
observed in the dose escalation Part and maximum tolerated dose (MTD) was considered not 
reached.
The first administration of BI 754111 treatment will take place at Cycle2 Day1. 
In Part 2, various doses cohorts will be investigated sequentially. In each cohort, the dose 
applied at Cycle2 Day1 will depend on the magnitude of the blockade observed in the 
previous dose cohort. It is expected to explore at least two different dose levels of BI 754111
in this trial.
From Cycle3 Day1, the dose BI 754111 dose recommended for the expansion phase of trial
1381-0002 will be be applied to all patients.
The treatment will be administered via infusion q3w.

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4.1.2.3
BI 754091
BI 754091 will be administered at a flat dose of 240mg to be administered via infusion q3w.
4.1.2.4
Dose modification for BI 754111 and BI 754091 treatments
There will be no dose reductions or escalations of BI 754091 or BI 754111 in any one patient.
All patients (including patients allocated to a different dose of BI 754111 treatment during 
the on-treatment assessment phase (Cycle2) in Part 2), will take the recommended expansion 
phase dose of BI 754111 (determined in the 1381-0002 trial) starting from Cycle 3 onward.
The dose may be delayed for up to 6 weeks because of AEs, following discussion with the 
sponsor.
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 or 
baseline) of the AE, both BI 754091 and BI 754111 must be started together.
The study treatments BI 754091 and BI 754111 should be permanently discontinued for 
CTCAE Version 5.0 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 ULN or total bilirubin >3 times ULN, inability to taper steroids to 10 mg or less 
prednisone 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.
4.1.3
Method of assigning patients to treatment groups
After assessment of all in- and exclusion criteria, each eligible patient will be entering the 
trial in their respective study Part.
In Part 1, the patients will be entered sequentially.
After review of Part 1 data, the SMC will make the decision whether or not to initiate Part 2.
Patients tested positive for tumor LAG-3 expression will be treated in various dose cohorts of 
BI 754111 and these dose cohorts will be managed sequentially based on the SMC decision. 
During the conduct of Part 2, up to five patients tested without LAG-3 expressing tumor will 
be entered sequentially.

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The appropriate medication number will be assigned. Note that the medication number is 
different from the patient number (the latter is assigned directly after informed consent was 
obtained). Site personnel will enter the medication number in the CRF.
4.1.4
Drug assignment and administration of doses for each patient
The tracer dose (approximately 4mg in 20mL) of [89Zr]Zr-BI 754111 will be injected 
intravenously via a pump in 10 min with flushing (10 mL physiologic saline). The mass dose 
might be adapted as per SMC decision. The injection will take place at the department of 
 Each patient will be administered [89Zr]Zr-
BI 754111 up to 2 times during the trial, once at Cycle1 no later than Day8 and at Cycle2
after the administration of BI 754091/BI 754111 treatment, if applicable (all patients in Part 1 
and only patients tested positive for tumor LAG-3 expression in Part 2).
BI 754091 will be administered via intravenous infusion at the dose of 240mg. The first 
administration of BI 754091 treatment will take place at Cycle1 Day1 for each patient.
BI 754111 will be administered via intravenous infusion at the recommended expansion dose
per trial 1381-0002. The first administration of BI 754111 treatment will take place at Cycle2
Day1 for each patient. 
In Part 2, patients tested positive for tumor LAG-3 expression will be administered a lower or 
a higher dose of BI 754111 treatment at Cycle2 only. The dose allocated at these patients in 
Cycle2 will be confirmed by the SMC.
At Cycle2 and onwards, BI 754091 and BI 754111 treatment will be administered 
concomitantly. 
For the preparation and administration of BI 754091 and BI 754111, please refer to the 
instruction provided in the ISF.
For each compound, the different timepoints of administration and the different doses are 
summarized in the table below.

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Table 4.1.4: 1
Administration of doses per study part
Treatment Cycle
Study Part
Day
Dose to be administered
Cycle1
Baseline assessment 
Part 1 and Part 2
C1 Day1
BI 754091 treatment: 240mg
No later 
than day8
[89Zr]Zr-BI 754111: 4mg or adapted mass dose
Cycle2
On-treatment 
assessment 
Part 1
C2 Day1
BI 754091 treatment: 240mg
BI 754111 treatment: recommended exp. dose
[89Zr]Zr-BI 754111: 4mg or adapted mass dose 
Part 2
C2 Day1
BI 754091 treatment: 240mg
BI 754111 treatment: allocated dose per SMC 
decision
[89Zr]Zr-BI 754111: 4mg or adapted mass dose
Cycle 3 and further 
cycles
Part 1 and Part 2
Cx Day1
BI 754091 treatment: 240mg
BI 754111 treatment: recommended exp. dose
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
CRF will contain information on allocated treatment.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products BI 754091 and BI 754111 will be provided by BI. [89Zr]Zr-
BI 754111 will be produced at the 
 campus, with a production license being in 
place. Production is performed under the responsibility of the hospital pharmacist (Qualified
Person). 
All products will be packaged and labelled in accordance with the principles of Good 
Manufacturing Practice (GMP). Re-supply to the site will be managed by BI in collaboration 
with the investigational site, which will also monitor expiry dates of supplies available at the 
site.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
BI 754091 and BI 754111 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.

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If the storage conditions are found to be outside the specified range, the BI clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
[89Zr]Zr-BI 754111 should be stored at 2-8°C until use. Prior to drawing up in a syringe it 
should be warmed up to room temperature. It can be kept in a syringe for approximately 
1 hour.
4.1.8
Drug accountability
The investigator or pharmacist/investigational drug storage manager will receive the 
investigational treatment drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the clinical trial protocol (CTP) by the institutional review board 
(IRB)/ethics committee (EC)

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the Principal Investigator
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or pharmacist/investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or warehouse/drug distribution centre or alternative disposal of 
unused products. If applicable, the sponsor or warehouse/drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator/pharmacist/investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. Unused and Partially used 
trial drugs will be destroyed on site at the end of the trial (after relevant reconciliations have 
been completed and records reviewed by the clinical monitor).
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used or special emergency procedures to be 
followed in this trial.
Rescue medications to reverse the action of BI 754111 or BI 754091 are not available.
Therefore, potential side effects of the study drugs have to be treated symptomatically.

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Concomitant therapy, with reasons for taking each treatment, must be recorded in the eCRF 
during the screening and treatment periods, starting at the date of signature of the 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.
Permitted concomitant medications include:

If medically feasible, patients taking regular medication should be maintained on it 
throughout the trial.

To reduce the risk of IRRs, 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.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 eligibility 
criteria.

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.

Granulocyte colony stimulating factors should not be used prophylactically during the 
first 3 weeks of any cohort. Thereafter, prophylactic colony stimulating factors may be 
used according to institutional standards.

For symptom control, palliative radiotherapy is permitted during the trial, except during 
the biodistribution imaging phases as it could interfere with the imaging evaluation. 
Palliative radiotherapy is allowed provided that the reason for radiotherapy does not 
reflect PD and does not interfere with response assessment. Lesions that have been 
exposed to radiotherapy are no longer evaluable, and may not be included in the 
assessment of the non-target lesions and the overall assessment. Unless in emergency 
situations, the BI Medical Monitor should be contacted prior to the administration of 
palliative radiotherapy.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment

No other investigational therapy or anticancer agent should be given to patients. If such 
agents are required for a patient, then the patient must first be withdrawn from the trial.

Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor 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.

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
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.
4.2.2.2
Restrictions on diet and life style
The usual restrictions on diet and life style that were already applicable for a given patient 
before entry into the trial, according to his/her medical condition, have to be continued.
4.2.2.3
Contraception requirements
Due to the advanced stage of disease of Phase I trial patient populations and the high medical 
need, WOCBP (for the definition please refer to Section 3.3.2) can be included in this trial
provided that they agree to use a highly-effective contraception method. 
WOCBP and men able to father a child must use highly effective methods of birth control per 
the ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly.
WOCBP and men able to father a child must use two medically approved methods of birth 
control throughout the trial, and for a period of at least 6 months after last trial drug intake. 
They must use one barrier method, i.e. condom or occlusive cap with spermicide, or 
vasectomized Partner, and one highly effective non-barrier method including oral, injected or 
implanted hormonal contraceptives, intrauterine device or system.
Male patients: men whose Partner is a WOCBP must use condoms and ensure their Partner is 
using an additional highly-effective method of birth control, during the trial and until at least 
6 months after the end of the trial treatment.
Female patients: WOCBP must use highly-effective methods of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly during the study, and for a period of at least 3 months after the last dose of study 
drug.
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion

Vasectomised sexual Partner with documented absence of sperm.
Or

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
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
Details of these contraception methods are described in the patient information in the ICF.
4.3
TREATMENT COMPLIANCE
BI 754111 and BI 754091 will be administered by i.v. infusion at the sites by the Investigator 
and/or trained site personnel, and dosing will be recorded in the eCRF. Therefore, actual 
dosing is expected to precisely follow the prescribed drug regimen. Missed or interrupted 
doses will be recorded in the eCRF with the associated reasons. The method of collecting 
dosing information assures that total exposure can be calculated programmatically taking into 
account any missing doses.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The treatment efficacy will be assessed according to RECIST Version 1.1 (R09-0262) and 
iRECIST (R17-0923) for the evaluation of the tumor response in patients with solid tumors. 
An overview of iRECIST will be found in Appendix 10.3.
The assessment by the Investigator and/or the local radiologist will be the basis for 
continuation or discontinuation of the trial in an individual patient (in addition to safety). The 
baseline imaging must have been performed within 4 weeks prior to start with anti-LAG-3 
treatment BI 754111 and the Investigator will record the target and non-target lesions in the 
eCRF. The same method of assessment and the same technique must be used to characterise 
each reported lesion at baseline and during treatment. Lesions in previously irradiated areas 
may not be considered measurable at baseline unless the lesions occurred after irradiation. 
The baseline tumor assessment will be performed as close as possible (and no more than 28 
days) to the start of the anti-LAG-3 treatment BI 754111 (i.e. within the week before Cycle1
Visit1 or during Cycle 1). Further assessments will be performed every 2 Cycles during the 
first 6 months and at the EOT visit (if not performed within the last 4 weeks). Following 6 
months of treatment, tumor assessments can be done once every 3Cycles, and at the 
discretion of the Investigator.
Following PD, a patient may continue to receive treatment for a maximum of a year if the 
Investigator, Medical Monitor, and sponsor agree that the patient is deriving clinical benefit.
Copies of CT/ Magnetic Resonance Imaging (MRI)/PET scan data will be collected by the 
sponsor for later radiomics assessment. It is planned to explore the potential for enhanced and 
improved baseline and on-treatment markers/ patterns of early efficacy based on 
comprehensive quantitative CT metrics, i.e. radiomics features, assessed in standard-of-care 
medical imaging data.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.

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This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Blood (venous) samples will be collected at the times indicated in the Flow Chart and will be 
analysed by the sites’ local safety laboratories. Screening laboratory assessments performed 
within 72 hours of the first trial treatment administration are not required to be repeated on 
Cycle 1 Day 1. In cases where screening laboratory investigations have been performed 
>72 hours prior to the first trial treatment intake, the results of the new laboratory 
investigations performed within 72 hours of the first trial treatment administration must be 
available to confirm eligibility.
The tests to be performed are described in Table 5.2.3: 1.

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Table 5.2.3: 1 
Safety laboratory tests
Hematology
Red blood cell count, haemoglobin, haematocrit, mean 
corpuscular volume, white blood cell count, and differential 
blood count will be expressed in absolute values, and 
platelets will be measured
Biochemistry 
Standard safety panel:
glucose, sodium, potassium, chloride, calcium, phosphate, 
venous bicarbonate HCO3, creatinine, creatinine 
phosphokinase (CPK), AST, ALT, alkaline phosphatase, 
lactate dehydrogenase (LDH), bilirubin, total protein, 
albumin, urea nitrogen (or urea), uric acid and troponin
Baseline additional panel then when clinically indicated: 
cholesterol, triglycerides, c-peptide, and creatine 
phosphokinase
In case of pathological creatine phosphokinase: 
CPK-MB, additional troponin I and myoglobin should be 
reactively tested and the findings documented
Thyroid panel (TSH, free T4, and free T3): 
at the time of each standard biochemistry panel
To be analysed in case of symptoms of pancreatitis:
amylase and lipase
Urinalysis
Urine (pH, glucose, erythrocytes, leukocytes, protein, and 
nitrite) will be analysed by dipstick (semi-quantitative
measurements) during the screening visit, at the EOT visit, 
and as clinically indicated. In case of pathological findings, 
further evaluation must be performed and the findings 
documented
Pregnancy test
Beta human chorionic gonadotropin (β-HCG) pregnancy test 
in urine or serum will be performed for women of 
childbearing potential at screening, within 14 days prior to 
first trial treatment, on Day 1 of each cycle prior to 
administration of the treatment drug(s), before the start of 
each repeated cycle, and at the EOT visit.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the Potential DILI Checklist provided in the 
ISF). The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.

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5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and whether it is clinically relevant, if abnormal. ECGs may 
be repeated for quality reasons and the repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Other safety parameters
Not applicable
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, or

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. 

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Patients may be hospitalised for administrative reasons during the trial, including 
hospitalisation for respite care. These as well as hospitalisations/surgical procedures which 
were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalisation/surgical procedure has not 
changed/worsened after signing informed consent).
5.2.6.1.3
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the duration between discontinuation of the trial medication and must be 
reported as described in Section 5.2.6.2, subsections “AE Collection” and AE reporting to 
sponsor and timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which by their nature, can always be considered to be 
“serious” even though they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the electronic Data Capture (eDC)
system. These events should always be reported as SAEs as described above.
5.2.6.1.4
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of Particular concern for prospective safety monitoring and safety assessment within this 
trial, e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance DePartment within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs: irAEs, infusion-related AEs, potential DILI events, 
and hepatic injury are AESIs (see below).
Immune-related adverse events (irAEs)
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. All immune-relate events are to be reported as AEs. Some irAEs also 
need to be reported as AESIs as defined by the sponsor in Table 10.1: 1. If an Investigator 
determines a grade 3 event (not on the list) to be immune-related, the Investigator should also 
report that event as an AESI.
Recommendations for the management of irAEs are presented in Appendix 10.2.
Infusion-related reactions
To reduce the risk of IRRs, 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 BI 754111 and/or the 

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combination of BI 754111 plus BI 754091 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, permanently discontinue study drug(s).
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional 
standard may be administered prior to subsequent infusions at the discretion of the 
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the study, treatment with 
BI 754111 and BI 754091 will be permanently discontinued for the patient.
As with any mAb, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and trial personnel must be trained to recognise and treat anaphylaxis. The trial site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability 
to admit patients to an intensive care unit if necessary.
The following terms describe those events that are to be considered potential infusion-related 
AEs. Regardless of grade, these events are considered as AESIs and must be reported to the 
Sponsor within 24 hours of the event:

Allergic reaction

Anaphylaxis

Cytokine-release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential infusion-
related AE, the Investigator may also report that event as an AESI
Hepatic injury and potential drug-induced liver injury (DILI)
During the course of the trial the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets the 
hepatic injury definition or potential Hy´s Law criteria at any point during the trial.
The investigator participates, together with BI clinical project representatives, in review and 
assessment of cases meeting potential hepatic injury and Hy´s Law criteria. Hy´s Law 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than a DILI caused by the investigational product.
The investigator is responsible for recording data pertaining to these cases and for reporting 
them as AEs and/or SAE according to the outcome of the review and assessment in line with 
standard safety reporting processes.

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Hepatic injury definition:
In patient wit normal baseline hepatic function, hepatic injury is defined by the following 
alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

Mark peak ALT, and/or AST elevation ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Lab values meeting this definition of hepatic injury will need to be reported as an AESI.
Please follow the flowchart below for reporting hepatic injury / potential DILI cases.
Figure 5.2.6.1.4: 1
Processing of potential DILI cases
Hy´s Law cases have the following 3 components:

The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST

Among trial subjects showing such aminotransferase elevations, often with elevations 
much greater than 3 times ULN, one or more show elevation of serum total bilirubin to 
>2 times ULN, without initial findings of cholestasis (elevated serum ALP)

No other reason can be found to explain the combination of increased aminotransferase 
and total bilirubin, such as hepatitis A, B, or C; prexisting or acute liver disease, or 
another drug capable of causing the observed injury.

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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of AEs should be classified and recorded in the eCRF according to 
the CTCAE Version 5.0.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.

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5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the end of treatment (including the 
safety Follow-up period, a period of 30 days after the last dose of trial medication): all 
AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: the investigator does not need to actively 
monitor the patient for AEs but should only report any occurrence of cancer of new 
histology, related SAEs and related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the CRF.
The rules for Adverse Event Reporting exemptions still apply.
5.2.6.2.2
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.6.2.3
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form. The investigator should determine the causal relationship 
to the trial compounds.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of pre-existing conditions other than the underlying disease

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable” , or no further 
information can be obtained.

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5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial Participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.6.2.5
Exemptions to SAE reporting
Protocol specified outcome events should be collected on the appropriate CRF page only.
Disease progression is a trial endpoint for analysis of efficacy and as such is exempted from
reporting as an AE or an SAE. Progression of the subject's underlying malignancy will be 
recorded on the appropriate pages of the eCRF as Part of efficacy data collection only and 
will not be reported on the SAE Form. It will therefore not be entered in the safety database 
(ARISg) and hence not get expeditiously reported. Death due to disease progression is also to 
be recorded on the appropriate eCRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy, the event must be reported as an SAE on 
the SAE Form and on the eCRF.
Examples of exempted events of PD may be:

Progression of underlying malignancy (PD): if PD is clearly consistent with the suspected 
progression of the underlying malignancy as defined by the respective response criteria. 

Hospitalisation/procedures due solely to the progression of underlying malignancy (PD)

Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g., imaging, clinical measurement): if the symptom can exclusively be determined to be 
due to the progression/relapse of the underlying malignancy and does meet the expected 
pattern of progression for the disease under study.
Exempted events are collected and tracked following a protocol specified monitoring plan. 
Exempted events are monitored at appropriate intervals throughout the study.
Lab values meeting the hepatic injury definition as defined in Section 5.2.6.1.4 will need to be
reported as AESI. PD reporting exemption does not apply to hepatic injury.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Plasma concentration of BI 754111 will be listed and evaluated descriptively. PK parameters 
will be calculated by non-comPartimental methods according to BI internal Standard 
Operating Procedure (SOP) (001-MCS-36-472).
5.3.2
Methods of sample collection
For quantification of analyte plasma concentrations, blood will be drawn for BI 754111 at the 
time points specified in PK time schedules in the Blood Sample Flow Chart. Pharmacokinetic 
sampling times and periods may be adapted by the Sponsor during the trial based on 
information obtained during trial conduct.  
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 (24h time clock) for each sample has to be 
recorded accurately.
Details on sample characteristics, collection, processing, handling, and shipment are provided 
in the Laboratory Manual.
Plasma samples may be used for further methodological investigations (e.g., stability testing), 
however only data related to the analyte or bioanalytical assay will be generated by these 
investigations. The trial samples will be discarded not later than 5 years after the final trial 
report has been signed.  
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a PK/PD relationship is planned.

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5.6
OTHER ASSESSMENTS
5.6.1
FDG-PET/CT procedure
A standard static diagnostic FDG-PET will be performed during screening for the assessment 
of tumor viability and necrosis. This procedure will be performed in accordance with 
European Association of Nuclear Medicine (EANM) FDG-PET/CT procedures guidelines for 
tumor imaging (R18-1536).
5.6.2
[89Zr]Zr-BI 754111 PET scan procedure
All PET scans will be performed on a PET/CT scanner (e.g. 
 Ingenuity TF). All 
patients will undergo whole body PET scans at various time points, e.g. t = 72 and t = 144 
hours post-injection. The PET scans will be preceded by a 30 mAs low-dose CT, used for 
attenuation correction and anatomical localization of the PET-signal. Following CT, a total 
body PET scan will be acquired. PET scans consist of 10-12 bed positions, depending on the 
length of the patient, of various time lengths, usually 5 minutes each. Total acquisition time 
per scan, including low dose CT will be around 60 minutes. 
PET data will be normalized and corrected for randoms, tissue attenuation, decay, scatter and 
dead time. PET-CT data will be reconstructed with TF-OSEM, resulting in a transaxial 
spatial resolution of ~7 mm in the centre of the field of view. Regions of interest (ROIs) will 
be defined using the CT images which are co-registered to the PET-CT data. ROIs around the 
organs which accumulate 89Zr (e.g. liver, lung and other metastatic lesions) will be drawn 
manually directly on the PET images. All tissue concentrations will be related to the blood
concentration (venous samples). The radioactivity concentrations in all regions for all 
imaging time points will be recorded digitally in a spreadsheet. 
Quantitative accuracy of 89Zr-PET scans was previously confirmed in 
 center using 
phantom studies and comparisons between PET-derived and biopsy tumor radioactivity 
concentrations (R18-1538, R18-1539). 
A blood sample (6 mL) will be drawn at four early time points post injection of [89Zr]Zr-
BI 754111 (after CTP 3.0) and at each [89Zr]Zr-BI 754111 PET scan to determine 89Zr-kinetics 
based on measurements of radioactivity. See Blood Sample Flow Chart for time schedule.
The detailed procedures of [89Zr]Zr-BI 754111 PET/CT scanning will be described in the lab 
manual at the site.

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Analysis of PET data:
Tumor volumes of interest will be delineated using semi-automated in-house developed 
software. SUVmax, SUVmean and SUVpeak will be calculated for the tumor and visible lymph 
nodes (R18-1536, R18-1537).
5.6.3
Assessment of anti-drug antibodies (ADAs)
The presence of anti-drug antibodies (ADAs) against BI 754111 will be assessed using a 
validated immunoassay in a tiered approach (screening, confirmatory, and titration analysis 
as appropriate).
For ADA assessments (BI 754111), the specified blood volume will be drawn into blood-
drawing tubes at the time points listed in the Blood Sample Flow Chart and the detailed blood 
sampling schedule. Details on sample characteristics, processing, handling, and shipment are 
provided in the Laboratory Manual.
After completion of the trial, plasma samples may be used for further methodological 
investigations, e.g., stability testing. However, only data related to the ADAs will be 
generated by these additional investigations. 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.
Note that for some disease indications, it may be necessary to use plasma samples collected 
prior to administration of study treatments in order to assess the performance of the ADA 
assay.
5.7
APPROPRIATENESS OF MEASUREMENTS
All assessments have been planned in accordance with traditional oncology Phase I trial
methodology except the iRECIST that is a new guideline for response assessment in trial 
testing immunotherapeutics and is still to be validated, so this guideline will be used as an 
exploratory efficacy assessment in this trial.
All PET scan acquisition procedures that will be performed in this trial are standard.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients that have met the inclusion criteria and not met the exclusion criteria for the Part they 
are participating in and who have signed a written ICF, are eligible for Participation in the 
trial. Patients will visit the clinical site at the time points specified in the Flow Chart.
Each cycle has duration of 21 days.
At Cycle1 and Cycle2, the visit will be conducted through multiple days, driven by the LAG-
3 PET assessments procedures:

Cycle1 will start with the administration of the anti-PD1 treatment BI 754091 at Day1.
The procedures for baseline LAG-3 PET assessment will start with the injection of the 
tracer [89Zr]Zr-BI 754111 that should be done no later than Day8, followed by the 
PET/CT scans. 

Cycle2 will start with the first administration of the anti-LAG-3 treatment BI 754111 in 
combination with BI 754091 at Day1. The procedures for on-treatment LAG-3 PET 
assessment will start with the injection of the tracer [89Zr]Zr-BI 754111 that should be 
done at Day1 (after the infusion of BI 754091 and BI 754111) followed by the PET/CT 
scans. 
After Cycle2, the visits will be 1-day visit at day 1 of each cycle. 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. The next visit must then take place at the 
scheduled time after the first administration of the trial drug in the respective treatment cycle.
Once the decision for any reason is made for a patient to stop the treatment with the study 
treatment (BI 754091 and BI 754111), 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 EOT.
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 all portions of the trial are presented in the Flow 
Chart of this protocol. The key procedures required include:

FDG-PET for assessment necrosis and tumor viability at screening

PET scan for LAG-3 biodistribution and tumor uptake assessments 

Blood samples for PK concentration BI 754111

Blood samples for radioactivity concentration post [89Zr]Zr-BI 754111 injection and at
LAG-3 PET assessments 

Reporting of all AEs occurring after the ICF has been signed

Baseline and on-treatment blood samplings for biomarker and immunogenicity
assessments

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
Tumor biopsy for assessment of LAG-3 expression at screening

Tumor tissue (5 slices) from tumor biopsy taken prior to the anti-PD-1/PD-L1 treatment, 
if available

Optional tumor biopsies for autoradiography and Flow cytometry at C1

Tumor assessments (based on CT/PET and/or MRI scan) according to RECIST 
Version 1.1 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 the anti-LAG-3 treatment
BI 754111 for the first 6 months, and then every 3 Cycles (9 weeks) thereafter. The 
baseline tumor assessment must be performed within 28 days prior to the start of the anti-
LAG-3 treatment BI 754111.
6.2.1
Screening period
The screening period may occur over a period of 15 days (period within the trial and before 
the first administration of BI 754091). For the detailed description of the tests to be 
performed during this period and their timing, please refer to the Flow Chart.
6.2.1.1
Baseline Conditions
Demographics (sex, year of birth, race, and ethnicity where allowed), information on tobacco
and alcohol use, and baseline conditions will be collected during the screening visit.
6.2.1.2
Medical History
6.2.1.2.1
Medical history of cancer
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumor site will be 
reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumor, (lymph) node, 
and metastasis (TNM Classification of Malignant Tumours (TNM)) classification will be 
provided as obtained at diagnosis and at trial screening. Previous surgeries will be reported.
Previously administered chemotherapy, tyrosine kinase inhibitor treatment, vaccine therapy, 
antibodies therapy, immune therapy, and hormone therapy will be reported, including start 
and end dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumor progression after previous 
lines of treatment will be recorded, if known.
6.2.1.2.2
Other medical history
Past diseases and/or concomitant diagnoses relevant to patient's safety during the trial as 
judged by the Investigator will be recorded in eCRF.

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6.2.1.3
Concomitant medications
Past medications relevant to patient's safety during the trial as judged by the Investigator will 
be recorded in eCRF. From the date of signature of the ICF, all concomitant medications will 
be recorded (see Section 4.2.2 for details on concomitant medications)
6.2.2
Treatment period(s)
Please refer to the 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 as soon as possible but no later than 7 days after permanent 
discontinuation of the trial medications (BI 754091 and BI 754111) for any reason or e.g. 
when the Investigator decided with the patient to permanently discontinue the trial 
medications or became aware that the trial medications 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, tumor assessment/imaging must be 
performed at the time of EOT, unless it has been done within the past 4 weeks.
6.2.3.2
30-day safety follow-up visit
The safety follow-up visit is performed 30 (+2) days after the EOT visit. The information 
collected at this visit must include all new AEs that occurred after the EOT visit, and a 
follow-up of AEs ongoing at EOT.
A patient will be considered as having completed the trial if he/she discontinues because of
PD and has performed the safety follow-up visit 30 days after EOT, or was lost to follow up,
or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for any 
other reason, he/she will be considered as withdrawn.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is an open-label, non-randomised study consisting of two Parts. The main objective of 
this study is to determine the tumor accumulation of [89Zr]Zr-BI 754111 at baseline and its 
change upon treatment doses.
The primary endpoints are specified in Section 2.1.2. Further endpoints including 
pharmacokinetics (PK) are defined in Section 2.2.2. For both Parts of the study (Part 1 and 
Part 2) endpoints will be analysed by descriptive statistics. Inferential statistics is not planned 
(as explained in Section 7.2).
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in a confirmatory sense. All statistical 
analyses are exploratory even if they use confirmatory methods. Confidence intervals (CI)
will be computed and will be interpreted in terms of the exploratory character of the study, 
i.e. confidence intervals are considered as interval estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed. Adherence to the protocol will be checked. Important
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the trial statistical analysis plan (TSAP).
7.3.1
Primary endpoint analyses
The primary endpoint will be evaluated descriptively.
All evaluations will be based on the treated set (TS), unless otherwise stated. Patients who 
might not be evaluable for the baseline assessment of [89Zr]Zr-BI 754111 will be excluded 
from the primary endpoint analysis (to be decided no later than in the Report Planning
Meeting ). Exclusion of a subject’s data will be documented in the clinical trial report (CTR).
Association between tumor uptake and other imaging/efficacy or biomarker assessments will 
be investigated using generalized linear models. In addition, parameter-free correlation 
techniques, e.g. Kendall tau, will be provided where applicable. These analyses will be based 
on all data collected in the study.
In Part 2, an exploratory analysis might be performed to model the association between 
BI 754111 treatment dose vs. SUVs. These evaluations will be performed only if at least 3 
different BI 754111 doses are investigated with a sufficient number of patients per dose 
(minimum of 3 patients per dose cohort). 
The details of all aforementioned analyses will be provided in the TSAP.

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7.3.3
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment (i.e. 1st administration of anti-PD-1 treatment 
BI 754091 at Cycle1 Day1) and the safety follow-up (FU) 30 days after the last dose of trial
medications, will be assigned to the on-treatment period for evaluation. Statistical analysis 
and reporting of adverse events will concentrate on treatment-emergent adverse events, i.e. 
all adverse events occurring between start of treatment and end of the residual effect period. 
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of MedDRA at 
the 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.
7.3.4
Pharmacokinetic and pharmacodynamic analyses
Pharmacokinetic parameters as described in Section 2.2.2 will be calculated by means of 
noncomPartmental analysis. The derivation of PK parameters is described in BI internal SOP
(001-MCS-36-472).
Further details on analysis will be described in the TSAP.

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7.4
INTERIM ANALYSES
The sponsor will continuously monitor the safety. The design of the study foresees that the 
Sponsor and the SMC perform regular evaluations of all available data. These evaluations 
will be unblinded to dose.
Part 2 will commence based on SMC decision after review of all available data from Part 1.
7.5
HANDLING OF MISSING DATA
In general, no imputation will be performed on missing imaging/efficacy data. 
Missing baseline laboratory values will be imputed by the respective values from the 
screening visit. For Partial or missing AE onset and/or end dates, BI internal rules will be 
followed (see SOP Reference Document 001-MCG-156_RD-01).
No other imputations will be performed on missing data although every effort will be made to 
obtain complete information on all imaging, PK/PD, safety and efficacy endpoints.
7.6
RANDOMISATION
No randomisation will be performed. Patients will be assigned to the different Parts of the 
study by order of admission into the trial. 
In Part 2, patients tested positive for tumor LAG-3 expression will be assigned to various 
dose cohorts of BI 754111 by order of admission into the trial. Patients tested without LAG-3 
expressing tumor will be offered the trial treatment as described in Section 3.1 or may opt to 
cancel their trial Participation.
7.7
DETERMINATION OF SAMPLE SIZE
Up to 40 patients (up to 5 patients for Part 1 and up to 35 patients for Part 2) are planned to 
be entered in this trial. 
The planned sample size is not based on a power calculation but is judged to be adequate to 
fulfil the objectives and requirements of this exploratory trial. The exact number of patients
entered in the each Part will be defined by the SMC, but it will not exceed the planned 
sample size.
 
 

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized TriPartite Guideline 
for Good Clinical Practice (GCP), relevant BI SOPs, the European Union (EU) regulation 
536/2014 and other relevant regulations. Investigators and site staff must adhere to these 
principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
In exceptional cases, data may be published before the clinical trial report as long as this is 
discussed and agreed to by the investigators and the sponsor
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the local Ethics Committee (Dutch: Medisch-Ethische Toetsingscommissies 
(METc)) and competent authority (CA) according to national and international regulations. 
The same applies for the implementation of changes introduced by amendments.
Prior to patient Participation in the trial, written informed consent must be obtained from 
each patient according to ICH/GCP and to the regulatory and legal requirements of the 
Participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
Part of the trial records. A signed copy of the informed consent and any additional patient
information must be given to each patient.
The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 
The patient must be given sufficient time to consider Participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 

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place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor.
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Copies of tumor assessment scans will be collected by the sponsor for later Radiomics 
assessment. This could include CT/MRI/PET scans of the chest and abdomen and/or imaging 
of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate 

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method. Before sending or uploading those copies, the investigator must ensure that all 
patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient Participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial Participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.

Technical information collected on PK sampling days (e.g., PK sampling times, repeated 
vital signs linked with PK) may be collected on specific paper PK logs, which will be 
considered as source data for related entries in eCRF and are considered Part of the ISF.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB/IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. Food and Drug Administration (FDA)). They may review all CRFs and informed 
consents. The accuracy of the data will be verified by direct comparison with the source 
documents described in Section 8.3.1. The sponsor will also monitor compliance with the 
protocol and GCP.

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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
Exemptions from expedited reporting are described in Section 5.2.6.2, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third Parties is prohibited with the exceptions noted in Section 8.7. Patient
privacy will be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization (WHO) GCP handbook.
Personalized treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated as a result 
of the trial need to be available for inspection on request by the Participating physicians, the 
sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in Particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial Participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third Parties and other countries as specified in 
the biobanking ICF

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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at the trial site ends trial medication (as scheduled per protocol or prematurely). 
Individual investigators will be notified of suspected unexpected serious adverse reactions 
(SUSARs) occurring with the trial medication until 30 days after LPDD. Early termination 
of the trial is defined as the premature termination of the trial due to any reason before the 
end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC/CA in the member state will be notified about the trial milestones according to the 
local laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial is conducted at a site specialized in conducting PET studies for biodistribution and 
tumor uptake of radiolabled drugs.
A Coordinating Investigator is responsible to coordinate investigators at the Participating site.
Tasks and responsibilities are defined in a contract. 
A SMC composed of members of the trial site and members of the BI trial team will be 
established to review individual and aggregated data at regular intervals to assess the 
feasibility/specificity of the process, to evaluate the appropriacy of further enrolment in a 
cohort or the move to the next cohort and to support the identification of the best dose based 
on PET results and possible associated biomarkers. The SMC will also review safety and 
efficacy data to support the overall determination of the safety profile and risk/benefit ratio of 
the treatment.
Details of the SMC responsibilities and procedures are described in the SMC plan.
Relevant documentation on the Participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required 
activities, in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

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
direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of Local Clinical Monitor (CML), Clinical 
Research Associates (CRAs), and investigators of Participating country.
The organisation of the trial in the Participating country will be performed by the respective 
local or regional BI-organisation (Operating Unit (OPU)) in accordance with applicable 
regulations and BI SOPs.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
External laboratory services will be used in this trial. Details will be provided in the
Laboratory Manuals, available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, 
Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, 
Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation 
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Hodi FS, et al. Improved survival with ipilimumab in patients with 
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Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 
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Larkin J, et al.. Combined nivolumab and ipilimumab or monotherapy in 
untreated melanoma. N Engl J Med 2015. 373(1):23-34.
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Brahmer J, et al.. Nivolumab versus docetaxel in advanced squamous-cell 
non-small-cell lung cancer. N Engl J Med 2015. 373(2):123-135.
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Robert C, et al, KEYNOTE-006 Investigators. Pembrolizumab versus 
ipilimumab in advanced melanoma. N Engl J Med 2015. 372(26):2521-
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Robert C, 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. 
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Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, 
Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik 
AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine 
in ipilimumab-refractory or -naive melanoma. J Clin Oncol 2013. 
31(34):4311-4318.
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9.2
UNPUBLISHED REFERENCES
001-MCG-156_RD-01
Reference Document to Corporate Guideline: Handling of 
Missing and Incomplete AE Dates. Version 3.0
001-MCS-36-472
Corporate SOP: Standards and processes for analyses 
performed within Clinical Pharmacokinetics/
Pharmacodynamics. Version 3.0

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

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Table 10.1: 1 (con’t)
Immune-related adverse events of special interest
Hematologic (report as AESI if an irAE is ≥ Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)

Autoimmune haemolytic anaemia

Aplastic anaemia

Thrombotic thrombocytopenic purpura

Idiopathic (or immune) thrombocytopenia purpura

Disseminated intravascular coagulation

Haemolytic-uraemic syndrome

Any Grade 4 anaemia regardless of underlying mechanism
Hepatic (report as AESI if an irAE is ≥ Grade 2, or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)

Hepatitis

Autoimmune hepatitis

Transaminase elevations (ALT and/or AST)
Infusion Reactions (report as AESI for any grade)

Allergic reaction

Anaphylaxis

Cytokine release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
Neurologic (report as AESI for any grade)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as AESI if an irAE is ≥ Grade 2 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)

Uveitis

Iritis
Renal (report as AESI if an irAE is ≥ Grade 2)

Nephritis

Nephritis autoimmune

Renal failure

Renal failure acute

Creatinine elevations (report as an irAE if ≥ Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)

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Table 10.1: 1 (con’t)
Immune-related adverse events of special interest
Skin (report as AESI for any grade)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (report as AESI if an irAE is ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (report as AESI for any grade)

Myocarditis

Pancreatitis

Pericarditis

Any other Grade 3 event that is considered immune-related by the physician

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10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS
Management of immune-related adverse event toxicities associated with anti-PD-1 mAbs are 
presented below. BI 754091 and BI 754111 should be permanently discontinued for 
Grade 3-4 pneumonitis, Grade 3-4 adrenal insufficiency, Grade 4 diabetes mellitus, any 
grade encephalitis, Grade 4 hypophysitis, Grade 4 rash, Grade 3-4 or recurrent colitis 
of any grade, any recurrent Grade 3-4 AE, transaminase increased >5 times ULN or 
total bilirubin >3 times ULN (unless unequivocally attributably to another cause), 
inability to taper steroids to 10 mg or less prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to Grade 1 or less within 12 weeks.

Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
28 days.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
o
For Grade 3-4 events immediately treat with i.v. steroids. Administer additional 
anti-inflammatory measures, as needed.
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 3-4 
pneumonitis, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via i.v. infusion. For Grade 2 or higher diarrhea, 
consider gastro-intestinal (GI) consultation and endoscopy to confirm or rule out 
colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.
o
For Grade 3 or 4 diarrhea that persists >1 week, treat with i.v. steroids followed by 
high-dose oral steroids.
o
For Grade 3 or 4 colitis, or recurrent colitis of any grade, permanently discontinue
BI 754091 and BI 754111, and immediately treat with i.v. steroids followed by 
high-dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 3-4 or 
recurrent colitis of any grade, inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or persistent Grade 2-3 AEs that do not 
recover to Grade 1 or less within 12 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis) Grade 3, or
≥Grade 3 hyperglycaemia, if associated with ketosis (ketonuria) or metabolic acidosis

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o
For Type 1 diabetes mellitus Grade 3-4 or Grade 3-4 hyperglycaemia
•
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycaemia associated with metabolic 
acidosis or ketonuria.
•
Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated haemoglobin, and C-peptide.
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 4 
diabetes mellitus, any recurrent Grade 3 AE or persistent Grade 2-3 AE that does 
not recover to Grade 1 or less within 12 weeks.

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 28 days. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3 events, treat with an initial dose of i.v. corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 28 days. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
o
For Grade 4 events, permanently discontinue BI 754091 and BI 754111, and treat 
with an initial dose of i.v. corticosteroids followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days. Replacement of appropriate hormones may 
be required as the steroid dose is tapered.
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 4 
hypophysitis, any recurrent Grade 3 AE, inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or persistent Grade 2-3 AEs that do not 
recover to Grade 1 or less within 12 weeks.

Hyperthyroidism or Hypothyroidism:

Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
For Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism):
•
In hyperthyroidism, nonselective beta-blockers (e.g., propranolol) are 
suggested as initial therapy.
•
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
For Grade 3-4 hyperthyroidism
•
Treat with an initial dose of i.v. corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 28 days. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
BI 754091 and BI 754111 should be permanently discontinued for any recurrent 
Grade 3-4 AE, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.

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
Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with i.v. or oral corticosteroids
o
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 and BI 754111 should be permanently discontinued for any recurrent 
Grade 3-4 AE, transaminase increases >5 times ULN or total bilirubin >3 times 
ULN (unless unequivocally attributably to another cause), inability to taper 
steroids to 10 mg or less prednisone or equivalent within 12 weeks, or persistent 
Grade 2-3 AEs that do not recover to Grade 1 or less within 12 weeks.

Renal failure or nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 and BI 754111 should be permanently discontinued for any recurrent 
Grade 3-4 AE, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.

Adrenal insufficiency:
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 3-4 
adrenal insufficiency or persistent Grade 2 AEs that do not recover to Grade 1 or 
less within 12 weeks.

Rash:
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 4 rash, 
any recurrent Grade 3 AE or persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.

Encephalitis:
o
BI 754091 and BI 754111 should be permanently discontinued for any grade 
encephalitis.

Infusion reactions:
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.
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, permanently discontinue study drug(s).

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10.3
IRECIST
Immunotherapeutics may result in infiltration of immune cells leading to transient increase in 
the size in malignant lesions, or undetectable lesions becoming detectable. The criteria are 
identical to those of RECIST 1.1 in many respects but have been adapted to account for 
instances where an increase in tumour burden, or the appearance of new lesions, does not 
reflect true tumour progression. Key differences are described below. All responses defined 
using iRECIST criteria are designated with a prefix. iRECIST time-point and best overall 
responses will be recorded separately.
Confirming progression
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
unconfirmed progression (iUPD) and confirmed progression (iCPD). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD.
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is 
seen as evidenced by one or more of the following:

Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions
o
Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum
o
Continued unequivocal progression in non-target disease with an increase in 
tumour burden
o
Increase in size of previously identified new lesion(s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new lesions) 
or additional new lesions

RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). The prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response 
(BOR) providing that iCPD is not documented at the next assessment after iUPD.
New lesions
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in 
short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New Lesion-
Non-Target (NLNT) to allow clear differentiation from baseline target and non-target lesions.
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the sum of measures 
of original target lesions identified at baseline. Rather, these measurements will be collected 
on a separate table in the case record form.
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at 
least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression from 
iUPD with either an increase of at least 5 mm in the absolute value of the sum of NLT OR an 

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increase (but not necessarily unequivocal increase) in the size of NLNT lesions OR the 
appearance of additional new lesions

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Table 10.3: 1
Time-point (TP) iResponse
Target 
Lesions*
Non-Target 
Lesions*
New
Lesions*
Time Point Response
No prior 
iUPD**
Prior iUPD**; ***
iCR
iCR
No
iCR
iCR
iCR
Non-iCR/Non-
iUPD
No
iPR
iPR
iPR
Non-iCR/Non-
iUPD
No
iPR
iPR
iSD
Non-iCR/Non-
iUPD
No
iSD
iSD
iUPD with no 
change OR 
decrease from 
last TP
iUPD with no 
change OR 
decrease from last 
TP
Yes
NA
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥5 mm in SOM 
for NLT or any increase for NLNT) or 
number.
iSD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based 
in further increase in size of NT disease (need 
not meet RECIST 1.1 criteria for unequivocal 
PD)
iUPD
Non-iCR/Non-
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based 
on:
o further increase in SOM of at least 5 mm, 
otherwise remains iUPD
iUPD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based 
on further increase in:
o previously identified T lesion iUPD SOM ≥5 
mm and / or
o NT lesion iUPD (prior assessment - need not 
be unequivocal PD)
iUPD
iUPD
Yes
iUPD
Remains iUPD unless iCPD confirmed based 
on further increase in:
o previously identified T lesion iUPD ≥5 mm 
and / or
o previously identified NT lesion iUPD (need 
not be unequivocal) and /or
o size or number of new lesions previously 
identified
Non-iUPD/PD Non-iUPD/PD
Yes
iUPD
Remains iUPD unless iCPD confirmed based 
on
o increase in size or number of new lesions 
previously identified
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD would be the 
same.
** in any lesion category.
*** previously identified in assessment immediately prior to this TP.

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All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below.
Table 10.3: 2
iRECIST Best Overall Response (iBOR)
TPR1
TPR2
TPR3
TPR4
TPR5
iBOR
iCR
iCR
iCR, iPR, 
iUPD, NE
iUPD
iCPD
iCR
iUPD
iPR, iSD, NE
iCR
iCR
iCR, iPR, iSD, 
iUPD, NE
iCR
iUPD
iPR
iPR
iPR, iSD, 
iUPD, NE
iPR, iSD, 
iUPD, NE, 
iCPD
iPR
iUPD
iSD, NE
iPR
iPR
iPR, iSD, 
iUPD, NE
iPR
iUPD
iSD
iSD, iUPD, NEiSD, iUPD, 
iCPD, NE
iSD, iUPD, 
iCPD, NE
iSD
iUPD
iCPD
Anything
Anything
Anything
iCPD
iUPD
iUPD
iCPD
Anything
Anything
iCPD
iUPD
NE
NE
NE
NE
iUPD

NE = not evaluable that cycle.

Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation.

For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be 
assigned at each TPR but is not shown in the table for ease of presentation.

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10.4
SPECIFIC COUNTRY ADAPTIONS
Ethical conduct of the study (addendum to Section 8)
This study will be conducted according to the principles of the Declaration of Helsinki 
(adopted by the 18th World Medical Association (WMA) General Assembly, Helsinki, 
Finland, June 1964 and last amended by the 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013and are consistent with ICH/Good Clinical Practice, and applicable regulatory 
requirements subject data protection.
Public disclosure and publication policy (addendum to Section 8)
Public disclosure and publication policy will follow Centrale Commissie Mensgebonden 
Onderzoek (CCMO) requirements and is available on website of CCMO (R18_3257).
Compensation for injury (addendum to Section 8)
The sponsor/investigator has a liability insurance which is in accordance with article 7,
subsection 9 of the WMO.
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical 
Research in Humans of 23th June 2003). This insurance provides cover for damage to 
research subjects through injury or death caused by the study.
Use and storage of data / body material (addendum to Section 8.3.3)
All coded data will be kept by the sponsor. This link will remain at the trial site for a 
maximum of 30 years 
Plasma samples may be used for further methodological investigations (e.g., stability testing), 
however only data related to the analyte or bioanalytical assay will be generated by these 
investigations. The trial samples will be discarded not later than 5 years after the final trial 
report has been signed (see Section 5.3.2).
Biobanking for remainders (leftover) from mandatory tumor samples collected for the 
purposes of the clinical trial, which would otherwise be discarded, can be stored in a biobank 
for up to 30 years for future research.
Study updates (addendum to Section 8.6)
Start and end date of the study as well as annual progress reports and notification of (early) 
termination study will be passed on to the Ethics Committee (METc).

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
30 Oct 2018
EudraCT number
EU number
2017-005046-30
BI Trial number
1381-0003
BI Investigational Product(s)
[89Zr]Zr-BI 754111, BI 754091 and BI 754111
Title of protocol
An open label Phase I PET imaging study to 
investigate the bio-distribution and tumor uptake of 
[89Zr]Zr-BI 754111 in patients with advanced non-
small cell lung cancer and head and neck squamous 
cell carcinoma treated with BI 754111 in 
combination with BI 754091
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
1. Section 1.4
2. Section 8.1
3. Section 9.1
4. Section 10.4
Description of change
1. Change regarding risk due to radiation 
burden 
2. Deletion of wording refering to legal 
representative and addition of local Ethics 
Committee reference
3. Deletion of obsolete unpublished reference
4. New section
Rationale for change
1. Text adapted to better describe the risk due 
to radiation exposure and to correctly 
describe the risk category.
2. Ethics committee requirement
3. Section to address country specific 
requirements

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11.2
GLOBAL AMENDMENT 2
Date of amendment
27 Jan 2020
EudraCT number
EU number
2017-005046-30
BI Trial number
1381-0003
BI Investigational Product(s)
[89Zr]Zr-BI 754111, BI 754091 and BI 754111
Title of protocol
An open label Phase I PET imaging study to 
investigate the bio-distribution and tumor uptake of 
[89Zr]Zr-BI 754111 in patients with advanced non-
small cell lung cancer and head and neck squamous 
cell carcinoma treated with BI 754111 in 
combination with BI 754091
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
1. Flow chart
2. Blood sample flow chart
3. Section 1.4
4.
5. Section 3.1
6. Section 4.2.1
7. Section 5.1
8. Section 5.2.3
9. Section 5.2.6.1.4
10. Section 5.2.6.2.5
11. Section 5.4.1
12. Section 5.4.2
13. Section 5.6.2
14. Section 6.2
15. Section 9.1
16. Section 10.2 (Appendix) 
Description of change
1. Table and footnotes adapted for considering: 
a) “administration of pre-treatment 
medication”,

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b) optional biopsy at Cycle 1
c) changed timepoints for blood sampling,
d) changed timepoints for PET imaging
2. Table adapted for considering changed 
timepoints for PK radioactivity sampling,
BI754111 PK sampling and PET scan time 
points in cycles 1 and 2
3. Update on safety and efficacy information
4.
5. Adapted design for part 2
6. Change in pre-medication information
7. Correction 
8. Additional information in case of criteria for 
hepatic injury are fulfilled
9. Text related to AESI adapted for potential 
DILI events/hepatic injury and for infusion-
related reactions
10. Title correction and clarification on 
exempted events
11. Addition of optional biopsy at Cycle 1
12. Correction
13. Adaptation
14. Adaptation
15. Correction
16. Update
Rationale for change
1. Adaptations for considering: 
a) Prophylactic treatment to reduce the risk of 
infusion-related reaction –
b) Optional biopsies added to allow for 
 
 
 
 
 
 
c) Revised blood sampling time points: To better 
determine initial clearance, potential non-linearity 
due to major sink or internalization of [89Zr]Zr-
BI 754111 to determine if radioactivity 
concentration in blood correlates well with the 
image derived input function and the concentration 
of BI 754111. 
d) Change in PET scan timepoints has been made to 

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support kinetic based modelling of drug uptake in 
tumor lesions and organs/ tissues
2. See rational c) above
3. More recent safety and efficacy information 
has been added to update the benefit risk 
section of the protocol. In addition, the risk 
of infusion related reactions has been 
described
4.
5. Adapted design to consider the additional 
PET timepoints and the optional biopsy
6. 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
7. To correct erroneous reference
8. Language about drug-induced liver injury 
has been updated to clarify that the Potential 
DILI Checklist should always be completed 
when specified liver elevations occur.
9. Language about hepatic injury and potential 
DILI case has been updated to clarify the
criteria for liver abnormalities which prompt 
reporting as AESI and completion of 
potential DILI checklist. In addition, text has 
been added for pre-treatment medication 
prior to administration of the study treatment 
in order to reduce the risk of infusion related 
reactions and more detail has been provided 
on what to do in the event of a Grade 3 or 
higher infusion related reaction.
10. Clarification that hepatic injury does not 
apply for PD reporting exemption
11. Optional biopsy: same rational as above (1, 
b))
12. Text related to cytokines measurement has
been deleted as this does not apply in this 
trial
13. Adaptation for considering changed 
timepoints for PK radioactivity sampling in 
cycles 1 and 2
14. Adaptation for considering optional biopsy in 
C1 and changed timepoints for PK 
radioactivity sampling in C1 and C2
15. To correct for actual reference for iRECIST
16. To provide more detail on what to do in the 
event of an infusion related reaction

 
 
 
 
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An open label Phase I PET imaging study to investigate the bio-distribution and
tumor uptake of [89Zr]Zr-BI 754111 in patients with advanced non-small cell lung
cancer and head and neck squamous cell carcinoma treated with BI 754111 in
combination with BI 754091
Approval-Therapeutic Area 
27 Jan 2020 12:39 CET
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