An Open Label, Phase I Dose-finding Study of BI 754111 in Combination With BI 754091 in Patients With Advanced Solid Cancers Followed by Expansion Cohorts at the Selected Dose of the Combination in Patients With Non-small Cell Lung Cancer and Other Solid Tumors
Phase: PHASE1
Conditions: Neoplasms, Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c16043709-08
EudraCT No.:
2017-005042-29
BI Trial No.:
1381.2
BI Investigational 
Product:
BI 754111 and BI 754091
Title:
An open label, Phase I dose-finding study of BI 754111 in 
combination with BI 754091 in patients with advanced solid 
cancers followed by expansion cohorts at the selected dose of the 
combination in patients with non-small cell lung cancer and other 
solid tumors
Lay Title:
This study tests the new medicine BI 754111 alone or in 
combination with another new substance BI 754091 in patients 
with advanced cancer. The study tests different doses to find the 
best dose for continuous treatment.
Clinical Phase:
Phase I
Coordinating 
Investigator
Trial Clinical 
Monitor:
Phone: 
Fax: 
Status:
Final protocol (revised protocol [based on global Amendment 8])
Version and Date:
Version: 9.0
Date: 20 May 2020
Page 1 of 201
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
Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754111 and BI 754091
Protocol date:
09 Mar 2017
Trial number:
1381.2
Revision date:
20 May 2020
Title of trial:
An open label, Phase I dose-finding study of BI 754111 in combination with 
BI 754091 in patients with advanced solid cancers followed by expansion cohorts at 
the selected dose of the combination in patients with non-small cell lung cancer and 
other solid tumors
Clinical phase:
I
Objectives:
Part I (Dose-Escalation Cohorts):
The objectives of the dose-escalation portions of the trial are to:
∀
Investigate the safety, tolerability, and pharmacokinetics (PK) of escalating 
doses of BI 754111 in combination with BI 754091 (administered via
intravenous [i.v.] infusion once every 3 weeks [q3w]) in patients with advanced 
and/or metastatic solid tumours.
∀
Determine the maximum-tolerated dose (MTD) through monitoring dose-
limiting toxicities (DLTs) and/or to determine the dose of the combination of 
BI 754111 plus BI 754091 to be used in the expansion phase (Part II).
Part II (Dose-Expansion Cohorts):
The objectives of the dose-expansion portion of the trial are to:
∀
Further investigate the safety, tolerability, and PK of the selected expansion 
dose of the combination of BI 754111 plus BI 754091 in patients with non-
small-cell lung cancer (NSCLC), microsatellite stable (MSS) metastatic 
colorectal cancer (mCRC), or any anti-PD-1 or anti-PD-L1 pretreated solid 
tumour with high tumour mutational burden (TMB) and/or microsatellite 
instability high (MSI-H) and/or DNA mismatch repair deficient (MMRd),as 
defined in the entry criteria
∀
Explore the efficacy of the combination in patients with NSCLC, mCRC, or 
any solid tumour with high TMB and/or DNA MSI-H and/or MMRd (as 
defined in the entry criteria).
Methodology:
Part I (Dose-Escalation Cohorts):
For patients with solid tumours: open-label, non-randomised, dose-escalation 
into consecutive cohorts of BI 754111 in combination with BI 754091.
Dose escalation will be guided by Bayesian Logistic Regression Models
(BLRMs) with overdose control for BI 754111 + BI 754091 combination therapy.
Part II (Dose-Expansion Cohorts):
Open-label, non-randomised, dose-expansion cohorts with the selected dose of 
the combination in patients with NSCLC, MSS mCRC, or any anti-PD-1 or anti-
PD-L1 pretreated solid tumour with high TMB and/or MSI-H and/or DNA 
MMRd.
No. of patients: 
Part I (Dose-Escalation Cohorts):  Approximately 15 to 50 patients

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754111 and BI 754091
Protocol date:
09 Mar 2017
Trial number:
1381.2
Revision date:
20 May 2020
Part II (Dose-Expansion Cohorts): 160 patients total
Total entered:
Approximately 175 to 210 patients are planned to be enrolled in this trial.
Each treatment:
Part I: a minimum of 3 patients with solid tumours per dose-escalation cohort
Part II: 160 patients 
Diagnosis:
Part I (Dose-Escalation Cohorts):
Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic 
solid tumours
Part II (Dose Expansion Cohorts):
Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic 
solid tumours of one of the following types:
∀
Second and 3rd line NSCLC patients who progressed on anti-PD-1 or anti-
PD-L1 treatment after having achieved radiologically confirmed benefit 
(minimum of stable disease).
∀
Anti-PD-1 and anti-PD-L1 naïve second line or greater microsatellite stable 
mCRC. 
∀
Anti-PD-1 or anti-PD-L1 pretreated (can include BI 754091) patients with any 
solid tumour with TMB high (≥10 mutations/Mb) and/or MSI-H and/or DNA 
MMRd
∀
First line NSCLC patients with wildtype (wt) epidermal growth factor receptor 
[EGFR] and anaplastic lymphoma kinase [ALK] tumors of squamous or non-
squamous origin.
Main criteria
for inclusion:
All Cohorts:
∀
Adult patients at least 18 years-of-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
Part I (Dose-Escalation Cohorts):
∀
Patients with a confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours (any type) 
∀
For patients in Part I with solid tumours:
-
For whom no therapy of proven efficacy exists, or who are not 
amenable to standard therapies.
-
Must have measurable lesions according to Revised Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and 
iRECIST
-
Previous treatment with an anti-PD-1 mAb is allowed as long as the 
last administration of the anti-PD-1 mAb on the previous treatment is 
a minimum of 60 days prior to starting treatment in this trial.
Part II (Dose-Expansion Cohorts):

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754111 and BI 754091
Protocol date:
09 Mar 2017
Trial number:
1381.2
Revision date:
20 May 2020
All patients must have measurable disease according to RECIST Version 1.1, 
must have at least 1 tumour lesion amenable to biopsy, and must be medically fit 
and willing to undergo a biopsy before first treatment (if adequate archival tissue 
is not available) and, unless clinically contraindicated, after 6 weeks on therapy.
∀
2nd or 3rd-line NSCLC patients:
-
Must have progressed on anti-PD-1 or anti-PD-L1 treatment after 
having achieved radiologically confirmed benefit (minimum of stable 
disease)
-
Must have had a minimum duration of benefit of 4 months, and 
minimum treatment duration of 2 months on the previous anti-PD-1 or 
anti-PD-L1 treatment without experiencing disease progression during 
that period.  
-
The anti-PD-1- or anti-PD-L1-containing treatment must have been 
the latest treatment regimen prior to enrolling in this trial
-
Latest treatment must be within >4 and <12 weeks before their first 
dose in this trial. Patients who have had anti-PD-1 or anti-PD-L1 
monotherapy as their first-line NSCLC treatment regimen must have a 
PD-L1 expression level of ≥1% at baseline (local validated testing).
∀
Anti-PD-1 or anti-PD-L1 treatment naïve patients with microsatellite stable 
mCRC 
-
Patients must have had ≥1 lines of systemic treatment 
∀
Anti-PD-1 or anti-PD-L1 pretreated patients with high TMB (≥10 
mutations/Mb) and/or MSI-H and/or DNA MMRd solid tumours
∀
1st-line squamous or non-squamous NSCLC patients:
-
Patients must be treatment naïve
-
Must be EGFR WT and ALK WT (only applicable to patients with 
non-squamous NSCLC)
-
Regardless of PD-L1 expression level.  However, the number of 
patients with high level of PD-L1 expression (≥50% PD-L1) will be 
limited to a maximum of 10 (local validated testing)
Main criterion
for exclusion:
∀
No previous treatment with anti-lymphocyte-activation gene 3 (LAG-3; 
CD223) agents.
∀
Untreated brain metastasis(es) that may be considered active.
Test products:
BI 754111 and BI 754091
Doses:
Part I (Dose-Escalation Cohorts):
For patients with solid tumours: Increasing doses of BI 754111 starting with 
4 mg in combination with BI 754091 at the RPIID (240 mg q3w) or a lower dose
selected by the 1381.2 Safety Review Committee upon review of evolving data 
from Study 1381.1 (an ongoing study of BI 754091 using a BLRM with overdose 
control in patients with advanced solid tumours). Dose escalation of BI 754111 in 
combination with BI 754091 will be guided by a BLRM with overdose control.

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754111 and BI 754091
Protocol date:
09 Mar 2017
Trial number:
1381.2
Revision date:
20 May 2020
Part II (Dose-Expansion Cohorts):
The selected expansion dose of the combination determined in Part I for patients 
with solid tumours.
For all cohorts, administration will be on Day 1 of each 21-day cycle.
Mode of 
administration:
Intravenous infusion
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 Medical Monitor and the sponsor.
Patients may be treated beyond initial radiological progression on a case-by-case 
basis (and after discussion with the medical monitor), if the investigator feels that 
it is in the patient’s best interest and patient consents to this.
Endpoints
Part I (Dose-Escalation):
Primary Endpoint:
∀
MTD of the BI 754111 plus BI 754091 combination
∀
Number of patients experiencing DLTs during the combination MTD 
evaluation period (Cycle 1, the first cycle of BI 754111 plus BI 754091 
combination therapy) in patients with solid tumours
Main Secondary Endpoints:
∀
PK parameters will be calculated for BI 754111 and for BI 754091: Cmax and 
area under the curve (AUC)0-504.
∀
Number of patients experiencing DLTs from start of treatment until end of 
treatment (in all cycles)
∀
Objective response (OR) for patients with solid tumours:
-
Confirmed complete response (CR) and partial response (PR)
according to RECIST Version 1.1 for patients with solid tumours as 
assessed by the Investigator throughout the entire treatment period.
Part II (Dose-Expansion Cohorts):
Primary Endpoint:
∀
Objective response: confirmed CR and PR according to RECIST Version 1.1 as 
assessed by the Investigator during the entire treatment.
Secondary Endpoints:
∀
Duration of response is the duration from the date of first documented PR or 
CR according to RECIST Version 1.1 as assessed by the Investigator to the 
date of PD or death.
∀
Disease control (DC) (CR, PR, or stable disease [SD] according to RECIST 
Version 1.1, as assessed by the Investigator).
∀
Progression-free survival (PFS) is the duration from the date of first treatment 
to the date of PD or death.

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754111 and BI 754091
Protocol date:
09 Mar 2017
Trial number:
1381.2
Revision date:
20 May 2020
∀
Number of patients experiencing DLTs from start of treatment until end of 
treatment.
Safety criteria:
Adverse events (AEs) according to CTCAE Version 5, incidence of DLTs for
determination of the MTD (Part A dose-escalation cohorts only), results of physical 
examinations, laboratory evaluations, vital signs, and electrocardiograms (ECGs).
Statistical methods:
Part I: Dose escalation will be guided by BLRMs with overdose control that will be 
fitted to binary toxicity outcomes. The estimate of parameters will be updated as 
data are accumulated using BLRMs. At the end of dose escalation, the toxicity 
probability at each dose (combination) level will be calculated to determine an 
estimate of the selected expansion dose of the combination of BI 754111 plus
BI 754091. If there are too few or no DLTs for BLRM guided dose selection, PK 
and/or biomarker data will be taken into consideration for dose determination.
Part II: Efficacy response endpoints will be summarised descriptively. For OR and 
DC, the frequency and proportion of patients and 95% two-sided confidence 
interval will be presented. For PFS and duration of response, the median and 95% 
two-sided confidence interval will be presented using the Kaplan-Meier method.
No hypothesis testing is planned in this trial.

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FLOW CHART 1: BI 1381.2 (REFMAL 485) TRIAL ASSESSMENTS: PART I: SOLID TUMOUR 
DOSE-ESCALATION COHORTS
Flow Chart 1
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Escalation Cycles 1, 2, and 4
Cycle 3 and 5+
End-of-
Treatmentn
(EOT) Visit
30-Dayb
Safety 
Follow-up
PFS 
Follow-uph
Assessments (Days)
-28 to -1
1
2
4
8 (±1)
15 (±1)
1 (±2)
(within 7 
days of EOT)
(+2)
Informed Consentc
X
Inclusion/Exclusion Criteria
X
Medical History and Demographicsd
X
Physical Examinationd, e
X
X
Xe
X
X
X
ECOG Performance Statusd, e
X
X
Xe
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
12-Lead Digital Electrocardiogramd, f
X
X
X
X(C3,5,6,8,10,12, 
etc and C3D15)
X
(X)
Haematology and Clinical Chemistry Labsd
X
X
X
X
X
X
Troponinq
X
X (C4)
X (C1,2)
X (C1)
X (C3,5)
Urinalysisd
X
X
X
X
Pregnancy Test for Women of Child-Bearing 
Potentiald, g
X
Xg
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X

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FLOW CHART 1: BI 1381.2 (REFMAL 485) TRIAL ASSESSMENTS: PART I: SOLID TUMOUR DOSE ESCALATION COHORTS
(Continued)
Flow Chart 1
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Escalation Cycles 1, 2,and 4
Cycle 3 and 5+
End-of-
Treatmentn
(EOT) Visit
30-Dayb
Safety 
Follow-up
PFS 
Follow-uph
Assessments (Days)
-28 to -1
1
2
4
8 (±1)
15 (±1)
1 (±2)
(within 7 
days of EOT)
(+2)
Survivalh
X
Blood Samples for 
,o
X
Xo
Xo
Xo
Blood Samples for BI 754111 PKj,o
X
X
X
X
X
Xo
Xo
Xo
Blood Samples for BI 754091 PKj,o
X
X
X
X
X
Xo
Xo
Xo
Tumour Assessmentsd, k
X
Every 6 weeks ±3 days for the first 6 months (then every 9 weeks ±3 days thereafter)
Administration of Pre-Treatment Medicationp
X
X
Study Drug Infusionl
X
X
DLT Assessmentm
X
X
X
X
X
X
X

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Flow Chart 1 Footnotes (Solid Tumour Escalation)
a
All cycles are 3 weeks (21 days) in duration. Patients will continue treatment with the study drugs until disease progression (PD) by RECIST and/or iRECIST, 
withdrawal of patient consent, an unacceptable toxicity occurs, or 1 year of treatment is completed, whichever occurs first. Patients will be allowed to stay on 
treatment in the case of initial radiological PD, if the Investigator feels that it is in the patient’s best interest and the patient signs an informed consent describing 
this circumstance. In addition, patients benefiting clinically and without PD may stay on trial after 1 year on a case-by-case basis after discussion with the 
Medical Monitor and the sponsor. Day 1 of Cycle 1 is defined as the day when the combination of BI 754111 and BI 754091 is administered.
b
Days are calculated as calendar days.
c
Informed consent must be obtained ≤28 days prior to the initiation of treatment.
d
Safety laboratory assessments including hematology, serum biochemistry, and urinalysis will be performed locally. The screening medical history and 
demographics, physical examination and Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), 
haematology, clinical chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, bilirubin, lactate dehydrogenase, serum glucose, creatine phosphokinase [CPK:
if CPK is elevated, then CPK-MB, troponin I, and myoglobin should be reactively tested], serum urea nitrogen (or urea), serum uric acid, and thyroid panel 
[TSH, free T4, and free T3]), urinalysis, and screening pregnancy test should be done ≤14 days prior to initiation of treatment. Additionally, amylase and lipase 
should be analysed in case of symptoms of pancreatitis. If these assessments are performed within 72 hours of initiation of treatment, they do not need to be 
repeated on Cycle 1 Day 1 with the exception of the ECOG performance status, an abbreviated physical examination, vital signs (pre- and post-infusion), and a 
single ECG required prior to first trial dose. Tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment and copies may be 
collected by the sponsor or designee. Refer to Section 5.3 for additional details. Vital signs are checked at every visit.
e
Physical examinations will be done at screening, on Day 1 of each treatment cycle, at the end-of-treatment (EOT) visit, and at the 30-day safety follow-up visit. 
However, patients will have an additional abbreviated physical examination (focused on the specific disease, at the Investigator’s discretion) on Cycle 1 Day 15.
ECOG performance status will be done at screening, on Day 1 of Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, and at 
the 30-day follow-up visit.
f
Single digitalised ECGs must be done before blood work or other procedures after 5 minutes of rest at screening, on Day 1 of every cycle through Cycle 6 and 
then on Day 1 of every other cycle thereafter (Cycles 8, 10, 12, etc.), on Day 15 of Cycles 1 through 4, at the EOT visit, and whenever the Investigator deems it 
necessary. An ECG is optional at the 30-day safety follow-up visit if the EOT visit ECG was normal and no drug-related abnormalities were detected in on-trial
ECGs (see Section 5.3.3).
g
Women of child-bearing potential must have a serum beta human chorionic gonadotropin (β-HCG) pregnancy test at screening. Thereafter, this test can be done 
in either serum or urine on Day 1 of each cycle, and at the EOT visit (see Section 5.3.4.4).
h
Additional progression-free survival (PFS) follow-up visits after the 30-day safety follow-up visit will only be performed for patients who did not progress on 
treatment. These will be performed once every 12 weeks at least (by telephone) until PD, introduction of a new anti-cancer treatment, death, loss to follow-up, 
withdrawal of consent, or end of the whole trial.

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i
Blood samples 
 will be collected from all patients as presented in the tables in Appendix 10.4. Each sample will be split into 
3 aliquots to allow 
for both BI 754111 and BI 754091 with one back-up sample (see Section 5.6.1).
j
Pharmacokinetic (PK) blood sampling: there is extensive PK sampling for solid tumour cohorts during Cycles 1, 2, and 4. It is strongly recommended that the 
visit days and sampling time points outlined in the Appendix 10.4 tables be followed closely. The permitted visit windows noted in the table footnotes should 
only be used if medically indicated. Please note that there are separate assays for determination of BI 754111 and BI 754091. Therefore, when PK samples are 
drawn during combination dosing, 2 tubes must be drawn at each time point. In order to assess the stability of BI 754091 and BI 754111 in whole blood, one 
additional blood sample will be taken at 1 hour post infusion from all subjects of the first dose group that exceeds 200 mg BI 754111 (see Section 5.4.3).
k
Tumour assessments should be done according to RECIST v1.1 and/or iRECIST, and should include computed tomography/positron emission tomography 
(CT/PET) scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an 
appropriate method (CT/PET scan or magnetic resonance imaging [MRI]). The same radiographic procedure must be used throughout the trial. Assessments
will be performed by the Investigator at screening and every 2 cycles (6 weeks ±5 days) for the first 6 months of treatment, once every 3 cycles (9 weeks 
±5 days) thereafter, at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator and copies may be collected by the 
sponsor or designee.
l
Dosing of BI 754111 and BI 754091 will be determined by the Safety Review Committee and communicated to sites as each new cohort opens for recruitment. 
Refer to Sections 4.1.2.1, 4.1.2.2, and 4.1.3 for further details.
m
Dose-limiting toxicities (DLTs) will be collected throughout the trial and will be assessed for dose-escalation decisions following the first cycle of BI 754111 in 
combination with BI 754091 (see Section 4.1.5).
n
If the decision is made to permanently discontinue study treatments during a scheduled visit, both BI 754091 and BI 754111 should be discontinued together 
and the EOT visit should be performed instead of the scheduled visit.
o
PK 
 blood samplings are to be collected during Cycles 1 through 12, Cycle 14, Cycle 17, at the EOT visit, and the 30-day safety follow-up (see the 
tables in Appendix 10.4 for specifics).
p
Pre-treatment medications (antihistamine and acetaminophen or paracetamol) should be administered at sufficient time prior to initiation of infusion to allow the 
agents to exert their influence. 
q
A measurement of troponin-I is to be performed if possible. If troponin-I cannot be measured, troponin-T can be measured instead as long as this is marked in 
the database.  
Optional assessments are noted in parentheses. Please refer to the specific footnotes.

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FLOW CHART 2: BI 1381.2 (REFMAL 485) TRIAL ASSESSMENTS: PART II: DOSE-EXPANSION COHORTS
Flow Chart 2
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Expansion Cycles 1, 2, and 4
Cycles 3, 5+
End-of-
Treatmentn
(EOT) Visit
30-Dayb
Safety 
Follow-up
PFS, OS
Follow-
uph
Assessments (Days)
-28 to -1
1
2p
4p
8 (±1)
15 (±1)
1 (±2)
(within 7 
days of EOT)
(+2)
Informed Consentc
X
Inclusion/Exclusion Criteria
X
Medical History and Demographicsd
X
Physical Examinationd, e
X
X
Xe
X
X
X
ECOG Performance Statusd, e
X
X
Xe
X
X
Vital Signsd
X
X
X (C1)
X 
(C1, 
4)
X
X
X
X
X
12-Lead Digital Electrocardiogramd, f
X
X
X
Xf (C3,5,6,8,10, 12, 
etc and C3D15)
X
(X)
Haematology and Clinical Chemistry Labsd
X
X
X
X
X
X
Troponinr
X
X (C4)
X (C1,2)
X (C1)
X (C3,5)
Urinalysisd
X
X
X
X
Pregnancy Test for Women of Child-
Bearing Potentiald, g
X
Xg
Xg
Xg
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Survivalh
X

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FLOW CHART 2: BI 1381.2 (REFMAL 485) TRIAL ASSESSMENTS: PART II: DOSE-EXPANSION COHORTS (Continued)
Flow Chart 2
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Expansion Cycles 1, 2, and 4
Cycles 3, 5+
End-of-
Treatmentn
(EOT) Visit
30-Dayb
Safety 
Follow-up
PFS, OS
Follow-
uph
Assessments (Days)
-28 to -1
1
2 p
4 p
8 (±1)
15 (±1)
1 (±2)
(within 7 
days of EOT)
(+2)
Blood Samples for 
X
Xo
Xo
Xo
Blood Samples for BI 754111 PKj
(Cycles with extensive PKs are noted in 
parentheses)
X
(C1,4)
X
(C1,4)
X
(C1,4)
Xj(C8)
Xj
Xj
Blood Samples for BI 754091 PKj
(Cycles with extensive PKs are noted in 
parentheses)
X
(C1,4)
X
(C1,4)
X
(C1,4)
Xj(C8)
Xj
Xj
Blood Samples for Biomarkers 
X
(C1&2)
X (C1)
X (C1)
X
Plasma Samples for Biomarkers 
X
(C1&2)
X (C1)
X (C1)
X (C1)
X
Biopsyl
X
X (C3D1 only)
(X)
Tumour Assessmentsd, m
X
Every 6 weeks ±3 days for 6 months (then every 9 weeks ±3 days thereafter)
Administration of Pre-Treatment 
Medicationq
X
X
BI 754111 & BI 754091 Infusions
X
X

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Flow Chart 2 Footnotes (Expansion Cohorts)
a
All cycles are 3 weeks (21 days) in duration. Patients will continue treatment with the study drugs until disease progression (PD) by RECIST and/or iRECIST, 
withdrawal of patient consent, an unacceptable toxicity occurs, or 1 year of treatment is completed, whichever occurs first. Patients will be allowed to stay on treatment 
in the case of initial radiological PD, if the Investigator feels that it is in the patient’s best interest and the patient signs an informed consent describing this 
circumstance. In addition, patients benefiting clinically and without PD may stay on trial after 1 year on a case-by-case basis after discussion with the Medical Monitor 
and the sponsor. Day 1 of Cycle 1 is defined as the day when the combination of BI 754111 and BI 754091 is administered.
b
Days are calculated as calendar days.
c
Informed consent must be obtained ≤28 days prior to the initiation of treatment.
d
Safety laboratory assessments including haematology, serum biochemistry, and urinalysis will be performed locally. The screening medical history and demographics, 
physical examination and Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), haematology, clinical chemistry 
(sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase, bilirubin, lactate dehydrogenase, serum glucose, creatine phosphokinase [CPK: if CPK is elevated, then CPK-MB, 
troponin I, and myoglobin should be reactively tested], serum urea nitrogen [or urea], serum uric acid, and thyroid panel [TSH, free T4, and free T3]), urinalysis, and 
screening pregnancy test should be done ≤14 days prior to initiation of treatment. Additionally, amylase and lipase should be analysed in case of symptoms of 
pancreatitis. If these assessments are performed within 72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 Day 1 with the exception of the 
ECOG performance status, an abbreviated physical examination, vital signs (pre- and post-infusion), and a single ECG required prior to first trial dose. Tumour 
assessments (scans) should be performed ≤28 days prior to initiation of treatment and copies may be collected by the sponsor or designee. Refer to Section 5.3 for 
additional details. Vital signs are checked at every visit.
e
Physical examinations will be done at screening, on Day 1 of each treatment cycle, at the end-of-treatment (EOT) visit, and at the 30-day safety follow-up visit. 
However, patients will have an additional abbreviated physical examination (focused on the specific disease, at the Investigator’s discretion) on Cycle 1 Day 15. ECOG 
performance status will be done at screening, on Day 1 of Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, and at the 30-day 
follow-up visit.
f
Single digitalised ECGs (or analog ECG if digital not available) must be done before blood work or other procedures after 5 minutes of rest at screening, on Day 1 of 
every through Cycle 6 and then every other cycle thereafter (Cycles 8, 10, 12, etc.), on Day 15 of Cycles 1 through 4, at the EOT visit, and whenever the Investigator 
deems it necessary. An ECG is optional at the 30-day safety follow-up visit if the EOT visit ECG was normal and no drug-related abnormalities were detected in on-
trial ECGs (see Section 5.3.3).
g
Women of child-bearing potential must have a serum beta human chorionic gonadotropin (βHCG) pregnancy test at screening. Thereafter, this test can be done in either 
serum or urine on Day 1 of each cycle, and at the EOT visit (see Section 5.3.4.4).
h
Patients enrolled in Protocol Version 4.0 or later: Additional overall survival (OS) and progression-free survival (PFS) follow-up visits after the 30-day safety 
follow-up visit will be performed once every 12 weeks at least (by telephone) until death, loss to follow-up, withdrawal of consent, or end of the whole trial. Patients 
enrolled in Protocol Version 3.0 and earlier: Additional PFS follow-up visits after the 30-day safety follow-up visit will only be performed for patients who did not 
progress on treatment. These will be performed once every 12 weeks at least (by telephone) until PD, introduction of a new anti-cancer treatment, death, loss to follow-
up, withdrawal of consent, or end of the whole trial.

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j
Pharmacokinetic (PK) blood sampling: there is more intensive PK sampling during Cycles 1, 4, and 8 of dose-expansion. PK samples are also taken pre-treatment on 
Day 1 of all other cycles through Cycle 9 and then on Day 1 of every 3rd cycle. It is strongly recommended that the visit days and sampling time points outlined in the 
Appendix 10.4.2 table be followed closely. The permitted visit windows noted in the table footnotes should only be used if medically indicated. Please note that there
are separate assays for determination of BI 754111 and BI 754091. Therefore, when PK samples are drawn during combination dosing, 2 tubes must be drawn at each 
time point.
l
All patients in Part II (dose-expansion cohorts) must have tissue samples (fresh or archived [see requirements]) available for retrospective central PD-L1 testing. The 
following will be required (see Section 5.5.2.3 for details):
-
A minimum of 2 core needle biopsies or 1 punch biopsy must be taken between screening and the day before first treatment with BI 754091. Otherwise, two
core needle biopsies or 1 punch biopsy (refer to lab manual for specifications) from the most recent relapse (if within 6 months of trial start with no subsequent 
therapy) are acceptable.
-
Two core-needle biopsies or 1 punch biopsy on treatment at the end of Cycle 2 (after 6 weeks of treatment), preferably from the same lesion.
-
Another biopsy (optional) should be taken upon PD (according to RECIST v1.1 and iRECIST), if possible. An optional biopsy should also be taken if a patient 
has stable disease (SD) over 3 subsequent disease assessment periods.
m
Tumour assessments should be done according to RECIST v1.1 and iRECIST and should include computed tomography/positron emission tomography (CT/PET) scans 
of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method 
(CT/PET scan or magnetic resonance imaging [MRI]). The same radiographic procedure must be used throughout the trial. In case of suspected (but not confirmed) 
bone metastasis at screening, tumour assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative 
imaging (X-ray or CT scan) should be performed. Correlative imaging should then be repeated at each tumour assessment (see Section 5.2.1 for more detail). 
Assessments will be performed by the Investigator at screening and every 2 cycles (6 weeks ±5 days) for the first 6 months of treatment, once every 3 cycles (9 weeks 
±5 days) thereafter, at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator and copies may be collected by the sponsor 
or designee.
n
If the decision is made to permanently discontinue study treatments during a scheduled visit, both BI 754091 and BI 754111 should be discontinued together and the 
EOT visit should be performed instead of the scheduled visit assessments.
p
The clinic will telephone the patients on Days 2 and 4 of Cycle 2 and Day 2 of Cycle 4 in order to check on any adverse events. The patients will not be required to go 
to the clinic on these days.  

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q
Pre-treatment medications (antihistamine and acetaminophen or paracetamol) should be administered at sufficient time prior to initiation of infusion to allow the agents 
to exert their influence. 
r
A measurement or troponin-I is to be performed if possible. If troponin-I cannot be measured, troponin-T can be measured instead as long as this is marked in the 
database.
Optional assessments are noted in parentheses. Please refer to the specific footnotes.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1: BI 1381.2 (REFMAL 485) TRIAL ASSESSMENTS: PART I:
SOLID TUMOUR DOSE-ESCALATION COHORTS ....................................7
FLOW CHART 2: BI 1381.2 (REFMAL 485) TRIAL ASSESSMENTS: PART II: 
DOSE-EXPANSION COHORTS......................................................................11
TABLE OF CONTENTS ......................................................................................................16
ABBREVIATIONS................................................................................................................21
1.
INTRODUCTION...............................................................................................23
MEDICAL BACKGROUND.............................................................................23
1.1
DRUG PROFILES..............................................................................................24
1.2
1.2.1
BI 754111 .............................................................................................................24
1.2.2
BI 754091 .............................................................................................................24
2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT .......25
RATIONALE FOR PERFORMING THE TRIAL.........................................25
2.1
TRIAL OBJECTIVES........................................................................................27
2.2
2.2.1
Part I (dose-escalation cohorts) objectives........................................................27
2.2.2
Part II (dose-expansion cohorts) objectives......................................................28
BENEFIT-RISK ASSESSMENT.......................................................................28
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................31
OVERALL TRIAL DESIGN AND PLAN .......................................................31
3.1
3.1.1
Administrative structure of the trial .................................................................34
3.1.2
Safety Review Committee...................................................................................34
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUPS.........................................................................................35
SELECTION OF TRIAL POPULATION .......................................................35
3.3
3.3.1
Main diagnosis for trial entry ............................................................................35
3.3.2
Inclusion criteria .................................................................................................35
3.3.3
Exclusion criteria ................................................................................................37
3.3.4
Removal of patients from therapy or assessments...........................................40
Removal of individual patients .............................................................................40
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................41
3.3.4.2
4.
TREATMENTS...................................................................................................42
INVESTIGATIONAL TREATMENTS ...........................................................42
4.1
4.1.1
Identity of the investigational medicinal products...........................................42
BI 754111..............................................................................................................42
4.1.1.1
BI 754091..............................................................................................................42
4.1.1.2
4.1.2
Selection of doses in the trial..............................................................................43

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Starting dose of BI 754111 ...................................................................................43
4.1.2.1
Starting dose of BI 754091 ...................................................................................43
4.1.2.2
4.1.3
Dose-escalation scheme.......................................................................................43
4.1.4
Dose modifications ..............................................................................................44
4.1.5
Definition of dose-limiting toxicity ....................................................................45
4.1.6
Definition of maximum-tolerated dose..............................................................46
4.1.7
Definition of evaluable patient...........................................................................47
4.1.8
Method of assigning patients to treatment groups...........................................47
4.1.9
Administration of doses for each patient..........................................................47
4.1.10
Blinding and procedures for unblinding...........................................................48
4.1.11
Packaging, labelling, and re-supply...................................................................48
4.1.12
Storage conditions...............................................................................................48
4.1.13
Drug accountability.............................................................................................48
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
CONCOMITANT MEDICATIONS, AND RESTRICTIONS .......................49
4.2.1
Other treatments and emergency procedures..................................................49
4.2.2
Concomitant medications...................................................................................49
Permitted concomitant medications......................................................................49
4.2.2.1
Prohibited concomitant medications.....................................................................50
4.2.2.2
4.2.3
Restrictions ..........................................................................................................50
Restrictions on diet and life style..........................................................................50
4.2.3.1
Restrictions regarding women of childbearing potential......................................50
4.2.3.2
TREATMENT COMPLIANCE........................................................................51
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................52
TRIAL ENDPOINTS..........................................................................................52
5.1
5.1.1
Primary endpoints...............................................................................................52
5.1.2
Secondary endpoints...........................................................................................52
Secondary endpoints of Part I (dose escalation) of the trial .................................52
5.1.2.1
Secondary endpoints of Part II (dose expansion) of the trial................................53
5.1.2.2
ASSESSMENT OF EFFICACY........................................................................54
5.2
5.2.1
Tumour assessments ...........................................................................................54
ASSESSMENT OF SAFETY.............................................................................55
5.3
5.3.1
Physical examinations and ECOG performance status...................................55
5.3.2
Vital signs.............................................................................................................55
5.3.3
Electrocardiograms.............................................................................................56
5.3.4
Safety laboratory parameters ............................................................................56
Haematology.........................................................................................................56
5.3.4.1
Biochemistry.........................................................................................................56
5.3.4.2
Urinalysis ..............................................................................................................57
5.3.4.3
Pregnancy test .......................................................................................................57
5.3.4.4
5.3.5
Other safety parameters.....................................................................................57
5.3.6
Assessment of adverse events.............................................................................57
Definition of adverse event...................................................................................57
5.3.6.1
Definition of adverse reaction...............................................................................58
5.3.6.2

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Definition of serious adverse events.....................................................................58
5.3.6.3
Adverse events considered ‘Always Serious’.......................................................58
5.3.6.4
Adverse events of special interest (AESIs)...........................................................59
5.3.6.5
5.3.6.5.1
Dose-limiting toxicities (DLTs)............................................................................59
5.3.6.5.2
Immune-related adverse events (irAEs)................................................................59
5.3.6.5.3
Infusion-related reactions......................................................................................59
5.3.6.5.4
Hepatic injury and potential drug-induced liver injury (DILI).............................60
Severity of adverse events.....................................................................................62
5.3.6.6
Causal relationship of adverse events ...................................................................62
5.3.6.7
Adverse event collection and reporting ................................................................63
5.3.6.8
5.3.6.8.1
Adverse event collection.......................................................................................63
Pregnancy..............................................................................................................65
5.3.6.9
Exemptions to AE/SAE Reporting .......................................................................65
5.3.6.10
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................66
5.4.1
Assessment of pharmacokinetics .......................................................................66
5.4.2
Methods of sample collection for pharmacokinetic analyses..........................66
5.5.1
Methods of sample collection .............................................................................68
APPROPRIATENESS OF MEASUREMENTS..............................................70
5.7
6.
INVESTIGATIONAL PLAN.............................................................................71
VISIT SCHEDULE.............................................................................................71
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................71
6.2
6.2.1
Screening period..................................................................................................72
Baseline conditions ...............................................................................................72
6.2.1.1
Medical history .....................................................................................................72
6.2.1.2
Concomitant therapies...........................................................................................72
6.2.1.3
6.2.2
Treatment period ................................................................................................72
6.2.3
Follow-up period and trial completion..............................................................73
End-of-treatment visit ...........................................................................................73
6.2.3.1
30-day post-treatment safety visit.........................................................................73
6.2.3.2
Progression-free survival visits.............................................................................73
6.2.3.3
Overall survival visits ...........................................................................................73
6.2.3.4
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................74

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STATISTICAL DESIGN - MODEL.................................................................74
7.1
7.1.1
Statistical design – Part I (dose escalation).......................................................74
Combination BLRM .............................................................................................74
7.1.1.1
Statistical model assessment.................................................................................78
7.1.1.2
7.1.2
Statistical design – Part II (dose expansion cohorts) .......................................79
NULL AND ALTERNATIVE HYPOTHESES ...............................................79
7.2
PLANNED ANALYSES.....................................................................................79
7.3
7.3.1
Primary endpoint analyses.................................................................................79
Primary endpoint analyses for Part I.....................................................................79
7.3.1.1
Primary endpoint analyses for Part II ...................................................................79
7.3.1.2
7.3.2
Secondary endpoint analyses .............................................................................80
Secondary endpoint analyses for Part I.................................................................80
7.3.2.1
Secondary endpoint analyses for Part II ...............................................................80
7.3.2.2
7.3.4
Safety analyses.....................................................................................................81
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................82
INTERIM ANALYSES ......................................................................................82
7.4
HANDLING OF MISSING DATA ...................................................................83
7.5
RANDOMISATION ...........................................................................................83
7.6
DETERMINATION OF SAMPLE SIZE .........................................................83
7.7
7.7.1
Determination of sample size for Part I............................................................83
7.7.2
Determination of sample size for Part II ..........................................................83
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................87
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................87
DATA QUALITY ASSURANCE ......................................................................88
8.2
RECORDS...........................................................................................................88
8.3
8.3.1
Source documents ...............................................................................................88
8.3.2
Direct access to source data and documents.....................................................89
8.3.3
Storage period of records ...................................................................................89
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................90
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........90
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................90
TRIAL MILESTONES.......................................................................................91
8.6
9.
REFERENCES....................................................................................................92
PUBLISHED REFERENCES............................................................................92
9.1
UNPUBLISHED REFERENCES......................................................................97
9.2
10.
APPENDICES.....................................................................................................98
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....98
10.1
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS............100
10.2
HANDLING PROCEDURES FOR BLOOD SAMPLES FOR PLASMA 
10.3
CONCENTRATION-TIME MEASUREMENTS .........................................104

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TIME SCHEDULES FOR PHARMACOKINETIC, BIOMARKER, AND 
10.4
IMMUNOGENICITY BLOOD SAMPLING ................................................105
10.4.1
Schedules for PK, immunogenicity blood sampling – Part I dose-escalation 
cohorts................................................................................................................105
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.5
AND DATA SCENARIOS ...............................................................................110
10.5.1
Hypothetical data scenarios .............................................................................110
10.5.2
Operating Characteristics................................................................................113
11.
DESCRIPTION OF GLOBAL AMENDMENTS..........................................117

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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
CEOI
Plasma concentration at the end of infusion
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
Drug clearance
CLIA
Clinical Laboratory Improvement Amendments
CNS
Central nervous system
Cpre
Plasma concentration pre-dose
CR
Complete response/remission
CRu
Complete remission unconfirmed
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
DILI
Drug-induced liver injury
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EF
Ejection fraction
eGFR
Estimated glomerular filtration rate
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EOT
End-of-treatment visit
EWOC
Escalation with overdose control
FDG
Fluoro-deoxyglucose
FFPE
Formalin fixed and paraffin embedded
GCP
Good Clinical Practice
GEP
Gene-expression profile
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council Harmonisation
irAE
Immune-related adverse events
IRB
Institutional review board
iRECIST
Guidelines for response criteria for use in trials testing immunotherapeutics
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous

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LAG-3
Lymphocyte-activation gene 3
mAb
Monoclonal antibody
MAP
Meta-analytic predictive (approach)
mCRC
Metastatic colorectal cancer
MDSC
Myeloid-deprived suppressor cell
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHC-II
Major histocompatibility complex Class II
MRI
Magnetic resonance imaging
MSI-H
Microsatellite instability high
MTD
Maximum-tolerated dose
NSCLC
Non-small cell lung cancer
OR
Objective response
ORR
Objective-response rate
PBMC
Peripheral blood mononuclear cell
PD
Progression of disease
PD-1
Programmed cell death 1 (receptor)
PDc
Pharmacodynamics
PD-L1
Programmed cell death ligand 1
PET
Positron-emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial response/remission
q3w
Once every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual-effect period
RO
Receptor occupancy (assay)
RPIID
Recommended Phase II dose
SAE
Serious adverse event
SOP
Standard operating procedure
SRC
Safety Review Committee
TMB
Tumour mutational burden
T-regs
Regulatory T-cells
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal

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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
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).
Tumours use the immune-checkpoint pathways (such as the PD-1 and LAG-3 pathways) to 
evade anti-tumour immune responses. Tumour-infiltrating lymphocytes frequently express 
high levels of PD-1 in combination with other immune-checkpoint inhibitors including 

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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 tumour microenvironment. 
Engagement of the co-inhibitory receptors PD-1 and LAG-3 by their respective ligands 
inhibits T-cell function preventing an anti-tumour immune response. It is now well 
established that blockade of the PD-1 axis of the immune-checkpoint program results in 
reactivation of T-cell function and the antitumour immune response leading to tumour growth 
inhibition in some patients. Treatment of patients with advanced melanoma, non-small-cell 
lung cancer (NSCLC), renal cell carcinoma, and many other tumour 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).
DRUG PROFILES
1.2
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
BI 754091
BI 754091 is a humanised IgG4Pro isotype mAb that is also being developed as an i.v.
infusion for the treatment of cancer. BI 754091 has highly human frameworks and a low 
predicted immunogenicity score. The BI 754091 molecule has a molecular weight of 
approximately 148 kilodaltons. The antibody is composed of 2 heavy chains (446 amino 
acids each) and 2 light chains (218 amino acids each). The 4 polypeptide chains of the 
antibody are linked together by disulfide bonds. Each heavy chain contains one consensus 
sequence for N-linked glycosylation.
For a more detailed descriptions of the BI 754091 and BI 754111 profiles please refer to the 
respective Investigator’s Brochures (IBs).

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2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Most patients with locally advanced or metastatic tumours will succumb to their disease, 
justifying the substantial need for novel therapeutic strategies to improve the outcome for 
patients with advanced or metastatic malignancies.
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-
tumour activity and improved clinical outcome in a higher percentage of patients compared to 
checkpoint-inhibitor monotherapy. Clinical proof-of-concept for combination checkpoint-
inhibitor treatment has come from clinical trials evaluating the safety and efficacy of 
combination PD-1 and CTLA4 mAb in patients with advanced NSCLC, small-cell lung 
cancer, and melanoma. For example, the combination of nivolumab (anti-PD-1 mAb) with 
ipilimumab (anti-CTLA-4 mAb) in patients with small-cell lung cancer increased objective-
response rate (ORR) to 19% to 20% compared to 10% with nivolumab monotherapy (R16-
2707). In previously untreated patients with advanced melanoma, the combination of 
nivolumab and ipilimumab increased median progression-free survival (PFS) to 11.5 months 
from a PFS of 2.9 and 6.9 months achieved by ipilimumab or nivolumab monotherapies, 
respectively, in patients with low PD-L1 levels (R15-3696). The combination of nivolumab 
and ipilimumab has also resulted in significant improvement in ORR in patients with 
previously untreated NSCLC (39% to 47% for ipilimumab dosed every 6 week or every 
12 weeks, respectively) compared to the 23% ORR achieved by nivolumab monotherapy 
(R16-5545). Unfortunately, the improved efficacy of combined PD-1/CTLA4 came at the 
expense of safety. Grade 3 and 4 adverse event (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 (R15-3696; R16-5544). These findings clearly underscore the need for 
the development of more efficacious and better-tolerated alternative immunotherapy 
combinations.
Multiple other immune-checkpoint inhibitor combinations are currently in development 
including the combination of anti-PD-1 and anti-LAG-3 mAbs with encouraging preliminary 
results. Tumour-infiltrating lymphocytes not only express PD-1, but frequently co-express 
LAG-3 (R16-0872). Upon binding of PD-1 and LAG-3 to their respective ligands (PD-
L1/PD-L2 and MHC-II, respectively), an intracellular signal negatively regulating T-cell 
responses is induced. Combined neutralisation of PD-1 and LAG-3, using antagonistic mAbs, 
is expected to enhance reactivation of T-cells and improve tumour rejection beyond the level 
achieved by PD-1 neutralisation alone. This has been demonstrated in both in vitro and 
in vivo models (R16-0852, R16-0881). Therefore, compared to anti-PD-1 monotherapy, 

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combined blockade of the co-inhibitory receptors PD-1 and LAG-3 has the potential to better 
restore T-cell functionality and improve objective responses (ORs) and prolongation of 
overall survival in cancer patients. The combination of nivolumab and BMS-986016 (anti-
LAG-3 mAb) has recently been shown to have antitumour activity and an acceptable safety 
profile in multiple solid tumours and hematological malignancies (R16-5204; R16-5218).
Collectively, the currently available data clearly demonstrate the clinical benefits that patients 
with many tumour types gain from checkpoint-inhibitor monotherapy. It is also clear that 
combination checkpoint-inhibitor treatment has resulted in improved efficacy 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 LAG3. 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 patients with NSCLC
(R15-3696; R16-0852; R16-0868, R16-0881; R16-2707; R16-5335; R16-5545).
Multiple immune checkpoint inhibitors have been approved for the treatment of patients 
metastatic NSCLC including pembrolizumab, nivolumab and atazolizumab. In second line 
NSCLC, blockade of the PD-1 pathway with an anti-PD-1 or anti-PD-L1 mAbs results in 
significant improvement in response rate (approximately 20 % Vs. 9%)  and a significant 
improvement in overall survival (approximately 3 months) compared to standard of care 
chemotherapy (R16-0878; R15-3715; R16-1875; R16-5828).
It is postulated that treating patients with immune checkpoint inhibitor early in their treatment 
continuum, while there immune system is still relatively intact, may maximize the chance of 
response and prolonged survival.  To this end, immune checkpoint inhibitors have made 
remarkable changes to the standard of care for previously untreated patients with advanced 
NSCLC. Pembrolizumab monotherapy resulted in significant improvement in response rates, 
progression free survival and overall survival in previously untreated patients with NSCLC 
whose tumors express high level expression of PD-L1 of (to ≥50%) when compared to 
standard of care chemotherapy (R16-4803). As a result, pembrolizumab monotherapy is a 
now well-established treatment of choice as the replacement for cytotoxic chemotherapy in 
the first-line (R16-4803). However, approximately half the patients treated with 
pembrolizumab in this setting do not respond (response rate of 44.8%) and will require other 
immune therapy combination to achieve clinical benefit.  Indeed, recent data have 
demonstrated that response rates in previously untreated NSCLC by combining 
pembrolizumab with chemotherapy can be improved (approximately 61% and 48%-55%) in 
patients with ≥50% and ≥1% PD-L1 expression, respectively, by combination of 
pembrolizumab with chemotherapy (R16-4804; P18-03589).  However, the combination of 
pembrolizumab with chemotherapy is associated with a significant increase in toxicity, owing 
to the chemotherapy component, than checkpoint inhibitor monotherapy (R16-4804; P18-
03589). Therefore, finding more tolerable, less toxic checkpoint inhibitor combination to treat 
previously untreated NSCLC patients is of immense interest. As such, this trial aims to test 
the safety and efficacy of chemotherapy-sparing combination of BI 754091 with BI 754111 
in patients with previously untreated NSCLC.  The combination of BI 754091 with 

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BI 754111 has the potential to be less toxic than chemotherapy containing regimens and 
would reserve chemotherapy as a subsequent line of treatment for patients whose disease 
progresses.
Checkpoint inhibitor therapy has also proven effective (approximately 30-40% of patients
achieved objective response) in a subset of patients with MSI-H or DNA mismatch repair 
deficient metastatic colorectal cancer (mCRC) which tend to be highly immunogenic cancers 
(R16-1497; R18-1746). However, these characteristics occur only in a small fraction of 
mCRC (~5%).  The majority of mCRC patients are microsatellite stable for whom single 
agent immunotherapy has not been successful. As such, this trial will evaluate the utility of 
the combination BI754091 (anti-PD-1 mAb) with BI754111 (anti-LAG-3 mAb) in this 
microsatellite stable mCRC population who have progressed on the standard of care, a 
population with very high unmet medical need. 
The trial will also include a cohort of patients with solid tumours whose disease progressed 
while taking an anti-PD-1 or anti-PD-L1 regimen and whose tumours have high tumour 
mutational burden (TMB; defined as ≥ 10 mutations/megabase of DNA) or high
microsatellite instability (MSI-H). Both TMB-high and MSI-H are good predictive 
biomarkers of immunogenic tumours and response to immune checkpoint inhibitor therapy 
(R18-1492). As outlined above, the objective of this cohort is to explore the ability of the 
checkpoint inhibitor combination to restore immunotherapy responsiveness in this subset of 
anti-PD-1 or anti-PD-L1 resistant (both primary and acquired) with good predictive markers 
for response. If successful, such a regimen may provide a second immunotherapy treatment 
option with the potential for durable clinical benefit and possibly delay the need to initiate 
chemotherapy in some patients. 
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.
This 2-part trial is the first study with BI 754111 in humans and the second with BI 754091. 
The first part will include dose-escalation cohorts to determine the maximum-tolerated dose 
(MTD) and/or the selected expansion dose. The second part includes expansion cohorts at the 
selected expansion dose that will further evaluate the safety, tolerability, PK, biomarkers and 
the preliminary efficacy of the BI 754111 plus BI 754091 combination. The dose-escalation 
portion of the trial will enrol patients with advanced and/or metastatic solid tumours, while 
the dose-expansion portion will enrol patients with advanced and/or metastatic NSCLC,
previously treated microsatellite stable metastatic colorectal cancer (mCRC), or any anti-PD-
1 or anti-PD-L1 pretreated solid tumour with high tumour mutational burden (TMB ≥10 
mut/MB) and/or microsatellite instability high (MSI-H) and/or DNA mismatch repair 
deficient (MMRd).
TRIAL OBJECTIVES
2.2
2.2.1
Part I (dose-escalation cohorts) objectives
The objectives of the dose-escalation portions of the trial are to:

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∀
Investigate the safety, tolerability, and pharmacokinetics (PK) of escalating doses of 
BI 754111 in combination with BI 754091 (administered via intravenous [i.v.] infusion 
once every 3 weeks [q3w]) in patients with advanced and/or metastatic solid tumours.
∀
Determine the MTD through monitoring dose-limiting toxicities (DLTs) and/or to 
determine the dose of the combination of BI 754111 plus BI 754091 to be used in the 
expansion phase (Part II).
2.2.2
Part II (dose-expansion cohorts) objectives
The objectives of the dose-expansion portion of the trial are to:
∀
Further investigate the safety, tolerability, and PK of the selected expansion dose of the 
combination of BI 754111 plus BI 754091 in patients with NSCLC, microsatellite stable 
(MSS) metastatic colorectal cancer (mCRC), or any anti-PD-1 or anti-PD-L1 pretreated 
solid tumour with high tumour mutational burden (TMB) and/or microsatellite instability 
high (MSI-H), and/or DNA mismatch repair deficient (MMRd) as defined in the entry 
criteria [see Section 3.3].
∀
Explore the efficacy of the combination in patients with NSCLC, mCRC, or any solid 
tumour with high TMB and/or MSI-H and/or DNA MMRd (as defined in the entry 
criteria).
BENEFIT-RISK ASSESSMENT
2.3
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-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). Immune-
related AEs affect mainly the gastrointestinal tract (including diarrhoea 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 immune-related adverse 
event (irAE) (R16-0763; R16-0899).

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As previously mentioned, significant improvement in checkpoint inhibitor effect has been 
achieved with checkpoint inhibitor combination therapy. The combination of nivolumab and 
ipilimumab, for example, has resulted in significant improvement in ORR, compared to 
checkpoint inhibitor monotherapy in patients with NSCLC and melanoma (R16-5545, R15-
3696; R16-5544). Unfortunately, the improved efficacy of combined nivolumab and 
ipilimumab was associated with a significant increase in the rate and severity of AEs. Grade 3 
and 4 AE rates of 53% to 55% were reported with the full-dose combination of nivolumab 
and ipilimumab in patients with melanoma (R15-3696; R16-5544) and 33% to 37% with 
reduced dose and dosing frequency of the ipilimumab component in NSCLC compared to 
approximately 10% for nivolumab monotherapy in these populations (R15-3696; R16-5544).
Treatment with BI 754111 and BI 754091 is anticipated to be associated with a similar 
pattern of AEs. 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.
BI 754111 or BI 754091/BI 754111 combination treatment should be permanently 
discontinued for Common Terminology Criteria for Adverse Events (CTCAE) Version 5
Grade 3 or 4 pneumonitis, Grade 3 or 4 adrenal insufficiency, Grade 3 or 4 or recurrent colitis 
of any grade, Grade 4 diabetes mellitus, Grade 4 hypophysitis, Grade 4 rash, any grade 
encephalitis, any recurrent Grade 3 or 4 AE, transaminase values >5 times the upper limit of 
normal (ULN) or total bilirubin >3 times ULN, inability to taper steroids to 10 mg or less 
prednisone 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.
Please refer to the current version of the BI 754111 Investigator Brochure for the latest 
information on patients treated with BI 754111/BI 754091.
Based on pre-clinical data as well as clinical data obtained so far with BI 754091 as well as 
the combination of BI 754091 and BI 754111, the inhibitory effects of the combination of 
BI 754111 and BI 754091 may translate into a clinical benefit in cancer patients.
The benefit/risk ratio continues to be considered positive for patients with advanced cancers.  
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, the potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 

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evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters to 
ensure patients safety (see Section 5.3.6.5.4).

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a Phase I, open-label, non-randomised, multicentre trial of BI 754111 administered in 
combination with BI 754091 that will be conducted in 2 parts. The Part I portion of the trial
will consist of consecutive dose-escalation cohorts of BI 754111 in combination with 
BI 754091 administered to patients with advanced solid tumours. Possible cohort scenarios 
for Part I are presented in Figure 3.1: 1.
Figure 3.1: 1 Proposed Part I dose-escalation scheme
The dose-escalation phase will include intensive safety monitoring to ensure the safety of the 
patients and will be guided by Bayesian Logistic Regression Models (BLRM) with overdose 
control (EWOC). Following determination of the MTD and (or) the selected expansion dose
of the combination of BI 754111 and BI 754091, Part II will commence to further 
characterise the combination at the doses determined in Part I in patients with NSCLC, 
mCRC, or any solid tumour with high TMB and/or MSI-H and/or DNA MMRd.
It is planned that approximately 15 to 50 patients will be enrolled in Part I. The total number 
of patients will depend on the number of dose escalations necessary. The BLRM estimates 
the MTD by updating estimates of the probability of observing a DLT during the MTD 
evaluation period for each dose (or dose combination) level in the trial as patient information 
becomes available.
In general, it will be permitted to escalate to a dose that fulfils the EWOC principle (refer to 
Section 7). Details on handling borderline cases will be described in the dose-escalation plan. 
Successive cohorts of patients will receive doses of BI 754111 and BI 754091 until one dose 
level above the human therapeutic dose for LAG-3 (currently estimated at 400 mg) is 
reached. A cohort size of 3 patients will be treated at each dose level. Additional patients (up 
to 6 more) could be added to some previously evaluated cohorts to expand the safety and PK 
LAG-3 (200 mg) + PD-1 dose 
LAG-3 (80 mg) + PD-1 dose 
LAG-3 (20 mg ) + PD-1 dose 
LAG-3 (4mg ) + PD-1 dose 
LAG-3 (400 mg) + PD-1 dose 
LAG-3 (600 mg) + PD-1 dose 

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evaluation. Only one component of the combination (BI 754111 or BI 754091) will be 
changed at one time. They will not be escalated simultaneously.
A 10% screen-failure rate is anticipated, which assumes the sites have ‘pre-screened’ to find 
generally eligible patients. Therefore, the 10% screen-failure rate should only be for failure 
due to laboratory values, scans, etc.
After patients in a cohort have either experienced a DLT or have been observed for at least 
the MTD evaluation period (see Section 7.3.1.1) without experiencing a DLT, the Bayesian 
model will be updated with the newly accumulated data. The overdose risk will then be 
calculated for the dose combination, and escalation will be permitted to all doses of the dose 
combination that fulfil the EWOC criterion. Hypothetical data scenarios (examples in 
Section 10.5.1) will be calculated with potential cohort sizes and presented at the meetings 
with the Safety Review Committee (SRC, see Section 3.1.2). Based on the models and on 
additional information (patient profiles), the members of the SRC will reach a joint 
recommendation on the next dose level of BI 754111 in the dose combination to be 
investigated and the size for the next dose-escalation cohort. 
If DLTs are observed in the first 2 consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose level still fulfils the EWOC principle. Based on this information, the SRC will 
evaluate whether the next patients will be enrolled at the same dose level, or if they will be 
enrolled at a lower dose level.
The SRC may recommend stopping the dose-finding phase after the criterion for MTD 
(Section 7.1) is fulfilled. Further patients may be included to confirm this MTD estimate, i.e., 
to confirm that the EWOC criterion is still fulfilled. If no DLT is observed at a dose at which 
the efficacy is considered sufficient, the SRC may decide to include an additional number of 
patients at the same dose level and to declare this dose as the recommended dose for further 
development. The SRC can declare any dose that fulfils the EWOC criterion as the dose to be 
tested in the expansion phase, independent of the MTD estimate.

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Table 3.1: 1
Possible Cohort Scenarios for Solid Tumour Cohorts
Part I
Dose-Escalation Cohorts in Solid Tumour (Doses determined by the 
SRC)
Cohort A
LAG-3 Dose 1 (4 mg) & PD-1 Dose 1 (RPIID or a lower dose selected from 
the BI 1381.1 trial by the BI 1381.2 SRC)
Cohort B
LAG-3 Dose 2 (20 mg) & PD-1
Cohort C
LAG-3 Dose 3 (80 mg) & PD-1
Cohort D
LAG-3 Dose 4 (200 mg) & PD-1
Cohort E
LAG-3 Dose 5 (400 mg) & PD-1
Cohort F
LAG-3 Dose 6 (600 mg) & PD-1
Part II
Dose-Expansion Cohorts
Cohort G
Selected expansion dose in patients with 2nd and 3rd line NSCLC who 
progressed on anti-PD-1 or anti-PD-L1 treatment (as defined in the entry 
criteria)
Cohort H
Selected expansion dose in ≥ 2nd line microsatellite stable anti-PD-1 and anti-
PD-L1 treatment-naïve mCRC.
Cohort I
Selected expansion dose in patients with any solid tumour with high TMB 
and/or MSI-H and/or DNA MMRd solid tumours who have received 1 prior
anti-PD-1 or anti-PD-L1 treatment regimen.
Cohort J
Selected expansion dose in patients with 1st line epidermal growth factor 
receptor [EGFR] wildtype [WT] and anaplastic lymphoma kinase [ALK] WT 
NSCLC. Patients may have any level of PD-L1 expression, but only a 
maximum of 10 patients with PD-L1 high expression (≥50% PD-L1) will be 
enrolled.
Following determination of the dose from the Part I portion, 4 dose-expansion cohorts (2nd
and 3rd line NSCLC, anti-PD1 and anti-PD-L1 treatment–naïve mCRC, any solid tumour with 
high TMB and/or MSI-H, and 1st-line NSCLC), will be enrolled into Part II. The Part II 
portion of the trial will further evaluate the safety, tolerability, PK profile, biomarkers, and 
efficacy of the combination of BI 754111 and BI 754091.
Patients will continue study treatment until disease progression (PD) according to the 
Response Evaluation Criteria in Solid Tumours (RECIST) and the Guidelines for Response 
criteria for use in trials testing immunotherapeutics (iRECIST) (R17-0923) , withdrawal of 
patient consent, an unacceptable toxicity occurs, or 1 year of treatment is completed, 
whichever occurs first. Patients will be allowed to stay on treatment in the case of initial 
radiological PD, if the Investigator feels that it is in the patient’s best interest. In addition, 
patients without PD may stay on treatment after 1 year on a case-by-case basis after 
discussion with the Medical Monitor and the sponsor.

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3.1.1
Administrative structure of the trial
A contract research organisation, 
, is responsible for 
project management, medical management, site management, data management, site 
regulatory document management, management of the Trial Master File, some aspects of 
safety management and reporting, medical writing, and medical monitoring.
A Safety Review Committee (SRC), including representatives from clinical sites, the sponsor, 
and 
, will be established and is described in 
Section 3.1.2.
Relevant documentation on the participating investigators and other important participants, 
including their curricula vitae, will be filed in an Investigator Site File (ISF).
The statistical analysis will be done by BI according to BI Standard Operating Procedures 
(SOPs).
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs and 
SOPs as agreed upon and 
documented. A list of responsible persons and relevant local information can be found in the 
ISF.
An Interactive Response Technology (IRT) vendor will be used in this trial for development 
of shipment orders.
3.1.2
Safety Review Committee
Members of the SRC will include:
∀
 for the trial
∀
Principal Investigators, or delegates, from each investigational site
∀
BI Safety Physician, or delegate
∀
BI Team Member Medicine responsible for the project
∀
BI Project or Trial Statistician.
The BI Safety Physician, BI Team Member Medicine, or delegate, should always attend the 
SRC, if there are safety issues for discussion.
The 
Medical Monitor, or delegate, should always be 
present at the SRC.
Other BI and non-BI subject matter experts may also be invited, as appropriate. The SRC
documentation for this trial will define the exact membership and who should be present for 
decisions to be made.
The SRC will be responsible for assessing the progress of the clinical trial, including making 
safety and efficacy assessments at specified intervals, making dose-escalation decisions for 

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BI 754111, making dose selection decisions for BI 754091, making decisions on the next 
cohort size, and recommending to the sponsor whether to continue, modify, or stop the trial. 
To support their decision making, the SRC will have unblinded access to data from this trial 
and the ongoing study, BI 1381.1, which evaluates escalating doses of BI 754091 
monotherapy.
The tasks and responsibilities of the SRC will be documented. The SRC will maintain written 
records of all its meetings.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUPS
During Part I (dose-escalation) 3 patients with solid tumours per cohort is required, but the 
SRC may decide to increase the number by a maximum of 6 additional patients per cohort as 
needed. Decisions of the SRC will be guided by BLRMs with overdose control. An EWOC
design will increase the chance of treating patients at efficacious doses while reducing the 
risk of overdosing. This design is based on practical experience and is an efficient method 
due to its ability to identify the dose with a desired toxicity rate and its allocation of a greater 
proportion of patients to doses at or close to that desired dose (R13-4802; R13-4804; R13-
4805). The use of Bayesian models for Phase I studies has also been advocated by the 
European Medicines Agency (EMA) guideline on small populations (R07-4856) and by the 
FDA (R13-4881).
The results from this trial will form the basis for decisions for future studies.
SELECTION OF TRIAL POPULATION
3.3
A log of all patients enrolled into the trial (i.e., who have signed an informed consent form 
[ICF]) will be maintained in the ISF at the investigational site irrespective of whether or not 
they have been treated with investigational drug. Relevant data for all patients enrolled in the 
trial will be entered in the eCRF.
3.3.1
Main diagnosis for trial entry
Patients included in the dose-escalation cohorts (Part I) are not eligible to enter the dose-
expansion cohorts (Part II).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion 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 ICF prior to any trial-specific procedures, 
sampling, or analyses
2. Patients ≥18 years of age at the time of signature of the ICF
3. Part I (dose escalation):

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∀
Patients with a confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours (any type)
- For whom no therapy of proven efficacy exists, or who are not 
amenable to standard therapies.
- Must have measurable lesions according to RECIST v1.1
- Previous treatment with an anti-PD-1 mAb is allowed as long as the 
last administration of the anti-PD-1 mAb on the previous treatment is a 
minimum of 60 days prior to starting treatment in this trial.
4. Part II (dose expansion):
∀
Patients must have measurable disease per RECIST v1.1 criteria, must have at 
least 1 tumour lesion amenable to biopsy, and must be medically fit and 
willing to undergo a biopsy before first treatment (if adequate archival tissue is 
not available) and, unless clinically contraindicated, after 6 weeks on therapy.
∀
Dose Expansion Cohorts: Patients with a confirmed diagnosis of advanced, 
unresectable, and/or metastatic solid  tumours of one of the following types:
- Second and 3rd line NSCLC patients: 
•
Must have progressed on anti-PD-1 or anti-PD-L1 treatment 
after having achieved radiologically confirmed benefit 
(minimum of stable disease) 
•
Must have had a minimum duration of benefit of 4 months and 
minimum treatment duration of 2 months on the previous anti-
PD-1 or anti-PD-L1 treatment without experiencing disease 
progression during that period.
•
The anti-PD-1- or anti-PD-L1-containing treatment must have 
been the latest treatment regimen prior to enrolling in this trial
•
Must be within >4 and <12 weeks since the latest treatment and 
their first dose in this trial. Patients who have had anti-PD-1 or
anti-PD-L1 monotherapy as their first-line NSCLC treatment 
regimen must have a PD-L1 expression level of ≥1% at 
baseline (local validated testing).
- Anti-PD-1 or anti-PD-L1 treatment-naïve patients with microsatellite 
stable mCRC:
•
Patients must have had ≥ 1 line of treatment 
•
Must have microsatellite stable disease (identified using any 
validated test) 
•
Must be anti-PD-1 and anti-PD-L1 treatment naïve 
- Anti-PD-1 or anti-PD-L1 pretreated patients with any high TMB (≥10 
mutations/Mb) and/or MSI-H and/or DNA MMRd solid tumours
•
Patients must have high TMB (≥ 10 mutations/Mb) and/or 
MSI-H and/or DNA mismatch repair deficient (MMRd) 
(measured using any validated test).
•
Patients must have received 1 prior anti-PD-1 or anti-PD-L1 
treatment regimen.
- 1st-line squamous or non-squamous NSCLC patients:
•
Patients must be treatment naïve

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•
Must be EGFR and ALK wild type (only applicable to 
patients with non-squamous NSCLC)
•
Regardless of PD-L1 expression level. However, the number of 
patients with high level of PD-L1 expression (≥50% PD-L1) 
will be limited to a maximum of 10 patients
5. Eastern Cooperative Oncology Group (ECOG, R01-0787) score: 0 to 1
6. Life expectancy of at least 12 weeks after the start of the treatment according to the 
Investigator’s judgement
7. 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 (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.
3.3.3
Exclusion criteria
Patients must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Major surgery (major according to the Investigator’s assessment) performed within 
12 weeks prior to first trial treatment or planned within 12 months after screening, e.g.,
hip replacement
2. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.2) or any drug considered likely to interfere with the safe conduct of the 
trial
3. Previous enrolment in this trial
4. Any investigational or anti-tumour treatment, except BI 754091, within 4 weeks or within 
5 half-life periods (whichever is shorter) prior to the initiation of trial treatment. 
5. 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
6. Prior treatment with anti-LAG-3 agents
7. Patients with NSCLC that has epidermal growth factor receptor (EGFR) mutations or 
anaplastic lymphoma kinase (ALK) rearrangements. (only applicable to patients with
non-squamous NSCLC)
8. Presence of other active invasive cancers other than the one treated in this trial within
5 years prior to screening, with the exception of appropriately treated basal-cell 
carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumours 
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
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

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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:
-
Mean resting corrected QT interval (QTc) >470 msec
-
Any clinically important abnormalities (as assessed by the Investigator) in rhythm, 
conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, 
third degree heart block
-
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
-
Patients with an ejection fraction (EF) <55% or the lower limit of normal of the 
institutional standard will be excluded. Only in cases where the Investigator (or the 
treating physician or both) suspects cardiac disease with negative effect on the EF, 
will the EF be measured during screening using an appropriate method according to 
local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition 
scan). A historic measurement of EF no older than 6 months prior to first 
administration of study drug can be accepted provided that there is clinical evidence 
that the EF value has not worsened since this measurement in the opinion of the 
Investigator or of the treating physician or both.
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 subject, unlikely to complete the trial, or unable to comply with 
the protocol procedures.

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Table 3.3.3: 1
Laboratory values demonstrating inadequate organ function
Laboratory Parameter
Values for solid tumours
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

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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:
∀
The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
∀
The patient needs to take concomitant drugs that interfere with the investigational product
other than those listed under ‘Permitted concomitant medications’ (see Section 4.2.2.1).
∀
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy)
∀
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.
Given the patient’s agreement, the patient will undergo the procedures for the end-of-
treatment (EOT) visit and follow up as outlined in the appropriate flow chart (Flow Chart 1 or 
Flow Chart 2) and Section 6.2.3.
For all patients the reason for withdrawal (e.g., AEs) must be recorded in the electronic case 
report form (eCRF). These data will be included in the trial database and reported.
During the MTD evaluation period, patients withdrawn for a reason other than having a DLT 
or patients who miss more than one visit will be replaced after discussion between the 
sponsor and the Investigator if the information that needed to be collected during that visit is 
not available and makes the patient non-evaluable for the PK analyses or safety parameters 
(including evaluation for DLTs).
Patients who come off trial due to a DLT will not be replaced.
If a patient should become pregnant during the trial, the treatment with 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 5.3.6.9 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.

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Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the clinical trial protocol (CTP), or the 
contract disturbing the appropriate conduct of the trial.
4. Completion of treatment by all patients and the sponsor determines that sufficient survival 
data has been collected.
The Investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in the case of the third reason).

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

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4.1.2
Selection of doses in the trial
Starting dose of BI 754111
4.1.2.1
Research by Bai et al (R13-4749) found that the fixed-dosing approach (flat dosing) is the 
recommended first option for administration of mAbs in first-in-human studies. 
The starting dose of BI 754111 in patients with solid tumours will be 4 mg (based on 
0.05 mg/kg for an 80 kg patient) administered via i.v. infusion once every 3 weeks. The 
starting dose was based on the EC50 in the in vitro tetanus toxoid T-cell activation assay. In 
that assay, increasing concentrations of BI 754111 were combined with a fixed dose of BI 
754091 and IFNγ secretion was measured as an indication of T-cell activation (n00250935;
n00253546).
This starting dose is supported by the 13-week repeat-dose toxicity study in the cynomolgus 
monkey. Compared to the NOAEL in the Non-Human Primate study (Cmax 6,440 μg/mL and 
AUC 734,000 μg/mL*h), the 4 mg starting dose to an 80 kg patient is expected to result in an 
exposure margin of approximately 5,300-fold and 4,900-fold based on the predicted human 
steady state exposure of Cmax 1.2 μg/mL and AUC 150 μg/mL*h, respectively.
A sample dose-escalation scheme is shown in Section 4.1.3. The actual dose escalation will 
be guided by the BLRM, and the final decision will be made by the SRC (see Section 3.1.2).
Starting dose of BI 754091
4.1.2.2
The recommended Phase II dose of BI 754091 to be used in combination with BI 754111 is 
240mg every 3 weeks.  This dose of BI 754091 was determined by the SRC using the most 
recent safety information from another ongoing study, BI 1381.1. Based on emerging safety 
information in the 1381.1 and 1381.2 studies, the SRC may amend the dose of BI 754091 
used in this study. 
The dosing schedule of BI 754091 will be q3w, and is not anticipated to change.
4.1.3
Dose-escalation scheme
The dose of BI 754111 is planned to be escalated in cohorts. The sample dose levels to be 
assigned to separate cohorts of patients are listed in Table 4.1.3: 1. Intermediate or lower dose 
levels, depending on the number of DLTs observed in the trial, and dose levels higher than 
600 mg (as long as they fulfil the EWOC criterion) may be investigated if agreed upon by the
Investigator and sponsor.
In the Part I dose-escalation cohorts, dosing of BI 754111 will be administered with BI 
754091. The planned starting dose of BI 754091 will be the RPIID from study 1381.1 and the 
SRC will confirm this prior to starting dosing. The dose of BI 754091 may be increased or 
decreased based on DLTs and the overall safety profile of the combination. Possible cohort 
scenarios are presented in Table 3.1: 1.  These scenarios may change based on ongoing safety 
evaluations.

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Table 4.1.3: 1 Example of BI 754111 dose escalation*
Dose Escalation Rules
Example Dose Levels
Dose level
Increment from previous 
dose
Proposed dose
First
Starting dose
4 mg
Second
400%
20 mg*
Third
300%
80 mg*
Fourth
150%
200 mg*
Fifth
100%
400 mg*
Sixth
50%
600 mg*
*Actual dose assignments for individual patients will be communicated separately as 
determined by the SRC.
At the end of each treatment cohort, the SRC will evaluate the available data. The SRC will 
review all safety data including, but not limited to, DLTs and all CTCAE Version 5 Grade ≥2 
toxicity data during the first cycle of combination therapy for the solid tumour cohorts 
Updated safety data on other ongoing patients, including data in later cycles, will be 
discussed as well. Based on the findings of the SRC, a decision on the next dose level to be 
tested will be made.
4.1.4
Dose modifications
There will be no dose reductions or escalations of BI 754111 or BI 754091 in any one patient. 
The dose may be delayed for a patient for one cycle, plus an additional 3 weeks, because of 
AEs following discussion with the Medical Monitor.
During combination therapy, if treatment is held or discontinued due to an AE(s), both 
BI 754091 and BI 754111 will be held or discontinued together. If treatment is to be restarted
after resolution (≤ Grade 1) of the AE(s), both BI 754091 and BI 754111 must be started 
together.
The study drug(s) should be permanently discontinued for Grade 3 to 4 pneumonitis, Grade 
3 to 4 adrenal insufficiency, Grade 4 diabetes mellitus, any grade encephalitis, Grade 4 
hypophysitis, Grade 4 rash, Grade 3 to 4 colitis or recurrent colitis of any grade, any recurrent 
Grade 3 to 4 AE, transaminase increases >5 times ULN or total bilirubin >3 times ULN
(unless unequivocally attributed to another cause), inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or persistent Grade 2 to 3 AEs that do not recover 
to Grade 1 or less within 12 weeks. Study drug(s) should also be permanently discontinued 
for Grade 3 to 4 AEs that are classified as immune-related by the Investigator that are not 
listed in Appendix 10.1. Study drug(s) should be permanently discontinued if ≥ Grade 4 

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drug-related AEs are reported. Please see Appendix 10.2 for guidelines for management of 
immune-related adverse events.
In the event of an infusion-related reaction ≤Grade 2, the infusion rate of study drug(s) may 
be decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate. If an infusion-
related reaction is Grade 3 or higher in severity at any point during the study, study drug(s)
will be permanently discontinued (see Section 5.3.6.5.3).
4.1.5
Definition of dose-limiting toxicity
Dose-limiting toxicities (DLTs) will be recorded throughout the trial. Any DLT must be 
reported to the Medical Monitor by the Investigator or designee within 24 hours of first 
knowledge, and to the 
 as an SAE when 
appropriate. All DLTs will be agreed upon between the Sponsor, the Study Chair, the 
Medical Monitor, and the investigators after review of the data from each cohort. Only DLTs 
occurring in Part I during the first cycle of BI 754111 administered in combination with 
BI 754091 in the solid tumour cohorts will be used for dose-escalation decisions made by the 
SRC.
All relevant safety information (including DLTs) will be considered when selecting the 
selected expansion dose.
Previous anti-PD-l mAbs have been associated in the clinical setting with inflammatory 
adverse reactions resulting from increased or excessive immune-related adverse events
(irAEs), likely to be related to the mechanism of action. These adverse reactions, which can 
be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or other 
organ systems.
Severity of AEs will be graded according to CTCAE Version 5. Any of the following AEs 
will be classified as DLTs following review by the Investigators and the Medical Monitor, 
unless unequivocally due to underlying malignancy or an extraneous cause.
Haematologic toxicities:
∀
Any Grade 5 toxicity
∀
Neutropenia ≥ Grade 4 lasting for >5 days
∀
Febrile neutropenia of any duration (ANC <1.0 X 109 cells/L and fever ≥38.5°C)
∀
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding or a requirement 
for platelet transfusions
∀
Grade 4 anaemia unexplained by underlying disease.
Non-haematological toxicities:
∀
AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without initial 
findings of cholestasis (e.g., findings consistent with Hy's law or the FDA definition of 
potential DILI)

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∀
≥Grade 4 AST or ALT of any duration
∀
Any ≥Grade 3 non-haematologic toxicity with the following exceptions:
-
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with immunosuppressive 
therapy within 2 weeks
-
Grade 3 fatigue that persists <7 days
-
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
-
Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated with 
clinical or radiographic evidence of pancreatitis
-
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical intervention
-
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤Grade 1 either 
spontaneously or with conventional medical intervention
-
Alopecia
-
Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that 
are sufficiently managed with or without systemic corticosteroid therapy and/or 
hormone replacement therapy, and the patient is asymptomatic.
-
Grade 3 tumour flare.
∀
Any Grade 4 or 5 AE
∀
Any Grade 2 pneumonitis of any duration
∀
Any Grade 2 uveitis, eye pain, or blurred vision that does not respond to topical therapy 
and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment
∀
Any ≥ Grade 2 toxicity that persists and results in an inability to administer BI 754091 on
Cycle 2 Day 1.
The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays, will be analysed to determine if a 
given toxicity should be considered a DLT for dose escalation purposes.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria but 
occur after the first cycle of BI 754111 in combination with BI 754091. These, as well as all 
toxicities, will be monitored throughout the trial. If any late immune-related DLT is reported 
during dose-escalation, the BLRM will be rerun including the late immune-related DLT, and 
updated results will be reviewed in an SRC meeting (either scheduled or ad hoc) to 
recommend the next dose level and cohort size.
4.1.6
Definition of maximum-tolerated dose
The MTD may be considered reached if one of the following criteria is fulfilled:
1. The posterior probability of the true DLT rate in the target interval [0.16, 0.33) of the 
MTD is above 0.5, OR
2. At least 15 patients have been treated in the trial, of which at least 6 were at the MTD.

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4.1.7
Definition of evaluable patient
For decisions on dose escalation, an evaluable patient is defined as a patient who has received 
BI 754111 and either:
∀
has completed the first cycle of BI 754111 in combination with BI 754091
OR
∀
has experienced a DLT during the first cycle of BI 754111 in combination with 
BI 754091 .
4.1.8
Method of assigning patients to treatment groups
After assessment of all inclusion and exclusion criteria, each eligible patient in the Part I
dose-escalation portion of the trial will be assigned a dose of BI 754111 and a dose of 
BI 754091, as determined by the SRC.
To determine the dose or doses for subsequent cohorts, the available safety data (including 
DLTs, AEs that are not DLTs, and AE information), as well as the recommendations from the 
BLRM, will be evaluated by the SRC members at the dose-decision meeting.
The SRC must reach a consensus on whether to declare the MTD, escalate the dose any 
further, or de-escalate and/or expand recruitment into particular cohorts. Minutes from these 
meetings will be prepared and circulated to the trial team and each Investigator for comment 
prior to finalisation. Dose escalation will continue until at least one dose level higher than the 
estimated human therapeutic dose or until the trial is terminated for other reasons.
To further characterise the safety (e.g., specific suspected treatment-related AEs) or PK/
pharmacodynamic (PDc) profiles of the BI 754111 plus BI 754091 combination, one or 
several doses may be expanded. Dose escalation may be terminated at any time based on 
emerging safety concerns without establishing the selected expansion dose or the MTD.
In the second part (Part II dose expansion cohorts), all patients will be treated with the 
schedule and dose determined by the assessment of DLTs, available PK, and available 
biomarker results from the Part I portion of the trial. Patient numbers will be assigned as 
enrolment (screening) occurs.
4.1.9
Administration of doses for each patient
BI 754111 and BI 754091 will be diluted and administered via i.v. infusion according to the 
details in the Pharmacy Manual.
For Part I solid-tumour cohorts, dosing will be sequential for doses <80 mg LAG3 with 
BI 754091 infused first followed by infusion of BI 754111. The infusion duration for each 
will be specified in the pharmacy manual. It is anticipated that the entire infusion time will 
take ~1 hour. For doses ≥80 mg LAG3, the infusion will be simultaneously (infusion duration 
~1 hour).

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4.1.10
Blinding and procedures for unblinding
Not applicable in this open-label trial.
4.1.11
Packaging, labelling, and re-supply
The investigational products will be provided by BI. They will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice. Each site will be provided 
with an initial shipment of trial drug supply. It will be the responsibility of the Investigator or 
designee to monitor that supply to ensure the site has enough for current and potential 
patients.
will monitor expiry dates of trial drug to 
trigger replacement supplies as needed. Sites will request additional re-supply from 
 
by using the Drug Request and Shipment form, which is 
available in the ISF. Upon receipt of the request, 
will trigger drug supply for the site using an IRT ‘light’ system.
For details of packaging and the description of the label, refer to the ISF.
4.1.12
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
4.1.13
Drug accountability
The Investigator, or designee, will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
∀
Approval of the trial protocol and informed consent form (ICF) by the Institutional 
Review Board (IRB)
∀
Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the Principal Investigator
∀
Availability of a signed and dated CTP
∀
Availability of the proof of a medical license for the Principal Investigator
∀
Availability of Form 1572.
The Investigator, or designee, must maintain records of the products’ delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or alternative 
disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial patients. The 
Investigator, or designee, will maintain records that document adequately that the patients 
were provided the specified doses 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

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(after relevant reconciliations have been completed and records reviewed by the clinical 
monitor).
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
CONCOMITANT MEDICATIONS, AND 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.
4.2.2
Concomitant medications
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.
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
4.2.2.1
∀
If medically feasible, patients taking regular medication should be maintained on it 
throughout the trial.
∀
To reduce the risk of infusion related reactions, patients are to be pre-treated with an 
antihistamine and acetaminophen or paracetamol.  Pre-treatment should be administered 
at sufficient time prior to initiation of infusion to allow the agents to exert their effect.
∀
Supportive care and other medications that are considered necessary for the patient’s 
well-being may be given at the discretion of the Investigator.
∀
Blood transfusions are allowed at any time during the trial, except to meet inclusion 
criteria. There must be at least 4 weeks between a patient’s last transfusion and their 
screening laboratory assessment. Exceptions to this will be considered by the sponsor on 
a case-by-case basis.
∀
Patients already receiving erythropoietin at the time of screening for the trial may 
continue it, provided they have been receiving it for more than one month at the time trial
treatment is started. Prophylactic erythropoietin should not be started during the first 
3 weeks of any cohort, but may be started thereafter.
∀
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 for any lesion in the dose-
escalation part of the trial, except during the first cycle (in solid tumours) as it could 
interfere with the DLT evaluation for MTD/selected expansion dose determination. 
Following the first cycle of the dose-expansion phase (Part II), palliative radiotherapy is 
allowed only for non-target lesions, following discussion with the Medical Monitor, 

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provided that the reason for radiotherapy does not reflect PD and does not interfere with 
response assessment. Palliative radiotherapy is not allowed during the first cycle of any 
Part II cohort. Lesions that have been exposed to radiotherapy are no longer evaluable, 
and may not be included in the assessment of the non-target lesions and the overall 
assessment. These lesions may also not be used for a trial biopsy. Unless in emergency 
situations, the Medical Monitor should be contacted prior to the administration of 
palliative radiotherapy in the expansion phase.
Prohibited concomitant medications
4.2.2.2
∀
No other investigational therapy or anticancer agent should be given to patients. If such 
agents are required for a patient, then the patient must first be withdrawn from the trial.
∀
Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumour necrosis factor-alpha blockers are prohibited. Use of immunosuppressive 
medications for the management of investigational product-related AEs or in patients 
with contrast allergies is acceptable, and does not necessarily warrant immediate 
treatment discontinuation. In addition, use of inhaled, topical, intranasal corticosteroids or 
local steroid injections (e.g., intra-articular injection) is permitted. Temporary uses of 
corticosteroids for concurrent illnesses (e.g., food allergies, computed tomography (CT)
scan contrast hypersensitivity) are acceptable upon discussion with the Medical Monitor.
∀
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.
4.2.3
Restrictions
Restrictions on diet and life style
4.2.3.1
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.
Restrictions regarding women of childbearing potential
4.2.3.2
Due to the advanced stage of disease of Phase I trial patient populations and the high medical 
need, females of childbearing potential can be included in this trial provided that they agree 
to use a highly-effective contraception method. These are methods of birth control per the 
International Committee on Harmonisation (ICH) M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly.
Highly-effective methods of contraception include:
∀
Oral, injected, or implanted hormonal methods of contraception, or
∀
Intrauterine device or intrauterine system, or

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∀
‘Double-barrier’ methods of contraception: Male condom in combination with female 
diaphragm/cervical cap plus spermicidal foam/gel/film/cream.
Details of these contraception methods are described in the patient information in the ICF.
Women of childbearing potential must follow these methods during the trial and for at least 
6 months after the end of the trial treatment. Although use of a contraceptive pill is 
considered a highly-effective method of birth control, women of childbearing potential taking 
a contraceptive pill must use an additional barrier method for the entire duration of the trial
treatment intake and for 6 months after the end of the trial treatment intake.
Male patients with partners of childbearing potential must agree to use condoms and ensure 
their partner is using an additional highly-effective method of birth control, during the trial 
and until at least 6 months after the end of the trial treatment.
TREATMENT COMPLIANCE
4.3
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.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary endpoints
The primary endpoint of Part I (dose escalation) of the trial is the:
∀
MTD of the BI 754111 plus BI 754091 combination
∀
Number of patients experiencing DLTs during the combination MTD evaluation period
(first cycle of BI 754111 plus BI 754091 combination therapy) in patients with solid 
tumours.
The MTD is defined as the highest dose with less than 25% risk of the true DLT rate being 
above 33%. For definition of DLTs, refer to Section 4.1.5.
During the dose-escalation phase, BLRMs employing the EWOC principle will be used for 
selection of doses of BI 754111 and dose combinations to investigate, and for estimation of 
the combination MTD. Cohorts of patients will receive escalating doses of BI 754111 and in 
combination with BI 754091, doses of which may vary, until the MTD of the combination is 
reached or the selected expansion dose of the combination is determined. Each cohort will 
consist of newly enrolled patients. Estimation of the MTD during the escalation phase of the 
trial will be based upon the estimation of the probability of a DLT in the first cycle of 
BI 754111 plus BI 754091 combination therapy in the set of evaluable patients for the MTD. 
The corresponding methodology is described in Section 7.3.1.1 and Appendix 10.5. The 
MTD estimate or the selected expansion dose established during the dose-escalation portion
will be re-investigated after the expansion portion by re-running the BLRM including all data 
from the escalation and expansion portions, in particular also considering the DLT 
information from all combination treatment cycles.
The primary endpoint of Part II (dose expansion cohorts) of the trial is:
∀
Objective response (OR) - confirmed complete response (CR) and partial response (PR)
according to RECIST Version 1.1 as assessed by the Investigator during the entire 
treatment.
5.1.2
Secondary endpoints
Secondary endpoints of Part I (dose escalation) of the trial
5.1.2.1
The secondary endpoints of Part I (dose escalation) of the trial are the following:
∀
PK parameters to be calculated for BI 754111 after single and multiple doses of 
BI 754111 in combination with BI 754091, and also for BI 754091 after single and 
multiple doses of combination therapy include:
-
Cmax: maximum measured concentration of BI 754111/ BI 754091 in plasma
-
AUC0-504: area under the concentration-time curve of BI 754111 / BI 754091 in 
plasma over the time interval from 0 to 504 hours

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∀
Number of patients experiencing DLTs from start of treatment until end of treatment (in 
all cycles)
∀
Objective response (OR) for patients with solid tumours: confirmed CR and PR according 
to RECIST Version 1.1 as assessed by the Investigator throughout the entire treatment 
period.
Secondary endpoints of Part II (dose expansion) of the trial
5.1.2.2
The secondary endpoints of Part II (dose expansion cohorts) of the trial are the following:
∀
Duration of response is the duration from the date of first documented PR or CR
according to RECIST Version 1.1 as assessed by the Investigator to the date of PD or 
death.
∀
Disease control (CR, PR, or SD according to RECIST Version 1.1 as assessed by the 
Investigator.
∀
Progression-free survival (PFS) is the duration from the date of first treatment to the date 
of PD or death.
∀
Number of patients experiencing DLTs from start of treatment until end of treatment.

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ASSESSMENT OF EFFICACY
5.2
5.2.1
Tumour assessments
The tumour response in patients with solid tumours will be evaluated according to RECIST 
Version 1.1 (R09-0262) and irRECIST (R15-2005). 
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 treatment with the trial 
medication 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 used as target lesions. Tumour assessments will be performed at screening (as close as 
possible to the treatment start and no more than 28 days before the start of study treatment), 
every 2 cycles (6 weeks ±3 days) for the first 6 months, then every 3 cycles (9 weeks 
±3 days) thereafter, and at the EOT visit (if not performed within the previous 4 weeks).
If the patient stops trial medication intake for a reason other than PD, the tumour assessment 
according to RECIST and iRECIST will be performed according to standard of care until the 
last follow-up needed according to the protocol (PD, death, lost to follow-up, end of the trial).
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.
Digital copies of disease evaluation scans are to be collected and stored centrally 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 

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quantitative CT metrics, i.e. radiomics features, assessed in standard-of-care medical imaging 
data.
ASSESSMENT OF SAFETY
5.3
The safety of BI 754111 and BI 754091 will be assessed by a descriptive analysis of 
incidence and severity of AEs graded according to CTCAE (Version 5), the incidence of 
DLTs, laboratory data, and results of physical examinations. Safety will be assessed in a 
descriptive way without confirmatory analysis.
DLTs observed during the MTD evaluation period (the first cycle of BI 754111 plus BI 
754091 combination treatment) will be considered for MTD determination. However, all 
DLTs observed in all treatment cycles will be collected and will be considered for 
determining an expansion dose. The BLRM will be re-run to include the DLT information 
from all combination treatment cycles. Based on both estimates, the recommended dose for 
further development will be selected. 
At regular intervals, all available safety data including AEs qualifying as DLTs will be 
submitted to the SRC. The SRC will assess this information and provide recommendations 
for trial conduct and dose escalation. If there are too few or no DLTs for BLRM guided dose 
selection, PK and/or biomarker data will be taken into consideration for expansion dose
determination.
5.3.1
Physical examinations and ECOG performance status
Physical examinations will be performed at screening, prior to trial medication administration 
on Day 1 of each cycle, at the EOT visit, and at the 30-day safety follow-up visit. However, 
patients will have an additional abbreviated physical examination (focused on the specific 
disease, at the Investigator’s discretion) on Cycle 1 Day 15 of Part I cohorts only.
The physical examination will include measurement of height (screening only) and of body 
weight, and the evaluation of the ECOG performance score. Weight will be measured during 
screening and at each full physical examination (not during abbreviated physical 
examinations).
The ECOG score will be assessed at screening, on Day 1 of Cycles 1 and 2, on Day 1 of 
every other cycle beginning with Cycle 3 prior to trial medication intake, at the EOT visit, 
and at the 30-day safety follow-up visit.
5.3.2
Vital signs
Vital signs (blood pressure, body temperature, and pulse rate after 2 minutes of supine rest) 
will be recorded at the screening visit, before and after infusion during the first treatment, at 
every visit of treatment cycles (pre-infusion) including PK sampling days, at the EOT visit, 
and at the 30-day safety follow-up visit.

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5.3.3
Electrocardiograms
Local ECGs will be done throughout the trial. The ECG should be assessed by a physician 
(cardiologist if available). There will not be a centralised analysis. Single digitalised ECGs
(or analog ECG if digital not available) must be done after 5 minutes of rest at screening, on 
Day 1 of every cycle through Cycle 6 then every other cycle thereafter (Cycles 8, 10, 12, 
etc.), on Day 15 of Cycles 1 through 4, at the EOT visit, and whenever the Investigator deems 
it necessary. An ECG is optional at the 30-day safety follow-up visit if the EOT visit ECG 
was normal and no drug-related abnormalities were detected in on-trial ECGs.
When the ECG time point is concomitant with a blood sampling (or any other procedure), the 
ECG must always be performed prior to the blood sampling (or other procedure) to allow the 
recording in reproducible resting conditions. In case of drug-related ECG changes, additional 
ECG monitoring will be performed in later cycles of treatment, as deemed necessary by the 
Investigator.
Clinically relevant abnormal findings will be reported either as a baseline condition (if 
identified at the screening visit) or as AEs and will be followed up and/or treated as medically 
appropriate.
5.3.4
Safety laboratory parameters
Blood (venous) samples will be collected at the times indicated in the appropriate flow chart 
(Flow Chart 1 or Flow Chart 2) 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.
Haematology
5.3.4.1
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
5.3.4.2
The standard biochemistry panel will consist of glucose, sodium, potassium, chloride, 
calcium, phosphate, venous bicarbonate HCO3, creatinine, creatine phosphokinase (CPK), 
AST, ALT, alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, total protein, 
albumin, urea nitrogen (or urea), and uric acid. Troponin will be tested according to the times 
listed in the flow charts (Flow Chart 1 or Flow Chart 2). In case of pathological CPK, then 
CPK-MB, additional troponin I, and myoglobin should be reactively tested and the findings 
documented. A measurement of troponin-I is to be performed if possible. If troponin-I cannot 
be measured, troponin-T can be measured instead as long as this is marked in the database.

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A thyroid panel (TSH, free T4, and free T3) will be done at the time of each standard 
biochemistry panel.
Additionally, amylase and lipase should be analysed in case of symptoms of pancreatitis.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.3.6.5.4 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. 
Urinalysis
5.3.4.3
Urine will be analysed for pH, glucose, erythrocytes, leukocytes, protein, and nitrite by 
dipstick (semi-quantitative measurements) during the screening visit, on Day 1 of each cycle,
at the EOT visit, and as clinically indicated. In case of pathological findings, further 
evaluation must be performed and the findings documented.
Pregnancy test
5.3.4.4
A beta human chorionic gonadotropin (β-HCG) pregnancy test in serum will be performed 
for women of childbearing potential at screening, within 14 days prior to first trial treatment.
If done within 72 hours of Cycle 1 Day 1, this test does not need to be repeated on the first 
day of treatment. Thereafter, this test can be done in either serum or urine on Day 1 of each 
cycle, and at the EOT visit.
5.3.5
Other safety parameters
None
5.3.6
Assessment of adverse events
Definition of adverse event
5.3.6.1
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.

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Definition of adverse reaction
5.3.6.2
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorisation or from occupational 
exposure. Conditions of use outside the marketing authorisation include off-label use, 
overdose, misuse, abuse and medication errors.
Definition of serious adverse events
5.3.6.3
A serious adverse event (SAE) is defined as any AE that:
∀
results in death,
∀
is life-threatening. This refers to an AE 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
∀
prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity, or
∀
is a congenital anomaly / birth defect, or
∀
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may 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.
∀
Any suspected transmission via a medicinal product of an infectious agent is also 
considered an SAE.
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).
Adverse events considered ‘Always Serious’
5.3.6.4
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 5.3.6.8, subsections ‘AE Collection’ and ‘AE reporting to 
sponsor and timelines’.
In accordance with the EMA initiative on Important Medical Events, BI has assembled 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 given above. The latest list of ‘Always 

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Serious AEs’ can be found in the electronic document system. These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
5.3.6.5
The term ‘adverse event of special interest’ (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g., the potential for AEs based on knowledge from 
other compounds in the same class. AESI need to be reported within the same time frame that 
applies to SAEs and according to the information in Section 5.3.6.8.
For this trial, DLTs, infusion-related AEs, potential DILI events, hepatic injury, and 
qualifying irAEs, as defined in Appendix 10.2, are AESIs (see Section 5.3.6.5.2,
Section 5.3.6.5.3, and Section 5.3.6.5.4).
5.3.6.5.1
Dose-limiting toxicities (DLTs)
All DLTs are considered to be AESIs, and must be reported as such. The definition of DLT is 
presented in Section 4.1.5.
5.3.6.5.2
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-related 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.
5.3.6.5.3
Infusion-related reactions
To reduce the risk of infusion-related reactions, patients are to be pre-treated with an 
antihistamine and acetaminophen or paracetamol.  Pre-treatment should be administered at 
sufficient time prior to initiation of infusion to allow the agents to exert their effect. 
In the event of an infusion-related reaction ≤Grade 2, treat the symptoms accordingly with 
antihistamine or corticosteroids if needed. The infusion rate of BI 754111 and/or the 
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).

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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.
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 
Safety group 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.
5.3.6.5.4
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 the Medical Monitor and 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 SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.

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Hepatic injury definition:
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, and/or 
∀
aminotransferase (ALT, and/or AST) elevations ≥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 “Potential 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 “Potential DILI Checklist” should be 
followed. 
Lab values meeting this definition of hepatic injury will need to be reported as an AESI. 
Please follow the flow chart in Figure 5.3.6.5:4: 1 for reporting hepatic injury / potential DILI 
cases.
Figure 5.3.6.5:4: 1 Processing potential DILI cases in oncology

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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 also 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 viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury.
Severity of adverse events
5.3.6.6
The severity of AEs should be classified and recorded in the eCRF according to the CTCAE
Version 5.
Causal relationship of adverse events
5.3.6.7
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a medicinal product and an AE. An adverse reaction, in contrast to an 
AE, is characterised by the fact that a causal relationship between a medicinal product and an 
occurrence is suspected.
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.
Examples of 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 was evident.
∀
There is 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) exist.
∀
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g., Stevens-Johnson syndrome).
∀
There was an indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is diminished).

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Examples of 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 may occur weeks after discontinuation of the 
drug concerned).
∀
The event continued 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.
∀
The event disappeared even though the trial drug treatment continued or remained
unchanged.
∀
There may be 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).
Adverse event collection and reporting
5.3.6.8
5.3.6.8.1
Adverse event collection
The Investigator shall maintain and keep detailed records of all AEs in the patient files.
A schema of the safety follow-up period is presented in Figure 5.3.6.8.1: 1. The following 
must be collected and documented on the appropriate eCRF by the Investigator:
∀
From signing the ICF onwards until the end of treatment (including the Residual Effect 
Period [REP]; a period of 30 days after the last dose of trial medication) - all AEs (non-
serious and serious) and all AESIs.
∀
After the EOT (including the REP) until the individual patient’s end of trial - all related 
SAEs and all related AESIs.
∀
After the individual patient’s end of the trial, the Investigator does not need to actively 
monitor the patient for AEs, but should only report relevant SAEs and relevant AESIs of 
which the Investigator may become aware.
The rules for Adverse Event Reporting exemptions still apply.

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Figure 5.3.6.8.1: 1 Safety follow-up schema
All AEs which occurred through the treatment phase and throughout the REP will be 
considered as on treatment; please see Section 7.3.4. Events which occurred after the REP 
will be considered as post-treatment events.
Adverse event reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via secure e-mail connection or via fax
immediately (within 24 hours) to the 
 
:
∀
Secure email (
 SAE mailbox: 
) or 
∀
Fax (
 safety fax number): + 
For sites outside of the US, country-specific fax numbers will be provided in the ISF/Study 
reference manual.
The same timeline applies if follow-up information becomes available. On specific occasions,
the Investigator can inform the
upfront via telephone by calling the 
SAE 
reporting phone number (
). This does not replace the requirement to complete 
and fax the BI SAE form.
With receipt of any further information about 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.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and on the BI SAE Report form. The Investigator should determine the causal 
relationship to the trial medication.

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The following should also be recorded as (S)AEs/AEs in the eCRF and SAE form (if 
applicable):
∀    Worsening of pre-existing conditions
∀
Changes in vital signs, ECGs, physical examinations, and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs/AEs, including those persisting after an individual patient’s end of trial must be 
followed up until they have resolved, they have been sufficiently characterised, or no further 
information can be obtained.
Pregnancy
5.3.6.9
In rare cases, pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy to the 
 
. The Pregnancy Monitoring Form for Studies
(Part A) should be used.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner; in 
the event that consent cannot be obtained, information will be collected and reported in 
accordance with regulatory requirements. 
The outcome of the pregnancy associated with the drug exposure must be followed up and 
reported to the sponsor’s unique entry point on the Pregnancy Monitoring Form for Studies
(Part B).
The ISF will contain the Pregnancy Monitoring Forms for Studies (Parts 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 Studies 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.
Exemptions to AE/SAE Reporting
5.3.6.10
Disease progression is a trial endpoint for analysis of efficacy and as such is exempted from 
reporting as an AE or 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 or study drugs and the 

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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 (progressive disease [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 at Safety 
Review Meetings.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of pharmacokinetics
If data allow, the PK parameters of BI 754111 after single and multiple doses of BI 754111 in 
combination with BI 754091, and also for BI 754091 after single and multiple doses of 
combination therapy mentioned as secondary and further endpoints for Parts I and II (see 
Section 5.1.2 and Section 5.1.3, respectively) will be evaluated using non-compartmental 
analysis methods according to BI internal SOP (001-MCS-36-472_RD-01 [2.0] and 
 
SOP ‘SOP-1.PKA.03 Non-compartmental PK/PD Analysis’).
If deemed necessary, further PK parameters (other than those defined see Section 5.1.2 and 
Section 5.1.3) might be calculated.
5.4.2
Methods of sample collection for pharmacokinetic analyses
For quantification of analyte plasma concentrations, blood will be drawn for both BI 754111 
and BI 754091 (where appropriate) at the time points listed in the appropriate flow chart 
(Flow Chart 1 or Flow Chart 2) under PK sampling and specified in PK time schedules in 
Appendix 10.4 (Part I dose -escalation cohorts: Table 10.4.1: 1and Table 10.4.1: 2, and the 
Part II dose-expansion cohorts: Table 10.4.2: 1.
The 1 hour PK sample is to be drawn shortly after the end of the total infusion (of 
BI 754091 and BI 754111).
Pharmacokinetic sampling times and periods may be adapted by the Sponsor during the trial 
based on information obtained during trial conduct (e.g., preliminary PK data). Such changes 
would be implemented via non-substantial Clinical Trial Protocol Amendments.

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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 
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.

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5.5.1
Methods of sample collection
Pre- and on-treatment tumour biopsy collections for biomarker and PDc analyses will be 
mandatory from all patients in the Part II dose-expansion portion of the trial. In addition,
biopsies should be taken according to the flow chart (Flow Chart 1 or Flow Chart 2) and
Section 5.5.2.3. All samples must be adequately labelled by the trial site personnel. Details 
about tumour tissue and blood sample collection, plasma/serum preparation, required tubes, 
labelling of tubes, storage and shipment (frequency and addresses) will be provided in the 
ISF.

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APPROPRIATENESS OF MEASUREMENTS
5.7
All assessments have been planned in accordance with traditional oncology Phase I trial
methodology.

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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Patients meeting the inclusion and 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 appropriate flow chart (Flow Chart 1 or Flow 
Chart 2). 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. For the biopsies and 
PK sampling procedures of Cycle 1, the patient must however still be under treatment and not 
in a treatment break period in order to perform the evaluations planned for the missed 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 
combination of BI 754111 plus BI 754091, an EOT visit must occur as soon as possible
(preferably within 7 days). After the EOT visit, the patient must undergo a follow-up 
evaluation 30 (+2) days after the last administration of study therapy.
Additional PFS follow-up visits after the 30-day safety follow-up visit will only be performed 
for patients who did not progress on treatment. These will be performed once every 12 weeks 
at least (by telephone) until PD, introduction of a new anti-cancer treatment, death, loss to 
follow-up, withdrawal of consent, or end of the whole trial.
The trial will be conducted according to the principles of GCP.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The procedures required at each trial visit in both portions of the trial are presented in the 
relevant flow charts (Flow Chart 1 or Flow Chart 2) of this protocol. The key procedures 
required include:
∀
PK samples throughout the trial
∀
Reporting of all AEs occurring after the ICF has been signed
∀
Baseline and on-treatment blood biomarker and immunogenicity assessments
∀
Tumour biopsy biomarker assessments
∀
Tumour assessments (based on CT/positron emission tomography [PET] and/or magnetic 
resonance imaging [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 BI 754111 for the first 6 months, and then every 3 cycles 
(9 weeks) thereafter.

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6.2.1
Screening period
The screening period may occur over a period of 28 days (period within the trial and before 
the first intake of BI 754111). For the detailed description of the tests to be performed during
this period and their timing, please refer to the appropriate flow chart (Flow Chart 1 or Flow 
Chart 2).
Baseline conditions
6.2.1.1
Demographics (sex, birth date, race, and ethnicity where allowed), information on tobacco
and alcohol use, and baseline conditions will be collected during the screening visit.
Medical history
6.2.1.2
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumour site will 
be reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumour, (lymph) 
node, and metastasis (TNM) classification will be provided as obtained at diagnosis and at 
trial screening. Previous surgeries will be reported.
Previously administered chemotherapy, tyrosine kinase inhibitor treatment, vaccine therapy, 
antibodies therapy, immune therapy, and hormone therapy will be reported, including start 
and end dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
lines of treatment will be recorded, if known.
For first line NSCLC cohort, in medical history, last tumor size measurements taken prior to 
screening in the trial will be collected where available. 
Concomitant therapies
6.2.1.3
Relevant concomitant diagnoses and/or therapies present at trial entry and/or during 
screening and relevant to the patient’s safety during the trial as judged by the Investigator
will be recorded in the eCRF (see Section 4.2.2 for details on concomitant medications). 
Post-trial therapy for advanced or metastatic disease will also be documented.
6.2.2
Treatment period
Please refer to the relevant flow chart (Flow Chart 1 or Flow Chart 2) for a detailed 
presentation of each visit during the treatment period.

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6.2.3
Follow-up period and trial completion
End-of-treatment visit
6.2.3.1
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason, as soon as possible, but no later than 7 days after permanent discontinuation of the 
trial medication or when the Investigator decided with the patient to permanently discontinue 
the trial medication or became aware that the trial medication had been terminated.
The assessments of the EOT visit will then be performed instead of at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of treatment discontinuation, unless it has been done within the past 
4 weeks.
30-day post-treatment safety visit
6.2.3.2
The safety follow-up visit is performed 30 (+2) days after permanent discontinuation of the 
trial medication. The information collected at this visit must include all new AEs that 
occurred after the EOT visit, and a follow-up of AEs ongoing at EOT.
A patient will be considered as having completed the trial if he/she discontinues because of
PD and has performed the safety follow-up visit 30 days after EOT, or was lost to follow up,
or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for any 
other reason, he/she will be considered as withdrawn.
Progression-free survival visits
6.2.3.3
Additional follow-up visits after the 30-day safety follow-up visit will only be performed for 
patients who did not progress on treatment. These will be performed once every 12 weeks at 
least (by telephone) until PD, introduction of a new anti-cancer treatment, death, loss to 
follow-up, or end of the whole trial as specified in Section 3.3.4.
Overall survival visits
6.2.3.4
Additional follow-up visits after the 30-day safety follow-up visit will be performed for 
patients in the dose-expansion cohorts who enrol in Protocol Version 4.0 and beyond. These 
will be performed once every 12 weeks at least (by telephone) on the same schedule as PFS 
survival visits until death, loss to follow-up, or end of the whole trial as specified in 
Section 3.3.4.2. If the sponsor determines that enough OS data has been collected from select 
cohorts, sites could be instructed to discontinue OS visits for those cohorts.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is Phase I, open-label, dose-escalating trial to determine the MTD(s) for BI 754111 in 
combination with BI 754091 in patients with solid tumours to recommend a combination 
dose for Part II dose-expansion cohorts. In addition, the safety and PK profiles, biomarkers, 
and efficacy of BI 754111 in combination with BI 754091 will also be assessed.
7.1.1
Statistical design – Part I (dose escalation)
The objective of Part I of the trial is to determine the MTD(s) of BI 754111 in combination 
with BI 754091 and to recommend a combination dose for Part II (dose expansion cohorts). 
To determine the MTD(s), patients are entered sequentially into escalating dose cohorts and a 
combination BLRM will be applied. 
Combination BLRM
7.1.1.1
The Part I dose escalation will be guided by a Bayesian 5-parameter logistic regression model 
with overdose control (see R15-4233).
The logistic regression model is defined as follows. Let π1,d1 be the probability of having a 
DLT when giving dose d1 of BI 754091 as monotherapy, and π2,d2 the probability of having a 
DLT when giving dose d2 of the combination partner BI 754111 as monotherapy, 
respectively. A logistic regression model is used to model the dose-toxicity relationship for 
each component individually: 
BI 754091 part: 
logit(π1,d1) =log(α1) + β1log(d1/d1*)
BI 754111 part:
logit(π2,d2) =log(α2) + β2log(d2/d2*)
where logit(π) = log(π /(1- π)), the reference doses d1* = d2* = 200 mg are set for BI 754091 
and BI 754111, respectively.
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination of dose d1, d2 is obtained as 
π0
12,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds
odds(π0
12,d1,d2)= π0
12,d1,d2 /(1- π0
12,d1,d2)
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 

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between BI 754091 and BI 754111, a dose-dependent interaction term -∞<η<∞ is introduced 
to the model by the following definition:
odds(π12,d1,d2) = odds(π0
12,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the a variable describing the observed number of DLTs from nd1,d2
patients at the dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
The prior distributions for θ1 and θ2 will be specified as mixtures of two multivariate normal 
distributions, i.e.
f(θk) = a1,k f1(θk) + a2,k f2(θk) 
with
a1,k, a2,k the prior mixture weights, k=1,2 and 
fi(θk) = MVN(μik, Σik) (k=1,2),
the multivariate normal distribution of the i-th component with mean vector μik and 
covariance matrix Σik, where 
Σ = 
	
,
	 ,	 ,


	 ,	 ,


	
,


Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
A weakly informative normal prior distribution will be used for η.
The estimated probability π12,d1,d2 of a DLT at each dose combination d1, d2 from the model 
will be summarised using the following intervals:
Under dosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over dosing: [0.33, 1.00]
The BLRM-recommended dose combination for the next cohort is the level with the highest 
posterior probability of the DLT rate falling in the target interval [0.16, 0.33) among the dose 
combinations fulfilling the EWOC principle. Per EWOC it should be unlikely (i.e., <25% 
posterior probability) that the DLT rate at the dose combination will exceed 0.33. However, 
the maximum allowable dose increment for the subsequent cohort will be no more than 400% 
for each compound.
The MTD may be considered reached if one of the following criteria is fulfilled:
The posterior probability of the true DLT rate in the target interval [0.16,0.33) of the MTD is 
above 0.5, OR
At least 15 patients have been treated in the study, of which at least 6 at the MTD.

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Prior derivation:
By the time BLRM is analyzed, safety data for BI 754091 are expected to be available from 
BI Study 1381.1. The information can be incorporated into the prior derivation meta-analytic 
predictive (MAP) approach. Exact details on the evaluations of the model using hypothetical 
data scenarios and operating characteristics are provided in the statistical appendix. 
For illustrative purposes only, we assume the following hypothetical data on BI 754091 are 
available and describe how prior distribution is derived using the MAP approach (Table 
7.1.1.1: 1). However, at the time when BLRM is performed for 1381.2, actual data available 
will be used instead.
Table 7.1.1.1: 1
Hypothetical data for BI 754091
Dose BI 754091 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
80 
3
0
240
3
0
400
3
0
* Hypothetical for BI 754091 tabulated for illustrative purposes only. Actual data source will be BI 1381.1 study.
The following steps were used to derive the prior distributions for all parameters:
For θ1 (BI 754091):
The meta-analytic-predictive prior was derived using the information of BI 754091 from BI 
Study 1381.1. This mixture component was assigned 90% weight.
A high-toxicity weakly-informative component was added with 10% weight based on the a 
priori assumption that the median DLT rate at the starting dose of 80 mg would equal 3% and 
the median DLT rate at 600 mg would equal 50%. This yields μ12 = (-1.895, 0.545). The 
standard deviations were set such that large uncertainty about the parameter means is 
reflected, and the correlation was set to 0, thus yielding σ12,11 = 2, σ12,22 = 1 and ρ12 = 0, 
respectively.
For θ2 (BI 754111):
A weakly-informative prior component was derived based on the a priori assumption that the 
median DLT rate at the starting dose of 4 mg would equal 5% and the median DLT rate at 
200 mg would equal 20%. This yields μ12 = (-1.386, -0.921). The standard deviations were 
set such that large uncertainty about the parameter means is reflected, and the correlation was 
set to 0, thus yielding σ21,11 = 2, σ21,22 = 1 and ρ21 = 0, respectively. This mixture component 
was assigned 90% weight.
A high-toxicity weakly-informative component was added with 10% weight based on the a 
priori assumption that the median DLT rate at the starting dose of 80 mg would equal 3% and 
the median DLT rate at 600 mg would equal 50%. This yields μ22 = (-1.895, 0.545). The 
standard deviations were set such that large uncertainty about the parameter means is 

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reflected, and the correlation was set to 0, thus yielding σ22,11 = 2, σ22,22 = 1 and ρ22 = 0, 
respectively.
The prior distribution for η will be based on the a priori assumption of positive interaction 
between the two compounds, a normal distribution with mean 0.1 and standard deviation 
0.707 was chosen. At the starting dose combination, the corresponding 95% prior interval 
covers an approximately 4-fold increase (or decrease) in the odds of a DLT over no 
interaction.
The parameters for prior distributions are given in Table 7.1.1.1: 2. The corresponding prior 
probabilities of a DLT at different dose combinations and the corresponding probabilities of 
under-dosing, targeted dosing and overdosing are shown in Table 7.1.1.1: 3. As can be seen 
from Table 7.1.1.1: 3, the highest dose combinations BI 754091 80 mg plus BI 754111 20 mg 
and the combination of BI 754091 240 mg and BI 754111 4 mg have prior probability of 
overdosing below 25%. Any dose combination at or below these levels fulfills the overdose 
criterion and is therefore a suitable starting dose combination.
Table 7.1.1.1: 2
Parameters for prior distributions
Parameter
Means, standard deviations, correlation
Mixture weight
log(α1), log(β1): component 1
-2.987, -0.092, 0.876, 0.806, -0.121
0.90
log(α1), log(β1): component 2
-1.895, 0.545, 2, 1, 0
0.10
log(α2), log(β2): component 1
-1.386, -0.921, 2, 1, 0
0.90
log(α2), log(β2): component 2
-1.895, 0.545, 2, 1, 0
0.10
η
0.1, 0.707, n/a
n/a

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Table 7.1.1.1: 3
Prior probabilities of DLTs
Dose 
(mg)
Dose 
(mg)
Probability of true DLT rate in 
Descriptive 
Statistics
Quantiles
BI 754091
BI 754111
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
80
4
  0.717
  0.137
  0.147
  0.152
  0.201
  0.003
  0.066
  0.780
80
20
  0.634
  0.164
  0.202
  0.193
  0.225
  0.004
  0.096
  0.838
80
80
  0.515
  0.196
  0.289
  0.253
  0.252
  0.009
  0.151
  0.892
80
200
  0.386
  0.219
  0.395
  0.327
  0.276
  0.016
  0.238
  0.933
80
400
  0.296
  0.191
  0.513
  0.412
  0.309
  0.019
  0.345
  0.978
80
600
  0.264
  0.168
  0.569
  0.459
  0.326
  0.017
  0.416
  0.993
240
4
  0.584
  0.218
  0.199
  0.210
  0.214
  0.018
  0.127
  0.842
240
20
  0.504
  0.236
  0.260
  0.249
  0.233
  0.022
  0.158
  0.880
240
80
  0.385
  0.252
  0.363
  0.311
  0.257
  0.027
  0.221
  0.921
240
200
  0.286
  0.218
  0.496
  0.394
  0.290
  0.025
  0.326
  0.964
240
400
  0.256
  0.149
  0.594
  0.486
  0.340
  0.010
  0.464
  0.994
240
600
  0.267
  0.116
  0.617
  0.530
  0.372
  0.003
  0.568
  0.999
400
4
  0.431
  0.268
  0.301
  0.280
  0.246
  0.028
  0.192
  0.936
400
20
  0.362
  0.273
  0.364
  0.317
  0.257
  0.032
  0.232
  0.949
400
80
  0.277
  0.250
  0.474
  0.381
  0.278
  0.034
  0.309
  0.968
400
200
  0.245
  0.172
  0.583
  0.467
  0.321
  0.017
  0.431
  0.989
400
400
  0.268
  0.105
  0.627
  0.541
  0.378
  0.003
  0.595
  0.999
400
600
  0.294
  0.075
  0.631
  0.568
  0.408
  0.000
  0.700
  1.000
The prior may be updated once the trial has started in case new data that can be used will be 
available. The prior that is used for each BLRM analyses for the SRC meetings will be 
documented in the SRC meeting minutes, the prior used for the final analyses will be 
documented in the Trial Statistical Analysis Plan (TSAP).
Statistical model assessment
7.1.1.2
The model was assessed using 2 different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could 
occur in the actual trial, the maximal doses allowed in the next cohort by the model 
are investigated. Data scenarios thus provide a way to assess the ‘on-study’ behaviour 
of the model.
2. Simulated operating characteristics: these illustrate for different assumed true dose-
toxicity relationships, how often a correct dose would be declared as MTD by the 
model. They are a way to assess the ‘long-run’ behaviour of the model.

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In summary, the model showed reasonable behaviour as assessed by these metrics. More 
details can be found in Appendix 10.5. The simulations were conducted using R Version 
3.2.2 in conjunction with WinBUGS Version 1.4.
7.1.2
Statistical design – Part II (dose expansion cohorts)
Part II (dose expansion cohorts) of the trial will be designed as multiple open-label cohorts. 
Cohorts of approximately 40 patients with 2nd or 3rd line NSCLC, 40 patients with mCRC, 40
patients with any solid tumour with high TMB and/or MSI-H (as defined in the entry criteria, 
see Section 3.3), and 40 patients with 1st line NSCLC (this cohort will include up to 10 
patients with PD-L1 expression ≥50%) at the dose and schedule recommended by the SRC.
The analyses of the safety and efficacy for this portion of the trial will be descriptive and 
exploratory in nature.
NULL AND ALTERNATIVE HYPOTHESES
7.2
No formal hypothesis testing is planned in this trial.
PLANNED ANALYSES
7.3
No per protocol set will be used in the analysis. However, important protocol violations will 
be summarised. The TSAP will specify the important protocol violations in detail.
For the determination of the MTD, only MTD-evaluable patients will be considered. For the 
analysis of secondary and further endpoints, all patients in the treated set (i.e., patients treated 
with at least one dose of trial medication) will be included in the analysis. Any other analysis 
sets will be defined in the TSAP.
7.3.1
Primary endpoint analyses
Primary endpoint analyses for Part I
7.3.1.1
In order to identify the MTD(s) and the recommended dose(s) for Part II of the trial, the 
number of patients with DLTs at each dose combination during the Part I MTD evaluation 
period (the first cycle of the BI 754111 plus BI 754091 combination) must be presented by 
descriptive statistics. Patients who discontinue during the first treatment cycle for reasons 
other than a DLT will be excluded from the determination of the MTD.
In addition, the number of patients with DLTs that occurred during the entire treatment 
period, including Part I and Part II, will be summarised at each dose level. The BLRM will be 
rerun to re-evaluate the MTD and selected expansion dose together with all relevant data 
collected during Part II.
Primary endpoint analyses for Part II
7.3.1.2
The primary endpoint for Part II of the trial is OR defined by confirmed CR or PR according 
to RECIST 1.1 as assessed by the Investigator. Overall response will be analysed in terms of 

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OR rate (ORR), defined as the proportion of patients with best overall response of CR or PR 
determined and confirmed by RECIST 1.1. The ORR will be calculated and presented with 
95% two-sided confidence intervals using the exact Clopper-Pearson method.
7.3.2
Secondary endpoint analyses
Secondary endpoint analyses for Part I
7.3.2.1
The number of patients experiencing DLTs from start of treatment until end of treatment will 
be summarized by descriptive statistics.
Analyses of OR are described in Section 5.1.2.1. Overall response will be analysed in terms
of OR rate (ORR), defined as the proportion of patients with best overall response of CR or 
PR. The ORR will be calculated and presented with 95% two-sided confidence intervals 
using the exact Clopper-Pearson method.
Details on statistical inference for PK parameters, e.g., dose proportionality using Cmax and 
AUC0-504, etc., and all other secondary endpoints analysis will be specified in the TSAP.
Secondary endpoint analyses for Part II
7.3.2.2
Disease control (DC) will be analysed in terms of DC rate (DCR), defined as the proportion 
of patients with best overall response of CR, PR, or SD according to RECIST 1.1. 
Proportions will be presented with 95% two-sided confidence interval using the exact 
Clopper-Pearson method.
Duration of objective response (DoR) - for all patients with an OR, the duration of OR will be 
calculated as follows:
For patients with disease progression or death:
∀
Duration of OR [days] = date of outcome – date of first assessment indicating OR + 1
For patients without disease progression or death:
∀
Duration of OR (censored) [days] = date of outcome – date of first assessment indicating 
OR + 1
The censoring rules for OR (i.e., outcome and date of outcome) are described in the TSAP. 
The outcome will be assessed according to RECIST 1.1.
Kaplan-Meier estimates will be used to calculate median duration of OR.
Progression-free survival (PFS) is defined as time from first drug intake until disease 
progression or death from any cause, whichever occurs earlier. The date of progression will 
be based on the Investigator assessment according to RECIST 1.1.
For patients with ‘event’ as an outcome for PFS:
∀
PFS [days] = date of outcome – date of start of treatment + 1
For patients with ‘censored’ as an outcome for PFS:
∀
PFS (censored) [days] = date of outcome – date of start of treatment + 1

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The censoring rules for PFS (i.e., outcome and the date of outcome) are described in the 
TSAP.
Kaplan-Meier estimates will be used to display the distribution of PFS with 95% confidence 
intervals, using Greenwood’s variance estimate.
Analyses of PK parameters, i.e., Cmax and AUC0-504 will be described in Section 7.3.5. More 
details will be provided in TSAP.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. 
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. All 
AEs with an onset between start of treatment and end of the REP, a period of 30 days after 
the last dose of trial medication, will be considered ‘treatment-emergent’ and assigned to the 
treatment period for evaluation. 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 AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of MedDRA.
Laboratory data will be analysed quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as 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.

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7.3.5
Pharmacokinetic and pharmacodynamic analyses
Pharmacokinetic parameters as described in Section 5.4.1 will be calculated by means of non-
compartmental analysis. The derivation of PK parameters is described in BI internal SOP 
(001-MCS-36-472_RD-01 [2.0] and 
SOP ‘SOP-1.PKA.03 Non-
compartmental PK/PD Analysis’).
Further details on analysis will be described in the TSAP.
INTERIM ANALYSES
7.4
The sponsor will continuously monitor the safety. The dose-escalation design dictates that the 
sponsor and the SRC perform regular safety evaluations. These evaluations will be unblinded 
to dose.
If considered necessary, as soon as the MTD is determined, an evaluation of the safety 
aspects will be performed. Results of this evaluation will be documented and archived. If 
applicable, such an analysis will be defined in more detail in the TSAP.
No formal interim analysis of PK data is planned. However, exploratory analysis of PK will 
be done during the dose escalation part and may also be done during the expansion part, if 
considered reasonable.
Exploratory PK analyses will be based on planned sampling times, if information on actual 
times should not be available. The results of these evaluations will be preliminary and may be 
subject to change, as these do not involve a formal database lock. No interim report will be 
written for exploratory PK analyses.
If medically justified, further or fewer exploratory PK analyses may be performed.
An interim futility analysis will be performed for Cohort G, I, and J in Part II. Until a 
decision from the futility analysis is made, the enrolment for that cohort will not be stopped. 
The two-stage design is planned to stop further enrolment if the defined efficacy boundary 
(see Table 7.7.2: 1 and Table 7.7.2: 3) is not met at the first stage.
The interim analysis for Part II will be conducted when:
•
The last patient contributing to the interim analysis has completed the third on-
treatment imaging assessment (i.e. end of cycle 6).
If the last patient contributing to the interim analysis discontinues earlier than the third on-
treatment imaging, the interim futility analysis will be done at approximately 4 months after 
the first administration of that patient.
Data from 1381-0002 and 1381-0004 may be pooled for the interim futility decision making, 
if applicable. If considered necessary, an evaluation of the efficacy and safety aspects will be
performed. Results of this evaluation will be documented and archived. If applicable, such an
analysis will be defined in more detail in the TSAP.

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HANDLING OF MISSING DATA
7.5
In general, no imputation will be performed on missing efficacy data. For PFS data, every 
effort will be made to obtain date of progression for patients known to have progressed. 
Detailed censoring rules will be specified in the TSAP. Missing baseline laboratory values 
will be imputed by the respective values from the screening visit. No other imputations will 
be performed on missing data although every effort will be made to obtain complete 
information on all AEs, with particular emphasis on potential DLTs. For partial or missing 
AE onset and/or end dates, BI internal rules will be followed (see Reference Document 001-
MCG-156_RD01 “Handling of missing and incomplete AE dates”).
RANDOMISATION
7.6
No randomisation will be performed. Patients will be assigned to escalating dose groups by 
order of admission into the trial.
DETERMINATION OF SAMPLE SIZE
7.7
7.7.1
Determination of sample size for Part I
For Part I, no formal statistical power calculations of sample size were performed.
Approximately 50 patients for Part I (dose-escalation) are expected. Fewer or more patients 
might be needed based on the recommendation of the SRC and the actual number of cohorts 
tested.
7.7.2
Determination of sample size for Part II
For Cohorts G and I, it is considered clinically meaningful based on the current literature for 
the combination of BI 754111 and BI 754091 to achieve an underlying ORR of 25%. A 
futility boundary of an ORR of 10% will be used for the interim analysis. Assuming an 
underlying ORR of 25%, the probability of observing <2 responders out of 20 patients and 
stopping at the interim is 2%, and the probability of observing an ORR ≥20% at the final 
analysis is 81%. Alternatively, assuming an underlying ORR of 5%, the probability of 
stopping at the interim is 74% and the probability of observing an ORR ≥20% at the final 
analysis is 0%. Table 7.7.2: 1 summarizes the early stopping criteria and probabilities of 
observing certain ORRs based on different assumptions of the underlying ORR.
Table 7.7.2: 1 Early stopping criteria and probabilities of the two-stage approach in Cohorts 
G and I
Assumed 
underlying 
ORR
Early stopping 
criterion (observed 
ORR)
Early 
stopping 
probability
Observed ORR at 
final analysis
Probability of 
observed ORR 
at final analysis
5%
<10% (<2 out of 20)
74%
≥20% (≥8 out of 40)
0%
10%
<10% (<2 out of 20)
40%
≥20% (≥8 out of 40)
4%
15%
<10% (<2 out of 20)
18%
≥20% (≥8 out of 40)
24%

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Table 7.7.2: 1 Early stopping criteria and probabilities of the two-stage approach in Cohorts 
G and I (continued)
20%
<10% (<2 out of 20)
7%
≥20% (≥8 out of 40)
55%
25%
<10% (<2 out of 20)
2%
≥20% (≥8 out of 40)
81%
30%
<10% (<2 out of 20)
1%
≥20% (≥8 out of 40)
95%
For Cohort H, it is planned that 40 patients will be enrolled and no interim futility analysis 
will be performed. Based on the current literature, it is considered clinically meaningful if the 
combination of BI 754111 and BI 754091 will achieve an underlying ORR of 20%. With 40 
evaluable patients, an ORR of 15% or more would be observed with a probability of 
approximately 84% assuming a true response rate of 20%. The probability of observing a 
false positive signal, e.g., to observe an ORR of at least 15% if the underlying true ORR is 
5%, is around 1%. Table 7.7.2: 1 summarizes the probability of observing certain ORRs 
based on different assumptions of the underlying ORR.
Table 7.7.2: 2 Probabilities of observing certain objective response rates in Cohort H
True 
underlying OR 
rate
Patients in 
each cohort
Probability to observe at least
ORR ≥ 10%
(≥ 4 patients 
with OR)
ORR ≥ 15%
(≥ 6 patients 
with OR)
ORR ≥ 20%
(≥ 8 patients 
with OR)
20%
40
97.2%
83.9%
56.3%
15%
40
87.0%
56.7%
24.4%
10%
40
57.7%
20.6%
4.2%
5%
40
13.8%
1.4%
0.1%
For Cohort J, it is planned that a total of 40 patients will be enrolled, with a maximum of 10 
patients with PD-L1 high expression (≥ 50% PD-L1). In CheckMate 026, the ORR was 21% 
with nivolumab (N=101) compared with 26% in the chemotherapy group (N=81) for 1st line 
NSCLC patients with 1%≤ PD-L1 <50% (R19-0527). In KEYNOTE-189, the ORR was 
48.4% (95% CI, 39.5-57.4) with pembrolizumab plus chemotherapy (N=128) compared with 
20.7% (95% CI, 11.2-33.4) with chemotherapy alone (N=58) for patients with 1%≤ PD-L1
<50%; the ORR was 32.3% (95% CI, 24.3-41.2) with pembrolizumab plus chemotherapy
(N=127) compared with 14.3% (95% CI, 6.7-25.4) with chemotherapy alone (N=63) for 
patients with PD-L1 <1% (P18-03589). Based on the above literature, it is deemed clinically 
meaningful if the underlying ORR for the combination of BI 754111 and BI 754091 will be 
40% for patients with PD-L1 < 50%, and a futility boundary of 20% will be used for the 
interim analysis of this population in Cohort J. With 30-40 evaluable patients and assuming 
an underlying ORR of 40%, the probability of observing <4 responders out of 17 patients and 
stopping at the interim is 5%, and the probability of observing an ORR ≥35% at the final 
analysis is between 70% to 77%. Alternatively, assuming an underlying ORR of 15%, the 

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probability of stopping at the interim is 76% and the probability of observing an ORR ≥35% 
at the final analysis is 0%. Table 7.7.2: 3 summarizes the early stopping criteria and 
probabilities of observing certain ORRs based on different assumptions of the underlying 
ORR.

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Table 7.7.2: 3 Early stopping criteria and probabilities of the two-stage approach in Cohort J
Assumed 
underlying 
ORR
Early stopping 
criterion (observed 
ORR)
Early 
stopping 
probability
Observed ORR at final
analysis
Probability of 
observed ORR 
at final analysis
Assuming 30 patients with PD-L1 <50%
15%
<20% (<4 out of 17)
76%
≥35% (≥11 out of 30)
0%
20%
<20% (<4 out of 17)
56%
≥35% (≥11 out of 30)
2%
25%
<20% (<4 out of 17)
36%
≥35% (≥11 out of 30)
10%
30%
<20% (<4 out of 17)
20%
≥35% (≥11 out of 30)
26%
35%
<20% (<4 out of 17)
11%
≥35% (≥11 out of 30)
48%
40%
<20% (<4 out of 17)
5%
≥35% (≥11 out of 30)
70%
Assuming 40 patients with PD-L1 <50%
15%
<20% (<4 out of 17)
76%
≥35% (≥14 out of 40)
0%
20%
<20% (<4 out of 17)
56%
≥35% (≥14 out of 40)
2%
25%
<20% (<4 out of 17)
36%
≥35% (≥14 out of 40)
10%
30%
<20% (<4 out of 17)
20%
≥35% (≥14 out of 40)
29%
35%
<20% (<4 out of 17)
11%
≥35% (≥14 out of 40)
54%
40%
<20% (<4 out of 17)
5%
≥35% (≥14 out of 40)
77%

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, the ICH Harmonised Tripartite Guideline for GCP, relevant BI 
SOPs, and other relevant regulations.
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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor with regard 
to publication of the results of this trial are described in the Investigator contract. As a rule, 
no trial results should be published prior to finalisation of the Clinical Trial Report.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB and competent authority 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 signed ICF must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH/GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the ICF and any additional patient-information form 
retained by the Investigator as part of the trial records. A signed copy of the ICF and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The Investigator or delegate must give a full explanation to trial patients based on the ICF 
information. 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 or delegate obtains written consent of the patient’s 
own free will with the ICF after confirming that the patient understands the contents. The 
Investigator or delegate must sign (or place a seal on) and date the ICF. If a trial collaborator 
has given a supplementary explanation, the trial collaborator also signs (or places a seal on) 
and dates the ICF.

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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.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or the IRB or regulatory authorities. The quality assurance auditor will have access 
to all medical records, the Investigator’s trial-related files and correspondence, and the ICF
documentation of this clinical trial.
RECORDS
8.3
Electronic CRFs for individual patients will be provided by 
 
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 subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject 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 3 documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in the
medical records, will be acceptable.
Before providing any copy of patients’ source documents to the sponsor, 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 to ensure patient 
confidentiality.
Copies of tumour assessments scans may be collected by the sponsor upon request. This 
could include CT/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 method (CT/PET scan or 
MRI).
If the patient is not compliant with the protocol, any corrective action (e.g., retraining) must 
be documented in the patient file.

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For the eCRF, data must be derived from source documents, for example:
∀
Patient identification: gender, date or 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 AEs (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 
properly documented medical evaluation (in validated electronic format [if available])
∀
Completion of the 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 treatment in 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 
specifically for a protocol) to support inclusion/exclusion criteria makes the patient 
ineligible 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
will monitor the conduct of the trial by regular on-
site monitoring visits and in-house data quality reviews. The frequency of on-site monitoring 
will be determined by assessing all characteristics of the trial, including its nature, objective, 
methodology and the degree of any deviations of the intervention from normal clinical 
practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, and copies of laboratory and medical test results, 
which must be available at all times for review by the monitor, auditor, and regulatory 
inspector (e.g., FDA). The monitor and auditor may review all CRFs and ICFs. 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 ICH GCP.
8.3.3
Storage period of records
Trial sites:

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The trial sites must retain the source and essential documents (including ISF) according to the 
national or local requirements (whichever are is longer) valid at the time of the end of the 
trial.
Sponsor: The sponsor must retain the essential documents according to the sponsor’s SOPs.
will retain 
trial documents according to contractual agreements with the sponsor.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
Exemptions from expedited reporting are described in Section 5.3.6.10, if applicable.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. 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 GCP handbook. 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, the IRB, 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 from clinical trial participants and the corresponding data, in 
particular
∀
A Quality Management System has been implemented to ensure the adherence with the 
principles of GCP as outlined in 'Note For Guidance On Good Clinical Practice' 
(CPMP/ICH/13 5/95)
∀
The BI internal facilities storing and analysing biological samples and data from clinical 
trial participants as well as the laboratories' activities for clinical trials sponsored by BI
are regularly audited. The analytical groups and the banking facility are therefore assessed 
to be qualified for the storage and use of biological samples and data collected in clinical 
trials.
∀
Samples and data are used only if an appropriate ICF is available.

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TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the trial. 
The end of the trial is defined as the date of the last visit of the last patient in the trial (‘Last 
Patient Out’).
The ‘Last Patient Drug Discontinuation’ (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of suspected unexpected serious 
adverse reactions occurring with the trial medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.

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9.
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Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a 
novel member of the immunoglobulin gene superfamily, upon programmed 
cell death. The EMBO Journal. 1992;11(11):3887-95.
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Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. 
Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. 
Science. 2001;291(5502):319-22.
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Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. 
Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of 
immune evasion. Nature Med. 2002;8(8):793-800.
R16-2707
Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, et al. Nivolumab 
alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer 
(CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 
2016.
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Dong H, Zhu G, Tamada K, Flies DB, Deursen JMA van, Chen L. B7-H1 
determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. 
Immunity. 2004;20(3):327-36.
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Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in 
peripheral tolerance. Trends Immunol. 2001;22(5):265-68.
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Okazaki T, Okazaki I, Wang J, Sugiura D, Nakaki F, Yoshida T, et al. PD-1 
and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity 
in mice. J Exp Med. 2011;208(2):395-407.
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Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. 
Safety and Efficacy of Durvalumab (MEDI4736), an Anti–Programmed Cell
Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced 
Urothelial Bladder Cancer. J Clin Oncol. 2016;34:1-9.
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American Cancer Society. Cancer facts & figures 2016. 
http://www.cancer.org/acs/groups/content/@research/documents/document/ac
spc-0470 79.pdf (access date: 20 October); Atlanta: American Cancer Society 
2016.
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Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al, 
KEYNOTE-024 Investigators Pembrolizumab versus chemotherapy for PD-
L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-1833. 
R16-4804
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, 
Powell SF, et al, KEYNOTE-021 Investigators Carboplatin and pemetrexed 
with or without pembrolizumab for advanced, non-squamous non-small-cell 
lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 
study. Lancet Oncol, 2016; 17: 1497-1508.
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Lipson EJ, Gopal AK, Neelapu SS, Armand P, Spurgeon S, Leonard JP, et al. 
Initial Experience Administering BMS-986016, a Monoclonal Antibody That 
Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination 
With Nivolumab to Patients With Hematologic and Solid Malignancies. 31st 

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Ann Sci Mtg of the Society of Immunotherapy of Cancer (SITC), National 
Harbor, 9-13 Nov 2016 (Abstract).
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Initial Experience Administering BMS-986016, a Monoclonal Antibody That 
Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination 
With Nivolumab to Patients With Hematologic and Solid Malignancies. 31st 
Ann Sci Mtg of the Society of Immunotherapy of Cancer (SITC), National 
Harbor, 9-13 Nov 2016 (Poster).
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upregulation of PD-1, LAG-3 and CTLA-4 limits the efficacy of single agent 
checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2016.
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Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of 
LAG-3 in regulatory T cells. Immunity 2014;21:503-13.
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Workman CJ, Vignali DAA. Negative regulation of T cell homeostasis by 
lymphocyte activation gene-3 (CD223). J Immunol. 2005;174(2):688-95.
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Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-
Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related 
to CD4. J Exp Med. 1990;171(5):1393–1405.
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Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. 
Characterization of the major histocompatibility complex class II binding site 
on LAG-3 protein. Proc Natl Acad Sci USA. 1997;94:5744-49.
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Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali 
DAA. Lymphocyte activation gene-3 (CD223) regulates the size of the 
expanding T cell population following antigen activation in vivo. J Immunol. 
2004;172:5450-55.
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Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, 
et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 
2013;369(2):122-33.
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Hellmann MD, Gettinger SN, Goldman JW, Brahmer JR, Borghaei H, Chow 
LQ, et al. CheckMate 012: safety and efficacy of first-line (1L) nivolumab 
(nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 
2016;34(Suppl), Abstr 3001.
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Atezolizumab versus docetaxel in patients with previously treated non-small-
cell lung cancer (OAK): a phase 3, open-label, multicentre randomised 
controlled trial. Lancet 2017;389:255-265.
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Seymour L, Bogaerts J, Perone A, Ford R, Schwartz LH, Mandrekar S, et al., 
RECIST Working Group iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol 2017 18 (3), e143 - e152.
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Castellucci E, He T, Goldstein DY, Halmos B, Chuy J. DNA Polymerase ɛ
Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically 
Relevant Entity. Oncologist. 2018;22(5):497-502. doi: 
10.1634/theoncologist.2018-0034. Epub 2018 May 2.
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Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, Angelis F de, et 
al, KEYNOTE-189 Investigators Pembrolizumab plus chemotherapy in 

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metastatic non-small-cell lung cancer. N Engl J Med. 2018 doi: 
10.1056/NEJMoa1801005 [Epub ahead of print].
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Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-
Valette C, et al Nivolumab plus ipilimumab in lung cancer with a high tumor 
mutational burden.  N Engl J Med. 2018 Apr 16. doi: 
10.1056/NEJMoa1801946. [Epub ahead of print]
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Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai 
J, et al., Nivolumab in patients with metastatic DNA mismatch repair-deficient 
or microsatellite instability-high colorectal cancer (CheckMate 142): an open-
label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. 
doi: 10.1016/S1470-2045(17)30422-9.
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Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al, 
CheckMate 026 Investigators First-line nivolumab in stage IV or recurrent 
non-small-cell lung cancer. N Engl J Med 376 (25), 2415 - 2426 (2017).
UNPUBLISHED REFERENCES
9.2
n00250935
 Tetanus toxoid assay for BI 754091 in combination with BI 754111. 
20 Jul 2016.
n00253546
 Anti-LAG-3 mAb BI 754111 – Prediction of 
Human Pharmacokinetics and Therapeutic Dose. Report in preparation..
001-MCS-36-472_RD-01 Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses 
of Clinical Studies [actual version]

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10.
APPENDICES
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST
10.1
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 (reported as an AESI if ≥Grade 2)
∀
Acute interstitial pneumonitis
∀
Interstitial lung disease
∀
Pneumonitis
Colitis (reported as an AESI if ≥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 (reported as an AESI if ≥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 (reported as an AESI)
∀
Type 1 diabetes mellitus (if new onset)

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Table 10.1: 1 Immune-related adverse events of special interest (Continued)
Immune-related adverse events of special interest
Hematologic (reported as an AESI if ≥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 (reported as an AESI if ≥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 (reported as an AESI)
∀
Allergic reaction
∀
Anaphylaxis
∀
Cytokine release syndrome
∀
Serum sickness
∀
Infusion reactions
∀
Infusion-like reactions
Neurologic (reported as an AESI)
∀
Autoimmune neuropathy
∀
Guillain-Barre syndrome
∀
Demyelinating polyneuropathy
∀
Myasthenic syndrome
Ocular (report as an AESI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE)
∀
Uveitis
∀
Iritis

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Table 10.1: 1 Immune-related adverse events of special interest (Continued)
Immune-related adverse events of special interest
Renal (reported as an AESI if ≥ Grade 2)
∀
Nephritis
∀
Nephritis autoimmune
∀
Renal failure
∀
Renal failure acute
∀
Creatinine elevations (report as an irAE if ≥Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)
Skin (reported as an AESI)
∀
Dermatitis exfoliative
∀
Erythema multiforme
∀
Stevens-Johnson syndrome
∀
Toxic epidermal necrolysis
Skin (reported as an AESI if ≥ Grade 3)
∀
Pruritus
∀
Rash
∀
Rash generalized
∀
Rash maculopapular
∀
Any rash considered clinically significant in the physician’s judgment
Other (reported as an AESI)
∀
Myocarditis
∀
Pancreatitis
∀
Pericarditis
∀
Any other Grade 3 event that is considered immune-related by the physician
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS
10.2
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 >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:

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-
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.
-
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
-
For Grade 3-4 events immediately treat with i.v. steroids. Administer additional 
anti-inflammatory measures, as needed.
-
BI 754091 should be permanently discontinued for Grade 3-4 pneumonitis, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2 AEs that do not recover to Grade 1 or less within 
12 weeks.
∀
Diarrhoea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).
-
All subjects who experience diarrhoea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via i.v. infusion.  For Grade 2 or higher 
diarrhoea, consider GI consultation and endoscopy to confirm or rule out colitis.
-
For Grade 2 diarrhoea/colitis that persists greater than 3 days, administer oral 
corticosteroids.
-
For Grade 3 or 4 diarrhoea that persists >1 week, treat with i.v. steroids followed 
by high-dose oral steroids.
-
For Grade 3 or 4 colitis, or recurrent colitis of any grade, permanently discontinue
BI 754091 and immediately treat with i.v. steroids followed by high-dose oral 
steroids.
-
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
-
BI 754091 should be permanently discontinued for Grade 3-4 or recurrent colitis 
of any grade, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.
∀
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis) Grade 3, or
≥Grade 3 hyperglycaemia, if associated with ketosis (ketonuria) or metabolic acidosis
-
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.
-
BI 754091 should be permanently discontinued for Grade 4 diabetes mellitus, any 
recurrent Grade 3 AE or persistent Grade 2-3 AE that does not recover to Grade 1 
or less within 12 weeks.
∀
Hypophysitis:
-
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. 

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Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
-
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.
-
For Grade 4 events, permanently discontinue BI 754091, and treat with an initial 
dose of i.v. corticosteroids followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 28 days. Replacement of appropriate hormones may be required as the 
steroid dose is tapered.
-
BI 754091 should be permanently discontinued for Grade 4 hypophysitis, any 
recurrent Grade 3 AE, inability to taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.
∀
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
-
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 liothyroinine, is indicated per standard of care.
-
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.
-
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.
∀
Hepatic:
-
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with i.v. or oral corticosteroids
-
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.
-
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 28 days.
-
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
transaminase >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.

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∀
Renal failure or nephritis:
-
For Grade 2 events, treat with corticosteroids.
-
For Grade 3-4 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.
-
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.
∀
Adrenal insufficiency
-
BI 754091 should be permanently discontinued for Grade 3-4 adrenal 
insufficiency or persistent Grade 2 AEs that do not recover to Grade 1 or less 
within 12 weeks.
∀
Rash
-
BI 754091 should be permanently discontinued for Grade 4 rash, any recurrent 
Grade 3 AE or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.
∀
Encephalitis
-
BI 754091 should be permanently discontinued for any grade encephalitis.
∀
Infusion reactions:
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 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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HANDLING PROCEDURES FOR BLOOD SAMPLES FOR PLASMA 
10.3
CONCENTRATION-TIME MEASUREMENTS
Handling procedures for blood samples are presented in the Laboratory Manual.

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TIME SCHEDULES FOR PHARMACOKINETIC, BIOMARKER, AND 
10.4
BLOOD SAMPLING
10.4.1
Schedules for PK,
blood sampling – Part I dose-escalation
cohorts
Table 10.4.1: 1
Time schedule for PK and
sampling - Part I
dose-escalation cohorts (Cycles 1, 2, and 4 for solid tumour cohorts)
Treatm
ent
Cycles
Day
Time Point b
[hh:min]
CRF Time
/PTM
Event
PK BI 754111 & 
BI 754091c
1, 2, 
and 4
1
Just before 
BI 754091 (or 
combination) 
SOI
-1:00 to -0:05
Blood sampling
X
0:00
0:00
Start of BI 754091 
Infusion (or 
combination of 
BI 754111 / 
BI 754091)
---
Shortly after end 
of BI 754111 
infusiona
1:00
Blood sampling
Xd
4 hours post BI 
754091 SOIa
4:00
Blood sampling
X
7 hours post BI 
754091 SOIa
7:00
Blood sampling
X
2
24 hours post BI 
754091 SOI
24:00
Blood sampling
X
4
72 hours post BI 
754091 SOI
72:00
Blood sampling
X
8 (±1)
168 hours post 
BI 754091 SOI
168:00
Blood sampling
X
15
(±1)
336 hours post 
BI 754091 SOI
336:00
Blood sampling
X
 BI = Boehringer Ingelheim; CRF = Case Report Form; PK = pharmacokinetics; 
PTM = Planned Time; SOI = Start of infusion
a The planned total infusion duration is 1 hour. For cohorts receiving doses of BI 754111 <80 mg, the overall 
infusion duration (BI 754091+BI 754111) should also be as close to 1 hour as possible. In the event that total infusion 
duration is >15 minutes longer than planned, the subsequent time points for PK blood collection on the day of drug 
infusion should be adjusted accordingly (e.g., 1.25 hours post SOI). For cohorts receiving combination treatment using 
doses of BI 754111 <80 mg, the 1 hour PK sample is to be drawn shortly after the end of the BI 754111 infusion. Actual date 
and clock time of SOI, end of infusion and blood draws have to be recorded.
b The following windows of time are allowed for PK sampling:
∀
Predose (PTM -0:05): within 1 hour before next drug infusion
∀
Shortly after the end of infusion (PTM 1:00): within ±5 min of the end of infusion
∀
4 and 7 hours post SOI (PTM 4:00 and 7:00): ±15 minutes
∀
24 and 72 hours post SOI (PTM 24:00 to 72:00): ±1 hour
∀
168 and 336 hours post SOI (PTM 168:00 to 336:00): ±24 hour.
   Note: Time windows have been specified for procedural reasons; deviations do not automatically lead to exclusion 
of samples from data evaluation.

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c The specified blood volume for both BI 754111 and BI 754091 will be drawn into separate blood-drawing tubes. However, 
they should be collected in parallel at the specified time points after the start of the BI 754091 (or combination) infusion.
d. An additional blood sample will be taken one time from all subjects of the first dose group that exceeds 200 mg 
BI 754111.

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Table 10.4.1: 2
Time schedule for PK,
 
sampling - Part I dose-escalation cohorts (Solid 
tumour cohorts: Cycles 3, 5 to 12, 14, and 17 only)
Treatment
Cycle
Day
Time Point
a [hh:min]
CRF Time
/PTM
Event
PK BI 754111 and 
BI 754091 b
3, 5 to 12, 14, 
and 17 
1
Just before 
BI 754091
(or 
combination)
SOI
-0:05
Blood 
sampling
X
0:00
0:00
Start of 
BI 75409
1 infusion 
(or 
combinati
on of 
BI 75411
1/ 
BI 75409
1)
---
EOT
Blood 
sampling
X
FU
Blood 
sampling
X
; BI = Boehringer Ingelheim; CRF = Case Report Form; EOT = end of treatment; FU = follow 
up; MDSC = myeloid-deprived suppressor cell; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetics; PTM 
= Planned Time;; SOI = start of infusion
a The following windows of time are allowed for PK sampling:  Predose (PTM -0:05): within 1 hour before next 
drug infusion
   Note: Time windows have been specified for procedural reasons; deviations do not automatically lead to 
exclusion of samples from data evaluation.
b The specified blood volumes for both BI 754111 and BI 754091 will be drawn into separate blood-drawing 
tubes. However, they should be collected in parallel at the specified time points after the start of the BI 754091 
(or combination) infusion.

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STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.5
AND DATA SCENARIOS
One combination BLRM with overdose control is introduced in Section 7.1 with the prior 
distributions for the model parameters fully specified. Once patients in each cohort have 
completed the combination MTD evaluation period, the prior distribution will be updated 
through Gibbs sampling procedures with the accumulated DLT data from the MTD
evaluation period. Posterior probabilities for the rate of DLTs will be summarised from 
BLRM. Selection of the next dose will be based on these probabilities as well as on other
safety and laboratory data.
The purpose of this statistical appendix is to evaluate the model behaviour and model 
performance. To evaluate the model behaviour, Section 10.5.1 illustrates a series of different 
scenarios that mimic the ones which might arise during the actual study conduct. On-study 
recommendations for the next dose combinations by the BLRM with overdose control 
principle are also provided under various hypothetical outcome scenarios in early cohorts to 
show how EWOC facilitates on-trial dose-escalation decisions (see Table 10.5.1: 1).
In order to understand the long-term performance of the model, Section 10.5.2 presents
performance metrics (operating characteristics) that illustrate the precision of the design in 
estimating the MTD under various dose-toxicity relationships through computer simulation. 
These results are summarised in Table 10.5.2: 2. For simplicity reasons, a cohort size of 
3 patients who are all evaluable is assumed. In case a DLT is observed, an additional 
3 patients will be added to the current dose cohort. The simulations for scenarios and 
operating characteristics were conducted using R Studio Version 3.2.2 in conjunction with 
WinBUGS 1.4.3.
10.5.1
Hypothetical data scenarios
Hypothetical data scenarios during dose escalation are shown in Table 10.5.1: 1. These 
scenarios reflect potential on-study data constellations and related escalation as allowed by 
the model. It is assumed that each cohort has 3 patients who are all evaluable. At the 1st
occurrence of a DLT, additional 3 patients will be added to the current cohort. For each 
scenario, the probability of overdose for the current dose, as well as the next potential dose 
and related probabilities of under-dosing, target dose, and over-dosing are shown.
For example, Scenario 1A represents the case that no DLT is observed in the first 3 patients 
at the starting dose combination of BI 754091 240 mg plus BI 754111 4 mg (denoted by 
240 mg/4 mg for easier reference). In this case, 240 mg/80 mg is recommended as the next 
highest dose.
In Scenario 1B, 1 DLT is observed in the first cohort, i.e., 240 mg/4 mg. The next allowed 
dose combination by the model remains 240 mg/4 mg.

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Based on Scenario 1B, Scenario 1D illustrates a case where 1 DLT is observed in the first 
3 patients and additional 3 patients have been enrolled. No additional DLTs have occurred. 
The next allowed dose combination from the model is 240 mg /20 mg.
On the other hand, Scenario 1E represent a case that 1 DLT is observed in the first 3 patients 
and additional 1 DLT is observed in the subsequent 3 patients treated, i.e., 2 DLTs out of 
6 patients are observed at 240 mg / 4 mg. Model shows current dose exceeded threshold, i.e., 
25.8 >25% and hence dose escalation stops.
Scenario 1C represents a more extreme case that 2 DLTs are observed in the first cohort of 
three patients, i.e., 240 mg/4 mg. In this case, the model suggests current dose has already 
exceeded the overdose threshold, i.e., 63.0% >25%, and hence no further dose can be 
recommended.
Scenarios 2A – 2E represent the cases that the first two cohorts have completed evaluation at 
240 mg/4 mg and 240 mg/20 mg, respectively. In Scenario 2A, no DLTs are observed in the 
240 mg/4 mg cohort or 240 mg/20 mg cohort, model suggests 240 mg/80 mg as next 
recommended dose combination. In Scenario 2C, no DLTs are observed in the first
240 mg/4 mg cohort but 1 DLT out of 6 patients is observed in the 240 mg/20 mg cohort, the 
model recommends 240 mg/80 mg as next dose combinations for considerations of further 
escalation.
Scenarios 2B, 2D and 2E represents the 3 cases with higher toxicity, i.e., 1 out of 3, 2 out of 
6, and 3 out of 6 patients experienced DLTs. The recommended dose combinations are to 
remain current dose, remain current dose, and decrease to 240 mg/4 mg for Scenarios 2B, 2D 
and 2E, respectively.

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Table 10.5.1: 1
Hypothetical data scenarios
Scenario
Dose 
comb.
BI754091/
BI754111
(mg/mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
allowed
dose 
comb. 
(mg)*
Summary of toxicity by Combination 
model
P(under 
dose)
P(target 
dose)
P(over 
dose)
1A
240/4
0
3
0.036
240/80
0.546
0.275
0.180
1B
240/4
1
3
0.223
240/4
0.431
0.346
0.223
1C
240/4
2
3
0.631
None
n/a
n/a
n/a
1D
240/4
1
0
3
3
0.065
240/20
0.516
0.348
0.136
1E
240/4
1
1
3
3
0.258
None
n/a
n/a
n/a
2A
240/4
240/20
0
0
3
3
0.020
240/80
0.664
0.241
0.095
2B
240/4
240/20
0
1
3
3
0.123
240/20
0.527
0.350
0.123
2C
240/4
240/20
0
0
1
3
3
3
0.043
240/80
0.489
0.346
0.165
2D
240/4
240/20
0
1
1
3
3
3
0.151
240/20
0.400
0.449
0.151
2E
240/4
240/20
0
1
2
3
3
3
0.391
240/4
0.312
0.493
0.195
*The next dose combinations allowed by model are all listed. In actual trial dose escalation, only 1 compound will be 
escalated at each cohort.

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10.5.2
Operating Characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose with true DLT rate in the target 
interval can be approximated via simulation.
Table 10.5.2: 1 describes 3 assumed true dose-toxicity scenarios which were used to assess 
the operating characteristics of the combination model. These scenarios reflect a wide range 
of possible cases as follows:
∀
Scenario C1: aligned with prior means
∀
Scenario C2: low-toxicity scenario
∀
Scenario C3: high-toxicity scenario

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Table 10.5.2: 1 Assumed True Dose-Toxicity Scenarios
Scenario C1, 
P(DLT)
   Dose BI 754111 (mg)
Dose BI 754091 
(mg)
4        
20
80
200
400
600
80
0.170       0.200
0.240
0.320
0.400
0.450
240
0.220       0.280
0.320
0.400
0.460
0.550
400
0.260
0.300
0.360
0.480
0.500
0.600
Scenario C2, 
P(DLT)
Dose BI 754111 (mg)
Dose BI 754091 
(mg)
4        
20
80
200
400
600
80
0.040       0.080
0.180
0.200
0.25
0.300
240
0.080       0.180
0.200
0.250
0.30
0.350
400
0.180
0.200
0.250
0.300
0.35
0.400
Scenario C3, 
P(DLT)
Dose BI 754111 (mg)
Dose BI 754091 
(mg)
4        
20
80
200
400
600
80
0.250       0.280
0.320
0.400
0.500
0.650
240
0.280       0.320
0.400
0.500
0.650
0.750
400
0.320
0.400
0.500
0.650
0.750
0.850
Bold numbers indicate true DLT rates in the target interval [0.16, 0.33).
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rules:
∀
Escalate to the dose combination which maximizes the probability of the targeted 
toxicity region and satisfies the overdose criterion if it is ≤400% increase from the 
current dose.
∀
If the recommended dose combination satisfying the overdose criterion is > 400% 
increase in dose for each compound, then escalate to the highest dose combination 
which is ≤400% increase from the current dose for each compound.
∀
If any DLT occurs, extra 3 patients will be tested at the current dose combination.

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The MTD was considered reached if the following conditions are satisfied:
∀
The next recommended dose is the same as the current dose;
∀
At least 1 DLT is observed;
∀
At least 6 patients have been treated at the MTD dose combination declared by the 
model;
∀
At least 15 patients have been evaluated OR the posterior probability of targeted 
toxicity reaches 50%.
It was then assessed how often a dose was declared as MTD with true DLT rate in the 
underdose, targeted-, or over-dose range. Furthermore, the average, minimum and maximum 
number of patients per trial and the average number of DLTs per trial are reported. Results 
are shown in Table 10.5.2: 2.
Table 10.5.2: 2 Simulated Operating Characteristics
Scenario
% of Trials Declaring an MTD with True 
DLT Rate in
# Patients
# DLT
Underdose
Target dose
Overdose
Stopped
Mean
(Min-Max)
Mean
(Min-Max)
C1: Aligned with 
prior
0
69.0
2.8
28.2
17.82 (6-30)
4.111 (1-13)
C2: Low Tox
23.5
73.8
0.1
0.8
22.38 (6-36)
3.402 (1-11)
C3: High Tox
0
45.6
4.1
50.3
14.98 (6-33)
4.346 (1-13)
In Scenario C1, which reflects the case that the true dose-toxicity is approximately aligned 
with prior means, almost all of the simulated trials identified the MTD. Approximately 69.0% 
of trials were in the target interval and none of them were in the underdose interval. There 
were 2.8% in the overdose interval (see for three dose combinations with underlying true 
DLT rates between 36% and 60%) and 28.2% of the trials were prematurely stopped either 
because the MTD was not identified or because the probability of overdose associated with 
the simulated starting dose had already exceeded the 25% threshold.
Scenario C2 (Low-toxicity scenario) shows similar results with previous Scenario 1 overall. 
Only 0.1% of the simulated trials declared a MTD with a true DLT rate in the overdose 
interval. Most of the simulated trials, i.e., approximately 99%, identified the MTD with 
73.8% in the target dose interval and 23.5% are in the underdose interval.
Scenario C3 (High-toxicity scenario) illustrates a case with higher-than-expected toxicity. In 
this case, approximately 46% of the simulated trials identified the MTD within the target 
interval. Approximately 4% of the simulated trials declared the MTD in the overdose 
interval. Due to higher toxicity in this scenario, approximately 50% of the simulated trials 
were prematurely stopped for similar reasons as in Scenario 1.
By reviewing the metrics presented in Table 10.5.2: 2, it can be seen that the model is not 
sensitive to different scenarios of true DLT rates. Across three scenarios, the average number 
of patients participated in dose-escalation ranges from 14.98 to 17.82 and the average number 
of DLTs observed ranged from 3.402 to 4.346. In general, this model is conservative due to 

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the overdose control criteria. In all scenarios, the probabilities of recommending a dose 
combination with true P(DLT) ≥33% as MTD are much smaller than probabilities of 
recommending a dose combination with true P(DLT) between 16% and 33% as MTD.
In summary, the considered data scenarios demonstrate reasonable operating characteristics 
of the model. On-study recommendations based on the model are consistent with the clinical 
decision making process, and should be considered in conjunction with other available 
clinical information by the SRC in deciding the dose combinations to be tested in order to 
determine the MTD estimates.

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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
08 May 2017
EudraCT number
Not applicable
BI Trial number
BI 1381.2
BI Investigational Product(s)
BI 794111 and BI 754091
Title of protocol (previous - see 
below for title update)
An open label, Phase I dose-finding study of BI 
754111 as monotherapy and in combination with BI 
754091 in patients with advanced cancer followed 
by expansion cohorts at the RPIID of the 
combination in patients with NSCLC and other 
tumour types
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Protocol title
Description of change
An open label, Phase I dose-finding study of BI 754111 as 
monotherapy and in combination with BI 754091 in patients 
with advanced cancersolid cancers and of BI 754111 
monotherapy with subsequent combination with 
BI 754091 in patients with follicular lymphoma, followed 
by an expansion cohorts at the RPIID of the combination in 
patients with NSCLC and other tumour typesnon-small cell 
lung cancer
Rationale for change
In response to the FDA review and the subsequent design 
change, the title was changed to more accurately describe the 
study.

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Section to be changed
Synopsis and Section 2.2.1 Part I (dose-escalation cohorts) 
objectives
Description of change
The objectives of the dose-escalation portions of the trial 
are to:
∀
Investigate the safety, tolerability, and pharmacokinetics 
(PK) of escalating doses of BI 754111 as monotherapy 
for 2 cycles (2 doses in combination with BI 754091
(administered via intravenous [i.v.] infusion once every 3 
weeks [q3w]) in patients with advanced and/or metastatic 
solid tumours and.
∀
Investigate the safety, tolerability, and PK of 
escalating doses of BI 754111 as monotherapy for 2 
cycles (2 doses administered via i.v. infusion q3w) in 
patients with relapsed/refractory follicular lymphoma 
(FL)
∀
Investigate the safety, tolerability, and PK of escalating 
doses of BI 754111 in combination with BI 754091 
(administered via i.v. infusion q3w) added on to 
BI 754111 starting at Cycle 3 in patients with advanced 
and/or metastatic solid tumours and patients with 
relapsed/refractory FL, and investigate the PK of BI 
754091 in combination with escalating doses of 
BI 754111relapsed/refractory FL
∀
Investigate the safety, tolerability, and PK of escalating 
doses of BI 754111 in combination with BI 754091 with 
both of these monoclonal antibodies (mAbs) administered 
together from start of trial treatment in patients with 
advanced and/or metastatic solid tumours and investigate 
the PK of BI 754091 in combination with escalating 
doses of BI 754111
∀
Determine the maximum-tolerated dose (MTD) through 
monitoring dose-limiting toxicities (DLTs) and/or to 
determine the recommended Phase II dose (RPIID) of the 
combination of BI 754111 plus BI 754091
∀
Assess LAG-3 receptor occupancy (RO) in peripheral 
blood in patients with FL.
Rationale for change
In response to the FDA review, the study design changed to 
begin with combination dosing in patients with solid tumours. 
BI 754111 monotherapy will still be tested in patients with 
follicular lymphoma.
Section to be changed
Synopsis and Section 2.2.2 Part II (dose-expansion cohorts) 
objectives
Description of change
The objectives of the dose-expansion portion of the trial are 
to:
•
Further investigate the safety, tolerability, and PK of 
the RPIID of the combination of BI 754111 plus BI 754091 in 
patients with NSCLC (as defined in the entry criteria) and 
other tumour types (to be specified at a later date via protocol 
amendment)
•
Explore the efficacy of the combination in patients 
with NSCLC (as defined in the entry criteria) and other 
tumour types (to be specified at a later date via protocol 
amendment).

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Rationale for change
In response to the FDA review, statements regarding potential 
additional expansion cohorts are removed from the protocol.
Section to be changed
Synopsis - Methodology
Description of change
Part I (Dose-Escalation Cohorts):
OpenFor patients with solid tumours: open-label, non-
randomised, dose-escalation cohorts (into consecutive 
cohorts of BI 754111 in combination with BI 754091
For patients with FL: open-label, non-randomised, dose-
escalation into consecutive cohorts of BI 754111 
monotherapy for 2 cycles, with BI 754091 added to 
BI 754111 starting at Cycle 3, and cohorts of BI 754111 in 
combination with BI 754091 administered simultaneously). 
Cohorts for FL will start after a dose/dose combination has 
been cleared in cohorts of solid tumours.
Dose escalation in both patient populations will be guided 
by Bayesian Logistic Regression Models (BLRMs) with 
overdose control for BI 754111 monotherapy as well as for 
the BI 754111 + BI 754091 combination therapy as well as 
for BI 754111 monotherapy in patients with FL.
Part II (Dose-Expansion Cohort):
Open-label, non-randomised, dose-expansion cohorts with the 
RPIID of the combination in different tumour types treated in 
parallel cohortspatients with NSCLC.
Rationale for change
In response to the FDA review, dose expansion is more 
accurately described as being limited to a single cohort at this 
time.
Section to be changed
Synopsis - No. of patients
Description of change
Part I (Dose-Escalation Cohorts):  Approximately 2025
to 40 patients
Part II (Dose-Expansion Cohorts):  Approximately 9030
patients total
Part I: a minimum of 3 patients with solid tumours per 
dose-escalation cohort
Part II: approximately 30 patients per dose-expansion cohort
Rationale for change
To more accurately reflect the plausible number of subjects in 
dose escalation, and to address the FDA comment to limit 
dose expansion to a single cohort at this time.

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Section to be changed
Synopsis - Diagnosis
Description of change
Part II (Dose Expansion Cohorts):
Second and 3rd line NSCLC patients who progressed on 
anti-PD-1 or anti-PD-L1 treatment after having achieved 
radiologically confirmed benefit (minimum of stable 
disease) with a minimum treatment duration of 6 months on 
the previous anti-PD-1 or anti-PD-L1 treatment. The anti-
PD-1 or anti-PD-L1-containing treatment (excluding anti-
PD-1 or anti-PD-L1 in combination with chemotherapy) 
must have been the latest treatment regimen prior to 
enrolling into this trial with >4 and <12 weeks between 
latest treatment and their first dose in this trial. Patients that 
have had anti-PD-1 or anti-PD-L1 as their first-line NSCLC 
treatment regimen must have a PD-L1 expression level of 
≥50% at baseline.
Other indications may be evaluated in additional expansion 
cohorts.
Rationale for change
To clarify requirements for patients with NSCLC and to 
clearly limit dose-expansion to one cohort at this time.
Section to be changed
Synopsis - Main criteria for inclusion and Section 3.3.2
Description of change
∀
For patients in Part I with solid tumours:
-
For whom no therapy of proven efficacy exists, 
or who are not amenable to standard therapies.
-
Must have measurable lesions according to 
Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 and irRECIST
-
Previous treatment with an anti-PD-1 mAb is 
allowed as long as the last administration of the 
anti-PD-1 mAb on the previous treatment is a 
minimum of 60 days prior to startingthe first BI 
754091 treatment in this trial.
∀
For patients in Part I with FL:
-
Whose disease has progressed during or within 6 
months of treatment with at least 1 prior 
chemotherapeutic regimen, or who are not 
amenable to standard therapies.
-
Patients with histologically confirmed, 
relapsed or refractory FL for which there are 
no further treatment options available known 
to provide clinical benefit
∀
Part II (dose expansion):
-
Second and 3rd line NSCLC patients who 
progressed on anti-PD-1 or anti-PD-L1 
treatment after having achieved radiologically 
confirmed benefit (minimum of stable disease) 
with a minimum treatment duration of 6 months 
on the previous anti-PD-1 or anti-PD-L1 
treatment. The anti-PD-1- or anti-PD-L1-
containing treatment (excluding anti-PD-1 or 
anti-PD-L1 in combination with chemotherapy) 
must have been the latest treatment regimen 
prior to enrolling in this trial with >4 and <12 
weeks between the latest treatment and their first 

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dose in this trial. Patients who have had anti-PD-
1 or anti-PD-L1 as their first-line NSCLC 
treatment regimen must have a PD-L1 
expression level of ≥50% at baseline (local 
confirmed testing).
Rationale for change
Clarifications in the inclusion criteria to harmonize with the 
revised study design and provide clear definitions of follicular 
lymphoma and NSCLC patients
Section to be changed
Synopsis - Doses
Description of change
Part I (Dose-Escalation Cohorts):
For patients with solid tumours: Increasing doses of BI 
754111 starting with 80 4 mg in combination with
BI 754091 at the RPIID (RPIID if determined in trial 
1381.1 before the start of trial 1381.2, otherwise a or a 
lower dose that has been evaluated as safe from 1381.1) 
will be added to the BI 754111 at the beginning of Cycle 3 
or will be given simultaneously at the start of Cycle 1 
(simultaneous cohorts starting at or near the RPIID of the 
combination). The dose of BI 754091 will be 
chosenselected by the 1381.2 Safety Review Committee 
upon review of evolving data from theTrial 1381.1 (an
ongoing study 1381.1 (a study of escalating doses of 
BI 754091 using a BLRM with overdose control in patients 
with advanced solid tumours). Dose escalation of 
BI 754111 monotherapy and in combination with
BI 754091 will be guided by a BLRM with overdose 
control.

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For patients with FL: Recruitment in this cohort will 
start after a dose combination (of ≥200 mg BI 754111) is 
cleared in cohorts of patients with solid tumours. 
Cohorts in patients with FL will be started with 
BI 754111 monotherapy at 2 dose levels lower than the 
last (highest) dose level in patients with solid tumours.  
In case the 200 mg dose of BI 754111 is not reached, the 
starting dose for FL cohorts will be two dose levels 
lower than the highest dose cleared in the solid cancer 
patients, or 4 mg if no two lower dose levels are 
available. After 2 cycles of monotherapy, BI 754091 will 
be added. The dose of BI 754091 will be selected by the 
SRC (same as described above for solid tumours). Dose 
escalation of BI 754111 monotherapy as well as of the 
combination therapy after BI 754091 being added will 
be guided by BLRMs with overdose control.
Part II (Dose Expansion Cohorts):
The RPIID of the combination determined in Part I. for 
patients with solid tumours.
For all cohorts, administration will be on Day 1 of 21-
day cycles.
Rationale for change
Based on the recommendation of the FDA, the starting dose 
of BI 754111 has been set at 4 mg and the solid tumour 
cohorts will start with combination therapy.
Section to be changed
Synopsis - Duration of treatment
Description of change
One or both mAbsAdministration will be administered on 
Day 1 of 21-day cycles continue until progression of disease 
(PD) or), unacceptable toxicity, or a maximum treatment 
duration of 1 year. If the patient is benefiting clinically at 
1 year, he/she may continue after a case-by-case review with 
the Medical Monitor and the sponsor.
Rationale for change
To clarify treatment stopping criteria
Section to be changed
Synopsis - Endpoints
Description of change
Primary Endpoint:
∀
MTD of the BI 754111 plus BI 754091 combination
∀
Number of patients experiencing DLTs during the 
combination MTD evaluation period (Cycle 1, the first 
cycle of BI 754111 plus BI 754091 combination 
therapy) in patients with solid tumours
∀
Number of patients experiencing DLTs during the 
monotherapy MTD evaluation period (first two cycles of 
BI 754111) in patients with FL
∀
Number of patients experiencing DLTs during the 
combination MTD evaluation period (Cycle 3, the first 
cycle of BI 754111 plus BI 754091 combination therapy) 
in patients with FL.
Rationale for change
Clarifications required due to change in study design

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Section to be changed
Flow Charts
Description of change
∀
New Flow Chart for dose-escalation follicular lymphoma 
patients added to clarify that extensive PK testing in this 
patient population would be during Cycles 1, 2, and 3.  
Footnotes aligned with the FL patient population.
∀
The Flow Chart for dose escalation in patients with solid 
tumours was updated to show extensive PK testing during 
Cycles 1, 2, and 4 and receptor occupancy testing was 
moved (FL patients only). Footnotes were aligned with 
the solid tumour patient population.
∀
The titles of all Flow charts were continued to subsequent 
pages
Rationale for change
For clarity and to distinguish the extensive PK testing 
schedules between the patient populations.
Description of change
A row for troponin testing was added to all charts, CPK 
testing will occur at every cycle (not just at baseline), and
Section 5.3.4.2 was updated.
Rationale for change
To enhance cardiac safety testing
Description of change
Flow Chart 1 (Solid tumour cohorts) Footnote a - All cycles 
are 3 weeks (21 days) in duration. Patients will continue 
treatment with the study drug or study drugs until disease 
progression (PD) by RECIST and/or irRECIST, withdrawal of 
patient consent, an unacceptable toxicity occurs, or 1 year of 
treatment is completed, whichever occurs first. Patients will 
be allowed to stay on treatment in the case of initial 
radiological PD, if the Investigator feels that it is in the 
patient’s best interest. In addition, patients without PD may 
stay on trial after 1 year on a case-by-case basis after 
discussion with the Medical Monitor and the sponsor. Day 1 
of Cycle 1 is defined as the day when BI 754111 is first 
administered for the Part I monotherapy cohorts or when the 
combination of BI 754111 and BI 754091 is administered.
Rationale for change
In response to the FDA review, the study design changed to 
begin with combination dosing in patients with solid tumours.
Description of change
All Flow Charts Footnote f (and Section 5.3.3)- Single 
digitalised ECGs must be done before blood work or other 
procedures after 5 minutes of rest at screening, Cycle 1 Day 1, 
Cycle 3 Day 1, on Day 1 of every cycle through Cycle 6 and 
then on Day 1 of every other third cycle thereafter (Cycles 
86, 109, 12, etc.), on Day 15 of Cycles 1 through 4, at the 
EOT visit, and whenever the Investigator deems it necessary. 
An ECG is optional at the 30-day safety follow-up visit if the 
EOT visit ECG was normal and no drug-related abnormalities 
were detected in on-trial ECGs (see Section 5.3.3).
Rationale for change
To enhance cardiac safety testing

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Description of change
All Flow Charts Footnote g (and Section 5.3.4.4) - Women of 
child-bearing potential must have a serum beta human 
chorionic gonadotropin (βHCG) pregnancy test at screening. 
Thereafter, this test can be done in either serum or urine 
on Day 1 of each cycle, and at the EOT visit (see 
Section 5.3.4.4. Beginning with Cycle 3, urine dipstick tests 
can be done on Day 1 of odd-numbered cycles (Cycles 3, 5, 7, 
etc.).
Rationale for change
To clarify that serum or urine can be tested following the 
screening test, and for consistency across the program.
Description of change
All Flow Charts PK Footnotes - changed to specify that 
extensive PK sampling is done during Cycles 1, 2, and 4 for 
dose-escalation solid tumour cohorts and the dose-expansion 
cohort and are done during Cycles 1, 2, and 3 for the FL 
cohorts.
Rationale for change
For clarity and to distinguish the extensive PK testing 
schedules between the patient populations since the FL 
cohorts now have a separate Flow Chart.
Description of change
All Flow Charts End-of-treatment footnote - If the decision is 
made to permanently discontinue study treatments during a 
scheduled visit, both BI 754091 and BI 754111 should be 
discontinued together and the EOT visit should be 
performed instead of the scheduled visit assessments.
Rationale for change
In response to the FDA review, to clarify that both study 
drugs will be discontinued together, if necessary.
Section to be changed
2.3 Benefit Risk
Description of change
Based on these pre-clinical data, as well as clinical data 
obtained with BI 754091 and other anti-PD-1 mAbs, the 
inhibitory effects of the combination of BI 754111 and 
BI 754091 may translate into a clinical benefit in cancer 
patients. All doses planned to be tested are expected to have 
some clinical activity. The dose-escalation scheme for 
BI 754111 is guided by a Bayesian 2-parameter Logistic 
Regression Model (BLRM) (de-escalation of dose is possible 
in case of insufficient tolerability of a dose level) and is 
designed to escalate the dose quickly and minimise the risk of 
undue tolerability issues.
Rationale for change
Based on the recommendation of the FDA, the starting dose 
of BI 754111 was set at 4 mg, which is not in the range 
currently predicted to have clinical activity. This change, 
however, increases patient safety during first dosing in this 
first-time-in-man study.

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Section to be changed
Section 3.1 Overall trial design and plan
Description of change
This is a Phase I, open-label, non-randomised, multicentre 
trial of BI 754111 administered as a single agent and in 
combination with BI 754091 that will be conducted in 2 parts. 
The Part I portion of the trial will includeconsist of
consecutive dose-escalation cohorts of BI 754111 
monotherapy for 2 cycles with BI 754091 added from Cycle 3 
onward, and cohort(s) of BI 754111 in combination with 
BI 754091 administered simultaneously. The planned study 
population for Part I includes cohorts ofto patients with 
advanced solid tumours. Once combination dose escalation 
in solid tumors has reached the 200 mg BI 754111 dose 
level, dose-escalation cohorts in patients with FL will be 
initiated at two BI 754111 dose levels lower than the 
BI 754111 dose completed in the solid-tumor cohorts. In
case the 200 mg dose of BI 754111 is not reached, the 
starting dose for FL cohorts will be two dose levels lower 
than the highest dose cleared in the solid-tumour cohorts, 
or 4 mg if no two lower dose levels are available. The FL 
cohorts will start with 2 cycles of BI 754111 monotherapy 
to assess the PK and receptor occupancy of BI 754111 
before adding BI 754091 at the start of Cycle 3 and 
continuing treatment until disease progression or 
unacceptable toxicity. At least three FL dose levels will be 
assessed (unless infeasible) for PK purposes, and cohorts of 
patients with follicular lymphoma (FL). Cohorts for patients 
with FL will start after a dose has been cleared in cohorts of 
patients with solid tumours.dose escalation in FL cohorts 
will continue at least until a mean receptor occupancy 
>90% is achieved. Possible cohort scenarios for Part I are 
presented in and Figure 3.1: 1. Simultaneous administration 
cohort will start at the RPIID of the combination, once the 
RPIID of the combination has been determined in the cohorts 
where BI 754091 is added to BI 754111 starting at Cycle 3. 
Dose escalation of BI 754111 will continue until one dose 
level higher than the RPIID of the combination if allowed by 
the BLRMs.
Figure 3.1: 1 has been updated based on the new study design.
The dose-escalation phase will include intensive safety 
monitoring to ensure the safety of the patients and will be 
guided by Bayesian Logistic Regression Models (BLRM) 
with overdose control (EWOC) for BI 754111 monotherapy 
and for combination treatment. Following determination of 
the MTD and (or) the RPIID of the combination of BI 754111 
and BI 754091, Part II will commence to further characterise 
the combination at the doses determined in Part I in 
parallelpatients with NSCLC. Additional cohorts of patients 
with NSCLC and other tumour types that may include 
relapsed/refractory follicular lymphoma (to be specified at a 
later dateadded via protocol amendment.

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It is planned that approximately 2025 to 40 patients will be 
enrolled in Part I. The total number of patients will depend on 
the number of dose escalations necessary. The BLRM 
estimates the MTD of the combination by updating estimates 
of the probability of observing a DLT during the first cycle of 
BI 754111/BI 754091 combination therapy MTD evaluation 
period for each dose (or dose combination) level in the trial 
as patient information becomes available. Three separate 
BLRMs are specified for BI 754111 monotherapy in FL 
patients, the combination of BI 754111 and BI 754091 in 
solid tumour patients, and the combination of BI 754111 
and BI 754091 in FL patients, respectively. The DLT 
information from the LAG-3 monotherapy periods in patients 
with FL, the DLT information from the combination 
therapy period in patients with solid tumours and FL, as 
well as the DLT information of BI 754091 collected in the 
1381.1 study will be used to construct the priors for the 
BLRM, and therefore includedall be used in the dose-
escalation decision-making process.
In general, it will be permitted to escalate to a dose that fulfils 
the EWOC principle (refer to Section 7). Details on handling 
borderline cases will be described in the dose-escalation plan. 
Successive cohorts of patients will receive doses of 
BI 754111 and BI 754091 until one dose level above the 
human therapeutic dose for LAG-3 (currently estimated 
at 400 mg) is reached. A cohort size of 3 patients will be 
treated at each dose level.changed at one time. They will 
not be escalated simultaneously. Additional patients (up to 
6 more) could be added to some previously evaluated 
cohorts to expand the safety and PK evaluation. Only one 
component of the combination (BI 754111 or BI 754091)
will be changed at one time. They will not be escalated 
simultaneously.
If a DLT is observed during the BI 754111 monotherapy 
period in an FL cohort, three additional patients will be 
added to that cohort. The patient that experienced the DLT 
will not be able to receive treatment with BI 754091. If there 
are other patients at that dose level in the LAG-3 
monotherapy phase and they did not experience a DLT, they 
can have BI 754091 added and continue. The DLT will be 
immediately reviewed by the SRC and the remaining
patients will be monitored carefully as they continue to the 
combination treatment.
A 10% screen-failure rate is anticipated, which assumes the 
sites have ‘pre-screened’ to find generally eligible patients. 
Therefore, the 10% screen-failure rate should only be for 
failure due to laboratory values, scans, etc.

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Successive cohorts of patients will receive doses of BI 754111 
and BI 754091 until one dose level above the estimated 
human therapeutic dose for LAG-3 is reached. A cohort size 
of a minimum of 3 patients and up to 6 patients will be treated 
at each dose level. Additional patients (up to 6 more) could be 
added to some previously evaluated cohorts to expand the 
safety and PK evaluation. Only one component of the 
combination (BI 754111 or BI 754091) will be escalated at 
one time. They will not be escalated together.
After all patients in a cohort have either experienced a DLT or 
have been observed for at least the MTD evaluation period 
(see Section 7.3.1.12 cycles of BI 754111
monotherapy plus the first cycle after BI 754091 is added to 
BI 754111, and in the first cycle of BI 754111 in combination 
with BI 754091 administered simultaneously
[simultaneous cohorts]) without experiencing a DLT, the 
Bayesian models will be updated with the newly accumulated 
data.
Table 3.1: 1 is updated to separate the solid tumour cohorts 
from the FL cohorts for clarity and to take into consideration 
the new study design.
Following determination of the MTD and/or the RPIID from 
the Part I portion, a cohort of approximately 30 patients with 
NSCLC (as defined in the entry criteria) will be enrolled into 
Part II. The Part II portion of the trial will further evaluate the 
safety, tolerability, PK profile, biomarkers, and efficacy of the 
combination of BI 754111 and BI 754091. Other expansion 
cohorts in other tumour types (to be specified at a later date 
via protocol amendment) may be added to Part II of the trial.
Rationale for change
In response to the FDA review, the study design has been 
changed and it is clarified that the only expansion cohort 
currently planned is in patients with NSCLC, and that 
potential additional expansion cohorts may be added to the 
protocol by amendment.
Section to be changed
3.1.2 Safety Review Committee
Description of change
BI Project or Trial Statistician
Rationale for change
A member of the BI Biostatistics group is added as a member 
of the SRC.
Section to be changed
3.2 Discussion of Trial Design
Description of change
During Part I (dose-escalation) a minimum of 3 patients with 
solid tumours per cohort is required, but the SRC may decide 
to increase the number by a maximum of 6 additional 
patients per cohort as needed. Decisions of the SRC will be 
guided by BLRMs (one for BI 754111 monotherapy and one 
for BI 754111 + BI 754091 combination therapy) with 
overdose control. An EWOC design will increase the chance 
of treating patients at efficacious doses while reducing the risk 
of overdosing. This design is based on practical

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Rationale for change
To add precision to the description of cohort size and for 
clarity.
Section to be changed
3.3.2 Inclusion Criteria (in addition to the main criteria noted 
for the synopsis previously)
Description of change
Part I (dose escalation):
∀
Patients with a confirmed diagnosis of advanced, 
unresectable, and/or metastatic solid tumours (any type) and 
patients with histologically confirmed relapsed/refractory 
FL.
Rationale for change
To clarify this inclusion criterion.
Description of change
Inclusion #7 and #8 Females of Male or female patients. 
Women of childbearing potential (WOCBP)* (*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.) and men able to father a child-bearing potential who 
have had a negative serum pregnancy test at start of treatment, 
who are willing must be ready and able to use highly 
effective contraceptive measures from the timemethods of 
birth control (that result in a low failure rate of screening 
until less than 1% per year when used consistently and 
correctly) during trial participation and for at least 6 
months after trial discontinuation, who are not or will not be 
breast feeding, and who agree to have pregnancy tests at 
regular visits duringthe last administration of trial. A list of 
contraception methods meeting these criteria is provided 
in the patient information. Females not of childbearing 
potential must have evidence of such by fulfilling one of the 
following criteria at screening:
∀
Post-menopausal: defined as more than 50 years-
of-age and amenorrhoeic for at least 12 months following 
cessation of all exogenous hormonal treatments
∀
Documentation of irreversible surgical sterilization 
by hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy
∀
Women under 50 years-of-age would be 
considered postmenopausal if they have been amenorrhoeic 
for at least 12 months following the cessation of exogenous 
hormonal treatments, and have serum follicle-stimulating 
hormone and luteinizing hormone levels in the 
postmenopausal range for the institution.
Male patients must be willing to use barrier contraception 
(i.e., condoms) for the duration of the trial and for 6 months 
after trial treatment discontinuation.
Rationale for change
To align text with BI template contraception language

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Section to be changed
Section 3.3.3 Exclusion criterion added:
Description of change
Patients that have epidermal growth factor receptor 
(EGFR) mutations or anaplastic lymphoma kinase (ALK) 
rearrangements
Rationale for change
In response to an FDA recommendation, this exclusion 
criterion is added.
Section to be changed
Table 3.3.3: 1 Laboratory values
Description of change
(Re: Serum Creatinine) >1.5 X ULN or creatinine clearance
estimated glomerular filtration rate (eGFR) <30 
mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology 
([CKD-EPI]) Collaboration equation); confirmation of 
creatinine clearance eGFR is only required when creatinine is 
>1.5 X ULN.
Rationale for change
For accuracy and to align with IDMS standards.
Section to be changed
Section 4.1.2.1 Starting dose of BI 754111
Description of change
Given that the patients to be enrolled in this trial will have 
advanced/metastatic cancer, it is preferable to set the starting 
dose at a level that has the potential to offer the patients some 
clinical benefit. Research by Bai et al (R13-4749) found that 
the fixed-dosing approach (flat dosing) is the recommended 
first option for administration of mAbs in first-in-human 
studies. Hence, BI 754111 will be tested at a flat starting dose 
of 80 mg (based on 1 mg/kg for an 80-kg patient) to be 
administered via i.v. infusion q3w.
The starting dose of BI 754111 in patients with solid tumors 
will be 4 mg (based on 0.05 mg/kg for an 80 kg patient) 
administered via i.v. infusion once every 3 weeks. The 
starting dose was based on the EC50 in the in vitro tetanus 
toxoid T-cell activation assay. In that assay, increasing 
concentrations of BI 754111 were combined with a fixed 
dose of BI 754091 and IFNγ secretion was measured as an 
indication of T-cell activation (n00250935; n00253546).
This starting dose 80 mg is supported by the 13-week repeat-
dose toxicity study in the cynomolgus monkeys, which was 
conducted with BI 754111 and included a BI 754111/BI 
754091 combination arm. The monkey. Compared to the 
NOAEL in the Non-Human Primate study (Cmax 6,440 
μg/mL and AUC 734,000 μg/mL*h), the 4 mg starting dose 
to an 80 mg (based on 1 mg/kg for an average 80 kg patient) 
starting dose administered q3wkg patient is expected to 
result in an exposure margin of approximately 5,300-fold 
and 4,900-fold based on the predicted to have human steady 
state exposure of Cmax of 24 1.2 μg/mL and area under the 
curve (AUC) of 3,000150 μg/mL*h. The NOAEL was 
considered to be 100, respectively.

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Once combination dose escalation in solid tumors has 
reached the 200 mg/kg from the 13-week toxicity study in 
cynomolgus monkeys. Therefore, the safety margins are 268 
times greater and 245 times greater (based on Cmax and AUC, 
respectively) with a dose of 1 mg/kg q3w than they are BI 
754111 dose levels, dose-escalation cohorts in patients with 
the NOAEL in cynomolgus monkeysFL will be initiated at 
two BI 754111 dose levels lower than the BI 754111 dose 
completed in the solid-tumor cohorts. In case the 200 mg 
dose of BI 754111 is not reached, the starting dose for FL 
cohorts will be two dose levels lower than the highest dose 
cleared in the solid-tumour cohorts, or 4 mg if no two 
lower dose levels are available. The FL cohorts will start 
with 2 cycles of monotherapy then BI 754091 will be 
added.
Rationale for change
Based on the recommendation of the FDA, the starting dose 
of BI 754111 has been set at 4 mg and the solid tumour 
cohorts will start with combination therapy.
Section to be changed
Section 4.1.3 Dose escalation scheme
Description of change
In the Part I dose-escalation cohorts, dosing of BI 754111 will 
be administered as monotherapy for 2 cycles, andwith BI 
754091 will be added at the start of Cycle 3. The planned 
starting dose of BI 754091 will be the RPIID from study 
1381.1 and the SRC will confirm this prior to starting 
combination dosing. The dose of BI 754091 may be increased 
or decreased based on DLTs and the overall safety profile of 
the combination. It is planned that one or more cohorts in 
which both mAbs will be administered together at or near the 
RPIID of the combination beginning with Cycle 1 Day 1 
(simultaneous cohorts) will be conducted later in the dose-
escalation part of the trial. Possible cohort scenarios are 
presented in Table 3.1: 1. These scenarios may change based 
on ongoing safety evaluations.
Table 4.1.3: 1 was updated with the new planned dosing 
scheme.
At the end of each treatment cohort, the SRC will evaluate the 
available data. The SRC will review all safety data including, 
but not limited to, DLTs and all CTCAE Version 4.03 Grade 
≥2 toxicity data during the first cycle of combination 
therapy for the solid tumour cohorts and during the 
2 cycles of BI 754111 monotherapy plus the first cycle of the 
combination. For the simultaneous-start cohorts, the safety 
data generated during the first cycle of the BI 754111 plus 
BI 754091 combination will be evaluated by the SRC prior to 
dose escalationtherapy for the FL cohorts. Updated safety 
data on other ongoing patients, including data in later cycles, 
will be discussed as well. Based on the findings of the SRC, a 
decision on the next dose level to be tested will be made.
Rationale for change
Updated based on the new study design.

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Section to be changed
Section 4.1.4 Dose modifications
Description of change
There will be no dose reductions or escalations of BI 754111 
or BI 754091 in any one patient. The dose may be delayed for 
a patient for one cycle, plus an additional 3 weeks, because of 
AEs following discussion with the Medical Monitor.
During combination therapy, if treatment is held or 
discontinued due to an AE(s), both BI 754091 and BI 
754111 will be held or discontinued together.  If treatment 
is to be restarted after resolution (≤ Grade 1) of the AE(s), 
both BI 754091 and BI 754111 must be started together.
The study drug(s) should be permanently discontinued for 
Grade 3 to 4 pneumonitis, Grade 3 to 4 adrenal 
insufficiency, Grade 4 diabetes mellitus, any grade 
encephalitis, Grade 4 hypophysitis, Grade 4 rash, 
Grade 3 to 4 colitis or recurrent colitis of any grade, any 
recurrent Grade 3 to 4 AE, transaminase increases >5 
times ULN or total bilirubin >3 times ULN (unless 
unequivocally attributed to another cause), inability to 
taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2 to 3 AEs that do 
not recover to Grade 1 or less within 12 weeks. Study 
drug(s) should also be permanently discontinued for 
Grade 3 to 4 AEs that are classified as immune-related by 
the Investigator that are not listed in Appendix 10.1. Study 
drug(s) should be permanently discontinued if ≥ Grade 4 
drug-related AEs are reported.  Please see Appendix 10.2
for guidelines for management of immune-related adverse 
events.
In the event of an infusion-related reaction ≤ Grade 2, the 
infusion rate of study drug(s) may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 
50% of the initial rate until completion of the infusion. In 
patients experiencing infusion-related reactions ≤ Grade 2, 
subsequent infusions may be administered at 50% of the 
initial rate. If an infusion-related reaction is Grade 3 or 
higher in severity at any point during the study, study 
drug(s) will be permanently discontinued (see 
Section 5.3.6.5.3).
Rationale for change
In response to an FDA recommendation, clarifications were 
added concerning holding or discontinuing both study drugs 
when required. Links were added to the detailed descriptions 
of management of irAEs and infusion reactions.

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Section to be changed
Section 4.1.5 Dose-limiting toxicities
Description of change
Dose-limiting toxicities (DLTs) will be recorded throughout 
the trial. Any DLT must be reported to the Medical Monitor 
by the Investigator or designee within 24 hours of first 
knowledge, and to the 
 
as an SAE when appropriate. All DLTs will be 
agreed upon between the Sponsor, the Study Chair, the 
Medical Monitor, and the investigators after review of the 
data from each cohort. Only DLTs occurring in Part I during 
the first cycle of BI 754111 administered in combination 
with BI 754091 in the solid tumour cohorts and during the 
first 2 cycles of BI 754111 monotherapy plus the first cycle 
after BI 754091 is added to BI 754111, or in the first cycle of 
BI 754111 in combination with BI 754091 administered 
simultaneously the FL cohorts will be used for dose-
escalation decisions made by the SRC.
All relevant safety information (including DLTs) will be 
considered when selecting the RPIID.
Previous anti-PD-l mAbs have been associated in the clinical 
setting with inflammatory adverse reactions resulting from 
increased or excessive immune-related adverse events
activity (irAEs), likely to be related to the mechanism of 
action. These adverse reactions, which can be severe, may 
involve the gastrointestinal, skin, liver, endocrine, respiratory, 
renal, or other organ systems.
Severity of AEs will be graded according to CTCAE Version 
4.03. Any of the following drug-related AEs will be classified 
as DLTs following review by the Investigators and the 
Medical Monitor, unless equivocally due to underlying 
malignancy or an extraneous cause.
∀
For patients with solid tumours:
∀
Any Grade 5 toxicity
∀
Neutropenia ≥ Grade 4 lasting for >75 days
∀
Any grade febrileFebrile neutropenia of any duration 
(ANC <1.0 X 109 cells/L and fever ≥38.5°C)
∀
Neutropenia Grade 3 with documented infection
∀
Any Grade 4 thrombocytopenia, or Grade 3 
thrombocytopenia with bleeding or a requirement for 
platelet transfusions
∀
For patients with follicular lymphoma:
-
Neutropenia ≥ Grade 4 lasting for >7 days 
despite growth factor support
-
Any grade febrile neutropenia that does not 
resolve within 48 hours with appropriate 
treatment (antibiotics, antifungal, antiviral 
agents and growth factors)
-
Grade 4 thrombocytopenia lasting >7 days, or 
Grade 3-4 thrombocytopenia with clinically 
significant bleeding.
-
Failure to recover platelets to ≥75 x 109/L by 6 
weeks after dose administration

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∀
Failure to recover neutrophils (absolute neutrophil count 
[ANC]) ≥1.0 x 109/L by 6 weeks after dose 
administration.
Non-haematological toxicities (only those that changed):
-
Grade 3 endocrine disorders (thyroid, pituitary, 
and/or adrenal insufficiency) that are 
sufficiently managed with or without systemic 
corticosteroid therapy and/or hormone 
replacement therapy, and the patient is 
asymptomatic.
-
Grade 3 tumour flare.
∀
Any Grade 2 drug-relatedpneumonitis of any duration
∀
Any Grade 2 uveitis, eye pain, or blurred vision that 
does not respond to topical therapy and does not improve 
to Grade 1 severity within 2 weeks or requires systemic 
treatment
∀
Any treatment-related ≥ Grade 2 toxicity that persists and 
results in an inability to administer BI 754091 on Cycle 2 
Day 1.
Late immune-related DLTs are irAEs that meet the same 
grading criteria as DLT criteria but occur after the first 2 
cycles of BI 754111 monotherapy plus the first cycle after 
BI 754091 is added to BI 754111, or after the first cycle of BI 
754111 in combination with BI 754091 administered 
simultaneously in the solid tumour cohorts or after the first 
2 cycles of BI 754111 monotherapy plus the first cycle 
after BI 754091 is added to BI 754111 during the FL 
cohorts, but during the first 90-day assessment period. These, 
as well as all toxicities, will be monitored throughout the trial. 
If any late immune-related DLT is reported during dose-
escalation, the BLRM will be rerun including the late 
immune-related DLT, and updated results will be reviewed in 
an SRC meeting (either scheduled or ad hoc) to recommend 
the next dose level and cohort size.
Rationale for change
In response to an FDA recommendation, clarifications were 
added to the dose-limiting toxicity criteria.
Section to be changed
4.1.7 Definition of evaluable patient
Description of change
For decisions on dose escalation, an evaluable patient is 
defined as a patient who has received BI 754111 and either:
∀
has completed the first cycle of BI 754111 in 
combination with BI 754091 in the solid tumour 
cohorts or has completed the first 2 cycles of BI 754111 
monotherapy plus the first cycle after BI 754091 is added 
to BI 754111, or in the first cycle of BI 754111 in 
combination with BI 754091 administered 
simultaneously in the FL cohorts
OR

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∀
has experienced a DLT during the first cycle of BI 
754111 in combination with BI 754091 in the solid 
tumour cohorts or during the first 2 cycles of BI 754111 
monotherapy plus the first cycle after BI 754091 is added 
to BI 754111, or in the first cycle of BI 754111 in 
combination with BI 754091 administered 
simultaneously in the FL cohorts.
Rationale for change
To align with the new study design
Section to be changed
4.1.8 Method of assigning patients to treatment groups
Description of change
After assessment of all inclusion and exclusion criteria, each 
eligible patient in the Part I dose-escalation portion of the trial 
will be assigned a dose of BI 754111 and a dose of 
BI 754091, if enrolled into a cohort dosing both mAbs at the 
same time, as determined by the SRC.
Rationale for change
To clarify that this is true for all patients.
Section to be changed
4.1.9 Administration of doses for each patient
Description of change
BI 754111 and BI 754091 will be diluted and administered 
via i.v. infusion according to the details in the Pharmacy 
Manual.
For Part I solid tumour cohorts, dosing will be sequential 
for doses <200 mg LAG3 with BI 754091 infused first 
followed by infusion of BI 754111. The infusion duration 
for each will be specified in the Pharmacy Manual. It is 
anticipated that the entire infusion time will take ~1 hour. 
For doses ≥200 mg LAG3, the infusion will be 
simultaneously (infusion duration ~1 hour).
For Part I FL cohorts, patients will receive BI 754111 
monotherapy for 2 cycles before dosing with BI 754091 is 
added.
Rationale for change
Due to the new study design, the study will beginning with 
combination dosing. Therefore, clarifications on the dosing 
sequence are added.
Section to be changed
5.1.1 Primary endpoints
Description of change
The primary endpoint of Part I (dose escalation) of the trial is 
the:
∀
MTD of the BI 754111 plus BI 754091 combination
∀
Number of patients experiencing DLTs during the 
combination MTD evaluation period (first cycle of 
BI 754111 plus BI 754091 combination therapy) in 
patients with solid tumours.
∀
Number of patients experiencing DLTs during the 
monotherapy MTD evaluation period (first two cycles of 
BI 754111 monotherapy) in patients with FL
∀
Number of patients experiencing DLTs during the 
combination MTD evaluation period (Cycle 3, the first 
cycle of BI 754111 plus BI 754091 combination 
therapy) for patients with FL
Rationale for change
Clarifications based on the new study design

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Section to be changed
5.1.2.1 Secondary endpoints
Description of change
The secondary endpoints of Part I (dose escalation) of the trial 
are the following:
∀
PK parameters to be calculated for BI 754111 after single 
and multiple doses of BI 754111 monotherapy (FL 
cohort) and in combination with BI 754091, and also for 
BI 754091 after the first dosesingle and multiple doses
of combination therapy include:
-
Cmax: maximum measured concentration of BI 
754111/ BI 754091 in plasma
-
AUC0-504: area under the concentration-time 
curve of BI 754111 / BI 754091 in plasma over 
the time interval from 0 to 504 hours
Rationale for change
To add clarification based on the new study design
Section to be changed
5.2.1 Tumour assessments
Description of change
The tumour response in patients with solid tumors will be 
evaluated according to RECIST Version 1.1 (R09-0262) and 
irRECIST (R16-0342, R15-2005). For FL patients, contrast 
enhanced CT should be used. PET/CT scan should be 
done at baseline for all FL patients. For patients with 
fluoro-deoxyglucose (FDG)-avid FL, PET/CT scan should 
be used and repeated at week 12, week 24, and if CT 
results are compatible with a complete response. 
Additional PET/CT scans can be done at the discretion of 
the Investigator. Response will be evaluatedFor patients 
with follicular lymphoma, response will be evaluated using 
local PET/CT scans using Cheson response criteria for 
malignant lymphoma as outlined in 2007 (R10-1462) and 
revised in 2014 (R14-3387).
For the FL cohorts, bone marrow biopsies and aspirates 
will be taken at screening. Patients with bone marrow 
disease evident by the screening bone marrow biopsy or 
aspirates, should have repeat bone marrow and aspirate to 
assess bone marrow response if a complete response is 
suggested by imaging or if novel or recurrent bone 
marrow involvement is suspected. The bone marrow 
biopsy and aspirate should be collected within 2 weeks of 
detection of response in other lesions.
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 treatment with the trial medication 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 used as target lesions. Tumour 
assessments (including bone marrow assessment for 
patients with FL) will be performed at screening (as close as 
possible to the treatment start and no more than 28 days 
before the start of study treatment), every 2 cycles (6 weeks 

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±3 days) for the first 6 months, then every 3 cycles (9 weeks 
±3 days) thereafter, and at the EOT visit (if not performed 
within the previous 4 weeks).
Rationale for change
Clarifications for tumour assessments in patients with FL 
were added.
Section to be changed
Section 5.3.4.3 Urinalysis
Description of change
Urine will be analysed for pH, glucose, erythrocytes, 
leukocytes, protein, and nitrite by dipstick (semi-quantitative 
measurements) during the screening visit, on Day 1 of each 
cycle, at the EOT visit, and as clinically indicated. In case of 
pathological findings, further evaluation must be performed 
and the findings documented.
Rationale for change
To align with information in the flow charts.
Section to be changed
5.3.4.2 Biochemistry
Description of change
The standard biochemistry panel will consist of glucose, 
sodium, potassium, chloride, calcium, phosphate, venous 
bicarbonate HCO3, urea, creatinine, creatine phosphokinase 
(CPK), AST, ALT, alkaline phosphatase, lactate 
dehydrogenase (LDH), bilirubin, total protein, albumin, urea 
nitrogen, and uric acid. In addition, cholesterol, triglycerides, 
and c-peptide, and creatine phosphokinase (CPK) will be 
done at baseline and when clinically indicated. Troponin will 
be tested according to the times listed in the flow charts. In 
case of pathological CPK, then CPK-MB, additional troponin 
I, and myoglobin should be reactively tested and the findings 
documented.
Rationale for change
To enhance cardiac safety testing
Section to be changed
5.4.1 Assessment of pharmacokinetics
Description of change
If data allow, the PK parameters of BI 754111 after single and 
multiple doses of BI 754111 monotherapy (FL cohort) and in 
combination with BI 754091, and also for BI 754091 after the 
first dosesingle and multiple doses of combination therapy 
mentioned as secondary and further endpoints for Parts I and 
II (see Section 5.1.2 and Section 5.1.3, respectively) will be 
evaluated using non-compartmental analysis methods 
according to BI internal SOP (001-MCS-36-472_RD-01 
[actual version] and Kinesis SOP ‘SOP-1.PKA.03 Non-
compartmental PK/PD Analysis’).
Rationale for change
To clarify following study design change
Section to be changed
5.4.2 Methods of collection for pharmacokinetic analysis
Description of change
For cohorts receiving combination treatment using doses 
of BI 754111 <80 mg, the 1 hour PK sample is to be drawn 
before and as close as possible to the end of the infusion.
Rationale for change
To stress the importance of the timing of the of the 1 hour PK 
samples in the early cohorts.

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Section to be changed
5.5.1 Methods of sample collection
Description of change
Pre- and on-treatment tumour biopsy collections for 
biomarker and PDc analyses will be mandatory from all 
patients in the Part II dose-expansion portion of the trial. In 
addition, an optional biopsy should be taken after treatment 
discontinuation, if possible. Patients in the dose-escalation 
cohorts may consent to optional paired biopsies. All samples 
must be adequately labelled by the trial site personnel. Details 
about tumour tissue and blood sample collection, 
plasma/serum preparation, required tubes, labelling of tubes, 
storage and shipment (frequency and addresses) will be 
provided in the ISF.
Rationale for change
To clarify that paired biopsies will not be taken during dose 
escalation.
Section to be changed
Section 7.1 and Appendix 10.5
Description of change
The statistical methods were updated to reflect the new study 
design and starting dose. The sections were fully replaced and 
are not presented as such here.
Rationale for change
To update the statistical methods based on the study design 
changes.
Section to be changed
Section 9 References (new references added)
Description of change
R15-2005
Bohnsack O, Ludajic K, Hoos A. 
Adaptation of the immune-related response criteria: 
irRECIST. 39th Ann Cong of the European Society for 
Medical Oncology (ESMO), Madrid, 26-30 Sep 2014 
(Poster).
n00250935
Tetanus toxoid assay for BI 
754091 in combination with BI 754111. 20 Jul 2016.
n00253546
 Anti-LAG-3 
mAb BI 754111 – Prediction of Human Pharmacokinetics 
and Therapeutic Dose. Report in preparation.
R16-0342 Removed
Rationale for change
For completeness in the text and to add new study information
Section to be changed
10.2 Management of immune-related adverse events
Description of change
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 >5 times ULN or total bilirubin >3 times ULN 
(unless unequivocally attributed to another cause), 
inability to taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2-3 AEs that 
do not recover to Grade 1 or less within 12 weeks.

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∀
Hepatic:
-
For Grade 2 events, monitor liver function tests 
more frequently until returned to baseline values 
(consider weekly).
•
Treat with i.v. or oral 
corticosteroids
-
For Grade 3-4 events, treat with i.v. 
corticosteroids for 24 to 48 hours.
-
When symptoms improve to Grade 1 or less, a 
steroid taper should be started and continued 
over no less than 28 days.
BI 754091 should be permanently discontinued for any 
recurrent Grade 3-4 AE, transaminase >5 times ULN or total 
bilirubin >3 times ULN (unless unequivocally attributed to 
another cause), inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or persistent 
Grade 2-3 AEs that do not recover to Grade 1 or less within 
12 weeks.
Rationale for change
To clarify for the Investigators
Section to be changed
Section 10.4 Sampling tables
Description of change
Table 10.4.1: 1
Time schedule for PK, 
 
- Part I dose-
escalation cohorts (Cycles 1 & 2 only for FL cohorts and 
Cycles 1, 2, and 4 for solid tumour cohorts)
Added to Footnote a - For cohorts receiving combination 
treatment using doses of BI 754111 <80 mg, the 1 hour PK 
sample is to be drawn before and as close as possible to the 
end of the infusion.
Added Footnote c - BI 754111 monotherapy will only be 
administered during the first 2 cycles for patients in the 
FL cohorts. All solid-tumour cohorts will begin 
immediately with simultaneously or sequential (only 
cohorts with doses <200mg LAG3) administration of the 2 
study drugs.
Added Footnote e - An additional blood sample will be 
taken one time from all subjects of the first dose group 
that exceeds 200 mg BI 754111.
Deleted previous Footnote e -
testing results to be 
reported for both BI 754111 and BI 754091 (for simultaneous 
cohorts in patients with solid tumours).
Rationale for change
To clarify due to study design changes and to emphasize the 
importance of drawing the 1 hour PK samples as close to 
infusion end as possible.

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Description of change
Table 10.4.1: 2
Time schedule for PK, 
 
, and receptor occupancy (RO) sampling - Part I dose-
escalation cohorts (Cycle 3 FL cohorts only)
Added to Footnote a - The planned total infusion duration is 
~1 hour (refer to pharmacy manual for specific infusion
times depending on dose). For cohorts receiving 
combination treatment using doses of BI 754111 <80 mg, 
the 1 hour PK sample is to be drawn before and as close as 
possible to the end of the infusion.
Deleted previous Footnote d -
 testing results to be
reported for both BI 754111 and BI 754091 (for simultaneous 
cohorts in patients with solid tumours).
Rationale for change
To clarify due to study design changes and to emphasize the 
importance of drawing the 1 hour PK samples as close to 
infusion end as possible.
Description of change
Table 10.4.1: 3
Time schedule for PK, 
 
 and receptor occupancy (RO) sampling - Part I dose-
escalation cohorts (FL cohorts: Cycles 4 to 12, 14, and 17 
only; Solid tumour cohorts: Cycles 3, 5 to 12, 14, and 17 
only)
Footnote a - The following windows of time are allowed for 
PK sampling:
Predose (PTM -0:05): within 1 hour before next drug infusion
Immediately before end of infusion (PTM 1:00): within ±5 
min of the end of infusion
4 and 7 hours post SOI (PTM 4:00 and 7:00): ±15 minutes
24 through 336 hours post SOI (PTM 24:00 to 
336:00): ±1 hour.
Deleted previous Footnote c -
 testing results to be 
reported for both BI 754111 and BI 754091 (for simultaneous 
cohorts in patients with solid tumours).
Rationale for change
To clarify due to study design changes
Section to be changed
10.4.2
Schedules for PK, 
 
– Part II dose-expansion cohorts
Description of change
Table 10.4.2: 1
Time schedule for PK, 
 
 blood 
samplings - Part II dose-expansion cohorts (Cycles 1, 2, and 4 
only)
Deleted Footnote e
e PBMC/MDSC testing will be in cohorts of patients with 
NSCLC only.
Rationale for change
To clarify that there is currently one dose expansion cohort 
planned. The footnote is obsolete because only the cohort in 
NSCLC is planned at this time.

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Number of global amendment
2
Date of CTP revision
23 August 2017
EudraCT number
Not applicable
BI Trial number
BI 1381.2
BI Investigational Product(s)
BI 794111 and BI 754091
Title of protocol
An open label, Phase I dose-finding study of BI 
754111 in combination with BI 754091 in patients 
with advanced solid cancers and of BI 754111 
monotherapy with subsequent combination with BI 
754091 in patients with follicular lymphoma, 
followed by an expansion cohort at the RPIID of 
the combination in patients with non-small cell 
lung cancer
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Flow chart footnotes and Section 5.3.4.2 Biochemistry
Description of change
Additionally, amylase and lipase should be analysed in 
case of symptoms of pancreatitis.
Rationale for change
Additional safety testing added in case of pancreatitis
Section to be changed
Flow chart footnotes and Section 5.3.4.2 Biochemistry
Description of change
The standard biochemistry panel will consist of glucose, 
sodium, potassium, chloride, calcium, phosphate, venous 
bicarbonate HCO3, urea, creatinine, creatine phosphokinase 
(CPK), AST, ALT, alkaline phosphatase, lactate 
dehydrogenase (LDH), bilirubin, total protein, albumin, urea 
nitrogen (or urea), and uric acid.

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Rationale for change
To clarify that within the biochemistry panel, either urea 
nitrogen or urea will be collected (instead of both) 
depending on local practice.
Section to be changed
Study Flow Chart 1 Footnote j
Description of change
[…] In order to assess the stability of BI 754091 and BI 
754111 in whole blood, one additional blood sample will be 
taken at 1 hour post infusion from all subjects of the first dose 
group that exceeds 200 mg BI 754111 (see Section 5.4.3).
Rationale for change
To enable whole blood stability testing to be performed 
correctly in BI 754091.
Section to be changed
Study Flow Chart 2 Footnote k
Description of change
Pharmacokinetic (PK) blood sampling: there is extensive PK 
sampling for FL cohorts during Cycles 1, 2, and 3. It is 
strongly recommended that the visit days and sampling time 
points outlined in the Appendix 10.4 tables be followed 
closely. The permitted visit windows noted in the table 
footnotes should only be used if medically indicated. Please 
note that there are separate assays for determination of BI 
754111 and BI 754091. Therefore, when PK samples are 
drawn during combination dosing, 2 tubes must be drawn at 
each time point. In order to assess the stability of BI 754111 
in whole blood, one additional blood sample will be taken at 
1 hour post infusion from all subjects of the first dose group 
that exceeds 200 mg BI 754111 (see Section 5.4.3).
Rationale for change
Whole blood stability testing will not be done in the 
follicular lymphoma cohorts.
Section to be changed
Table 3.1: 1
Description of change
Changes made to Cohort H and I rows
Rationale for change
Corrections
Section to be changed
Section 3.3.3 Exclusion Criterion #4
Description of change
4.
Any investigational or anti-tumour treatment within 
4 weeks or within 5 half-life periods (whichever is 
shorter)30 days prior to the initiation of trial treatment. FL 
patients on chemotherapy immediately prior to current study 
may initiate treatment in this trial within 15 days of last 
chemotherapy dose following sponsor agreement.
Rationale for change
To clarify that the wash-out period may be shorter for 
drugs with a short half-life  
Section to be changed
Table 3.3.3: 1
Description of change
International Normalized Ratio (INR) (only tested if 
clinically indicated)
Rationale for change
To clarify that coagulation parameters need only be tested if 
clinically indicated
Section to be changed
Section 4.1.9 Administration of doses for each patient
Description of change
For Part I solid tumour cohorts, dosing will be sequential for 
doses <80200 mg LAG3 with BI 754091 infused first 
followed by infusion of BI 754111. The infusion duration for 
each will be specified in the pharmacy manual. It is 
anticipated that the entire infusion time will take ~1 hour. For 
doses ≥80200 mg LAG3, the infusion will be simultaneously 
(infusion duration ~1 hour).
Rationale for change
To align the protocol with the Pharmacy Manual

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Section to be changed
Section 4.2.2.1 Permitted concomitant medications
Description of change
[…]
For symptom control, palliative radiotherapy is permitted for 
any lesion in the dose-escalation part of the trial, except 
during the first cycle (in solid tumours) and the first
3 cycles (in FL) as it could interfere with the DLT evaluation 
for MTD/RPIID determination. […]
Rationale for change
To improve clarity concerning palliative radiation allowed for 
the different disease states
Section to be changed
Section 4.2.2.2 Prohibited concomitant medications
Description of change
[…]
∀
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, Ppatients should stop using 
these herbal medications 7 days prior to first dose of 
study treatment.
Rationale for change
To clarify that the Principal Investigator can make exceptions 
for prohibited herbal preparations/medications.
Section to be changed
Description of change
Rationale for change
Additional further endpoints are planned.
Section to be changed
Description of change
Rationale for change

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Section to be changed
Section 7.1.1.2 Combination BLRM for follicular lymphoma 
cohorts
Description of change
The parameters for prior distributions are given in 
Table 7.1.1.2: 3Table 7.1.1.1:2. The corresponding prior 
probabilities of a DLT at different dose combinations and the 
corresponding probabilities of under-dosing, targeted dosing 
and overdosing are shown in Table 7.1.1.2: 4Table 7.1.1.2: 3.
Alignment of some data points within the tables of this 
section were corrected.
Rationale for change
To link to correct tables and display correct alignment
Section to be changed
Section 7.4 Interim analyses
Description of change
[…]
No formal interim analysis of PK data is planned. However, 
exploratory analysis of PK will be done during the dose 
escalation part and may also be done during the expansion 
part, if considered reasonable. Furthermore, an exploratory 
analysis of immunogenicity may be performed at least once 
during the escalation part.
No pre-specified interim or exploratory PK analysis is 
planned for the dose-expansion Part II portion of the trial. 
Exploratory PK analyses will be based on planned sampling 
times, if information on actual times should not be 
available. The results of these evaluations will be preliminary 
and may be subject to change, as these do not involve a 
formal database lock. No interim report will be written for 
exploratory PK analyses.
[…]
Rationale for change
To clarify interim analyses of PK data
Section to be changed
Table 10.4.1: 1 and New Table 10.4.1:2
Description of change
Information for follicular lymphoma (FL) patients is removed 
from Table 10.4.1:1 (including Footnote c) and a new 
Table 10.4.1: 2 was created for FL patients during Cycles 1 
and 2. Information for FL patients during Cycle 3 is still in a 
separate table, now numbered Table 10.4.1: 3.
Additions made to the table and footnote specifying the 
timings of BI 75411 and BI 754091 infusions.
Last footnote (now Footnote c):  The specified blood volume 
for both BI 754111 and BI 754091 will be drawn into 
separate blood-drawing tubes. However, they should be 
collected in parallel at the specified time points after the 
start of the BI 754091 infusion(solid tumour cohorts).
Rationale for change
Removing the FL cohort information to a separate table will 
clarify this information for the sites.
To further stress that even though in some cases, BI 754111 
and BI 754091 are infused sequentially, the PK sampling for 
BI 754111 and BI 754091 can still be collected at the same 
time. The time point reference remains after the start of the 
first infusion.

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Number of global amendment
3
Date of CTP revision
31 January 2018
EudraCT number
Not applicable
BI Trial number
BI 1381.2
BI Investigational Product(s)
BI 794111 and BI 754091
Title of protocol
An open label, Phase I dose-finding study of 
BI 754111 in combination with BI 754091 in 
patients with advanced solid cancers and of 
BI 754111 monotherapy with subsequent 
combination with BI 754091 in patients with 
follicular lymphoma, followed by an expansion 
cohort at the RPIID of the combination in patients 
with non-small cell lung cancer
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Title page
Description of change
1. EudraCT No.: 2017-005042-29 Added
2. Coordinating Investigator role added and 
 
Physician 
 removed:
Rationale for changes
1. The row for EudraCT number had previously been 
removed from the template in error.

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2. Sites will be initiated in Europe, thus requiring a 
Coordinating Investigator rather than a Physician 
.
Section to be changed
Synopsis page 1 Trial sites
Description of change
Approximately 10 sites in Canada and the USA
Rationale for change
This detail is removed because study sites are not required 
to be pre-specified in the protocol and more sites will be 
identified.
Section to be changed
Synopsis - other changes to the synopsis are described as 
changes in the relevant sections in the body of the 
protocol.
Section to be changed
All Flow Charts Footnote c
Description of change
[…]clinical chemistry (sodium, potassium, phosphate, 
chloride, creatinine, calcium, venous bicarbonate HCO3, 
albumin, total protein, aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], alkaline phosphatase, 
bilirubin, lactate dehydrogenase, serum glucose, c-peptide 
[baseline only], serum cholesterol [baseline only], serum 
triglycerides [baseline only], creatine kinase [CK: if CK is 
elevated, then CK-MB, Troponin I, and myoglobin should be 
reactively tested, with further follow-up as clinically 
warranted], serum urea nitrogen, serum uric acid, and thyroid 
panel [TSH, free T4, and free T3]), […]
Rationale for change
It has been determined that these tests are not needed.
Section to be changed
Flow Chart 3 Footnote h
Description of change
Additional progression-free survival (PFS) follow-up visits 
after the 30-day safety follow-up visit will only be performed 
for patients who did not progress on treatment. These will be 
performed once every 12 weeks at least (by telephone) until 
PD, introduction of a new anti-cancer treatment, death, loss to 
follow-up, withdrawal of consent, or end of the whole 
trial.Patients enrolled in Protocol Version 4.0: Additional 
overall survival (OS) and progression-free survival (PFS) 
follow-up visits after the 30-day safety follow-up visit will 
be performed once every 12 weeks at least (by telephone) 
until death, loss to follow-up, withdrawal of consent, or 
end of the whole trial. Patients enrolled in Protocol 
Version 3.0 and earlier: Additional PFS follow-up visits 
after the 30-day safety follow-up visit will only be 
performed for patients who did not progress on
treatment. These will be performed once every 12 weeks 
at least (by telephone) until PD, introduction of a new 
anti-cancer treatment, death, loss to follow-up, 
withdrawal of consent, or end of the whole trial.
Rationale for change
To add overall survival (OS) visits to the protocol going 
forward and to clarify PFS visits in previous versions.

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Section to be changed
Flow Chart 2 - follicular lymphoma dose-escalation
Description of change
New row added for Biomarker 
 blood 
collections
New Footnote r added:  Blood samples for biomarker 
 
the dose-escalation cohorts in patients with FL only during 
Cycle 1 on Day 1 (pre-treatment), Day 8, Day 15, during 
Cycle 2 on Day 1 (pre-treatment), and again during Cycle 3 
on Day 1 (pre-treatment), Day 8, Day 15, during Cycle 4 on 
Day 1 (pre-treatment), and at the 30-day follow-up visit.
Rationale for change
This information will be an integral part of the dose-selection 
process moving forward in patients with FL.
Section to be changed
Flow Chart 3
Description of change
Footnote k: Blood samples for
 
 
 
 
 only during Cycle 1 on Day 1 (pre-treatment), Day 8, 
Day 15, during Cycle 2 on Day 1 (pre-treatment), and at the 
end-of-treatment30-day follow-up visit.
Footnote l: All patients in Part II (dose-expansion cohorts) 
must have tissue samples (fresh or archived [see 
requirements]) available for retrospective central PD-L1 
testing. The following will be required (see Section 5.5.2.3 
for details):
-
If available and taken within 6 months of study start, 
22 to 25 (4-5 μm) sections from an archival FFPE block 
should be collected. If adequate archival tissue is not 
available, 3 fine-needle biopsies must be taken between 
screening and the day before the first study drug treatment. 
For patients who do not have historic PD-L1 data derived 
from an FDA-approved test, part of this material may be used 
for local testing to obtain this information. 2 core needle 
biopsies or 1 punch biopsy (refer to lab manual for 
specifications) from the most recent relapse (if within 
6 months of trial start with no subsequent therapy); 
otherwise, a minimum of 2 core needle biopsies or 
1 punch biopsy must be taken between screening and the 
day before first treatment with BI 754091.
-
Two corefine-needle biopsies or 1 punch biopsy on 
treatment at the end of Cycle 2 (after 6 weeks of treatment), 
preferably from the same lesion.
-
Another biopsy (optional) should be taken upon PD 
(according to RECIST v1.1 and irRECIST), if possible. An 
optional biopsy should also be taken if a patient has 
Sstable disease (SD) over 4 months would also be qualified 
as a response (see Section 5.1.2.2), and a biopsy (optional) 

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would be taken at that time point3 subsequent disease 
assessment periods.
Footnote o: PK samples are to be collected during Cycles 
1, 4, and 8, at the EOT visit, and the 30-day safety follow-
up, and 
blood samplings are to be collected during 
Cycles 1 through 9, Cycle 12, Cycle 154, Cycle 187, and 
every 3rd cycle thereafter, at the EOT visit, and the 30-day 
safety follow-up (see the tables in Appendix 10.4 for 
specifics).
Rationale for change
Footnote k: to align with the updates to Tables 10.4.2: 1.
Footnote l: to clarify the requirements for biopsies to 
assure that enough tissue is available for the required 
testing, and to clarify when an optional biopsy should be 
taken in the event of prolonged stable disease.
Footnote o: to align with the updates to Tables 10.4.2: 1.
Section to be changed
Section 2.1 Rationale for conducting the trial
Description of change
[…]
This 2-part trial is the first study with BI 754111 in 
humans and the second with BI 754091. The first part will 
include dose-escalation cohorts to determine the 
maximum-tolerated dose (MTD) and/or the 
recommended Phase II dose (RPIID). The second part
includes expansion cohorts at the RPIID that will further 
evaluate the safety, tolerability, PK, biomarkers and the 
preliminary efficacy of the BI 754111 plus BI 754091 
combination. The dose-escalation portion of the trial will 
enrol patients with advanced and/or metastatic solid 
tumours and FL, while the dose-expansion portion will 
enrol patients with advanced and/or metastatic NSCLC.
Rationale for change
To further expand on the rationale for conducting the trial, 
particularly for the dose-expansion cohort that will begin 
recruitment soon.
Section to be changed
Section 2.2.1 Part I (dose-escalation cohorts) objectives
Description of change
Investigate the safety, tolerability, and PK of escalating 
doses of BI 754111 in combination with BI 754091 
(administered via i.v. infusion q3w), with BI 754091
added on to BI 754111 starting at Cycle 3 in patients with 
relapsed/refractory FL
Rationale for change
To clarify that BI 754091 is added to BI 754111 starting at 
Cycle 3.

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Section to be changed
Table 3.1: 1
Description of change
Several rows in this table were edited to be more explicit 
about the dosing combinations.  In addition, the dose-
expansion NSCLC population was clarified:
Recommended Phase II combination dose (RPIID) in 
patients with 2nd and 3rd line NSCLC who progressed on 
anti-PD-1 or anti-PD-L1 treatment (as defined in the entry 
criteria)
Rationale for change
To clarify dosing for the sites and to add more specific 
information about the expansion cohort.
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
[…]
7.
Patients with NSCLC that hasve epidermal growth 
factor receptor (EGFR) mutations or anaplastic lymphoma 
kinase (ALK) rearrangements
8.
Presence of other active invasive cancers other than 
the one treated in this trial within 5 years prior to screening, 
with the exception of appropriately treatedresected/ablated
basal or squamous-cell carcinoma of the skin, or carcinoma in 
situ carcinoma of the uterine cervix, or other local tumours 
considered cured by local treatment.
[…]
12.
Any of the following cardiac criteria:
-
Mean resting corrected QT interval (QTc) >470 
msec
-
Any clinically important abnormalities (as 
assessed by the Investigator) in rhythm, conduction, or 
morphology of resting ECGs, e.g., complete left bundle 
branch block, third degree heart block
-
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
-
Patients with an ejection fraction (EF) <55% or 
the lower limit of normal of the institutional standard will 
be excluded. Only in cases where the Investigator (or the 
treating physician or both) suspects cardiac disease with 
negative effect on the EF, will the EF be measured during 
screening using an appropriate method according to local 
standards to confirm eligibility (e.g., echocardiogram, 
multi-gated acquisition scan). A historic measurement of 
EF no older than 6 months prior to first administration of 
study drug can be accepted provided that there is clinical 
evidence that the EF value has not worsened since this 
measurement in the opinion of the Investigator or of the 
treating physician or both.
-
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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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
-
Ejection fraction <55% or the lower limit of normal 
of the institutional standard.
Rationale for change
Criterion #7: To clarify the patient population
Criterion #8:  To clarify exclusion of other active cancers 
and to align language across current studies with 
BI 754091.
Criterion #12: To clarify exclusion due to cardiac criteria 
and to align language across current studies with 
BI 754091.
Section to be changed
Section 3.3.4.2 Discontinuation of the trial by the sponsor
Description of change
[…]
4.
Completion of treatment by all patients and the 
sponsor determines that sufficient survival data has been 
collected.
Rationale for change
Clarification of the sponsor’s rights to discontinue the trial in 
case sufficient survival data has been collected.
Section to be changed
Section 4.2.2.1 Permitted concomitant medications
Description of change
[…]
•
Blood transfusions are allowed at any time during 
the trial, except to meet inclusion criteria. There must be at 
least 4 weeks between a patient’s last transfusion and 
their screening laboratory assessment. Exceptions to this 
will be considered by the sponsor on a case-by-case basis.
Rationale for change
This change clarifies the expectations for time since previous 
transfusions. This time line reflects the half-life of red blood 
cells.
Section to be changed
Description of change

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Rationale for change
To clarify the further endpoints for Part I.
Section to be changed
Description of change
Rationale for change
To clarify the further endpoints for Part II.
Section to be changed
Section 5.3.4.2
Biochemistry
Description of change
The standard biochemistry panel will consist of glucose, 
sodium, potassium, chloride, calcium, phosphate, venous 
bicarbonate HCO3, creatinine, creatine phosphokinase 
(CPK), AST, ALT, alkaline phosphatase, lactate 
dehydrogenase (LDH), bilirubin, total protein, albumin, urea 
nitrogen (or urea), and uric acid. In addition, cholesterol, 
triglycerides, and c-peptide will be done at baseline and when 
clinically indicated. Troponin will be tested according to the 
times listed in the flow charts. In case of pathological CPK, 
then CPK-MB, additional troponin I, and myoglobin should 
be reactively tested and the findings documented.
[…]
Rationale for change
It has been determined that these tests are not needed.
Section to be changed
Section 5.3.6.5.2 Immune-related adverse events (irAE)
Description of change
[…] The sponsor has defined a list of potential irAEs in 
Table 10.1: 1 in Appendix 10.1 that must be reported as 
AESIs. These irAEs must be reported as AESIs. If an 
Investigator determines another irAEevent (not on the list) 
should be an potential irAESI, the Investigator may also 
report that event as an AESI.

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Immune-related AEs are AEs associated with immunotherapy 
treatments that appear to be associated with the immune 
therapy’s mechanism of action. These adverse reactions, 
which can be severe, may involve the gastrointestinal, skin, 
liver, endocrine, respiratory, renal, or other organ systems. 
All immune-related events are to be reported as AEs. 
Some irAEs also need to be reported as AESIs as defined 
by tThe sponsor has defined a list of potential irAEs in Table 
10.1: 1. These irAEs must be reported as AESIs. If an 
Investigator determines another a Grade 3 event (not on the 
list) to be immune-related, should be a potential irAE, the 
Investigator may should also report that event as an AESI.
Rationale for change
To clarify the reporting of irAEs as AESI.
Section to be changed
Section 5.3.6.8.1 Adverse event collection
Description of change
[…]
For sites outside of the US, country-specific fax numbers 
will be provided in the ISF/Study reference manual.
[…]
The following should also be recorded as (S)AEs in the eCRF 
and SAE form (if applicable):
∀    Worsening of pre-existing conditions
∀
Changes in vital signs, ECGs, physical examinations, and 
laboratory test results, if they are judged clinically 
relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion 
they will be considered as baseline conditions.
All (S)AEs, including those persisting after an individual 
patient’s end of trial must be followed up until they have 
resolved, they have been sufficiently characterised, or no 
further information can be obtained.
Rationale for change
To clarify country-specific fax numbers will be provided for 
the reporting of AEs and to clarify that the excerpt is referring 
to all AEs (serious and non-serious) and not just serious AEs.
Section to be changed
Section 5.4.1
Assessment of pharmacokinetics and 
Section 7.3.5
Description of change
If data allow, the PK parameters of BI 754111 after single 
and multiple doses of BI 754111 monotherapy (FL cohort) 
and in combination with BI 754091, and also for BI 754091 
after single and multiple doses of combination therapy 
mentioned as secondary and further endpoints for Parts I and 
II (see Section 5.1.2 and Section 5.1.3, respectively) will be 
evaluated using non-compartmental analysis methods 
according to BI internal SOP (001-MCS-36-472_RD-01 [2.0] 
and 
Kinesis SOP ‘SOP-1.PKA.03 Non-
compartmental PK/PD Analysis’).
Rationale for change
 BV has changed their name to 
 
ED BV.

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Section to be changed
Section 5.4.2
Methods of sample collection for 
pharmacokinetic analyses
Description of change
[…]
The 1 hour PK sample is to be drawn shortly afterbefore and 
as close as possible to the end of the total infusion (of BI 
754091 and BI 754111).
Pharmacokinetic sampling times and periods may be 
adapted by the Sponsor during the trial based on 
information obtained during trial conduct (e.g., 
preliminary PK data). Such changes would be 
implemented via non-substantial Clinical Trial Protocol 
Amendments.
[…]
Rationale for change
To clarify when the 1-hour PK sample should be taken and 
to explain that sampling times may be changed in the 
future as more knowledge is gained.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 5.5 Assessment of Biomarkers
Description of change
Rationale for change
To clarify that the lab manual will contain details related to 
biopsy samples
Section to be changed
Section 5.5.1 Methods of Sample Collection
Description of change
Pre- and on-treatment tumour biopsy collections for 
biomarker and PDc analyses will be mandatory from all 
patients in the Phase Ib dose-expansion portion of the trial. In 
addition, an optional biopsy biopsies should be taken 
according to the flowchart and Section 5.5.2.3 after 
treatment discontinuation, if possible.
Rationale for change
To clarify the expectations regarding biopsy collection.

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Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change

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Section to be changed
Section 6.2.3.4
Overall survival visits (new section added)
Description of change
Additional follow-up visits after the 30-day safety follow-
up visit will be performed for patients in the dose-
expansion cohort who enrol in Protocol Version 4.0 and 
beyond. These will be performed once every 12 weeks at 
least (by telephone) on the same schedule as PFS survival 
visits until death, loss to follow-up, or end of the whole 
trial as specified in Section 3.3.4.2. If the sponsor 
determines that enough OS data has been collected from 
select cohorts, sites could be instructed to discontinue OS 
visits for those cohorts.
Rationale for change
Overall survival has been added to further endpoints for the 
dose-expansion part of the study, so this visit has been added 
to the study plan table (Flow Chart 3) for patients going 
forward and this section has been added.
Section to be changed
Section 7.2 Null and alternative hypotheses
Description of change
No formal hypothesis testing is planned in this trial. All 
analyses in this trial are descriptive and exploratory.
Rationale for change
To only present a statement about the hypotheses without 
including a description of analyses.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 7.4 Interim analysis
Description of change
No formal interim analysis of efficacy data is foreseen, 
although efficacy data when available may be considered as 
part of the safety evaluations.
[…]
Rationale for change
Clarification
Section to be changed
Table 10.1: 1 Immune-related adverse events of special 
interest
Description of change
This table defines immune-related AEs that must be 
reported as AESIs.
Each subsection was updated as for the following example:
Pneumonitis (reported as an AESI if ≥ Grade 2)
Rationale for change
To clarify that all immune related AEs are reportable AEs. 
When they meet the criteria listed in Table 10.1:1, they must 
also be reported as AESIs.

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Section to be changed
Tables 10.4.1: 1, 10.4.1: 2, and 10.4.1: 3: A few changes 
were made in the body of each of the tables for clarity and the 
footnotes changed (where applicable):
Description of change
a The planned total infusion duration is 1 hour. For cohorts 
receiving doses of BI 754111 <80 mg, the overall infusion 
duration (BI 754091+BI 754111) should also be as close to 1 
hour as possible. In the event that total infusion duration is 
>15 minutes longer than planned, the subsequent time points 
for PK blood collection on the day of drug infusion should be 
adjusted accordingly (e.g., 1.25 hours post SOI). For cohorts 
receiving combination treatment using doses of BI 754111 
<80 mg, the 1 hour PK sample is to be drawn before and as 
close as possible toshortly after the end of the BI 754111 
infusion. Actual date and clock time of SOI, end of infusion 
and blood draws have to be recorded.
b The following windows of time are allowed for PK 
sampling:
•
Predose (PTM -0:05): within 1 hour before next drug 
infusion
•
Shortly after Immediately before the end of 
infusion (PTM 1:00): within ±5 min of the end of infusion
[…]
c The specified blood volume for both BI 754111 and 
BI 754091 will be drawn into separate blood-drawing tubes. 
However, they should be collected in parallel at the specified 
time points after the start of the BI 754091 (or combination)
infusion.
Rationale for change
To improve clarity and to make it clear when certain PK 
samples should be drawn.
Section to be changed
Tables 10.4.1: 2, 10.4.1: 3, and 10.4.1: 4:
Description of change
A column for PBMC testing was added to each table.
Rationale for change
To clarify that this testing is to be done for patients with FL.
Section to be changed
Table 10.4.1: 4 Footnote b was updated:
Description of change
b The specified blood volumes for both BI 754111 and 
BI 754091 will be drawn into separate blood-drawing tubes. 
at the specified time pointsHowever, they should be 
collected in parallel at the specified time points after the 
start of the BI 754091 (or combination) infusion.
Rationale for change
To clarify the method for PK sampling when tubes for 
BI 754091 and BI 754111 are drawn at the same time point.
Section to be changed
Table 10.4.2: 1: Sampling in the expansion cohort
Description of change
One new table with updated and corrected sampling times 
replaced the 2 previous tables. The footnotes were updated as 
described for the dose-escalation tables, where applicable.
Rationale for change
New information from the dose-escalation cohorts has 
triggered a shift in sampling times.

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Number of global 
amendment
4
Date of CTP revision
29 May 2018
EudraCT number
Not applicable
BI Trial number
BI 1381.2
BI Investigational Product(s)
BI 794111 and BI 754091
Title of protocol (previous -
see below for title update)
An open label, Phase I dose-finding study of 
BI 754111 in combination with BI 754091 in patients 
with advanced solid cancers and of BI 754111 
monotherapy with subsequent combination with BI 
754091 in patients with follicular lymphoma, 
followed by an expansion cohort at the RPIID of the 
combination in patients with non-small cell lung 
cancer, metastatic colorectal cancer, solid tumors 
with high tumour mutational burden and/or 
microsatellite instability
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Protocol Title
Description of change
An open label, Phase I dose-finding study of BI 754111 in 
combination with BI 754091 in patients with advanced solid 
cancers and of BI 754111 monotherapy with subsequent 
combination with BI 754091 in patients with follicular 
lymphoma, followed by expansion cohorts at the RPIID
selected dose of the combination in patients with non-small cell 
lung cancer, metastatic colorectal cancer, solid tumors with 
high tumour mutational burden and/or microsatellite 
instabilityand other solid tumors

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Rationale for changes
The title was updated to more accurately describe the study 
with the changes made in this amendment
Rationale for change
The FL cohort is removed from the protocol
Section to be changed
Sections 7.1.1.2, 7.1.1.3, 10.5.1.2 and the Flowchart for the FL 
cohort 
Description of change
These sections were removed entirely
Rationale for change
The FL cohort has been difficult to recruit and the participating 
investigators indicate that the likelihood of finding patients for 
these cohorts was very small.  Additionally, newly available 
data indicated that LAG3 expression is not detectable in 
PBMCs from patients with FL making the objective of 
measuring receptor occupancy in these patients not attainable.
Rationale for change
The FL cohort is removed from the protocol
Section to be changed
Protocol Title, Synopsis, Amendment Text
Description of change
Any text mentioning the FL cohort was removed from these 
sections. 
Rationale for change
The FL cohort has been difficult to recruit and the participating 
investigators indicate that the likelihood of finding patients for 
these cohorts was very small.  Additionally, newly available 
data indicated that LAG3 expression is not detectable in 
PBMCs from patients with FL making the objective of 
measuring receptor occupancy in these patients not attainable.
Section to be changed
Protocol Title, Amendment Text, Synopsis
Description of change
RPIID selected expansion dose
Rationale for changes
The text has been updated to allow more flexibility in selection 
of the expansion dose(s) in this study. 
Section to be changed
Synopsis - other changes to the synopsis are described as 
changes in the relevant sections in the body of the protocol.
Section to be changed
Flow Chart 32
Description of change
What was Flow Chart 3 became Flow Chart 2
Rationale for change
The original Flow Chart 2 for FL patients was removed.

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Section to be changed
Flow Chart 1 and Flow Chart 2
Description of change
All cycles are 3 weeks (21 days) in duration. Patients will 
continue treatment with the study drugs until disease 
progression (PD) by RECIST and/or iRECIST, withdrawal of 
patient consent, an unacceptable toxicity occurs, or 1 year of 
treatment is completed, whichever occurs first. Patients will be 
allowed to stay on treatment in the case of initial radiological 
PD, if the Investigator feels that it is in the patient’s best interest 
and the patient signs an informed consent describing this 
circumstance. In addition, patients without PD may stay on 
trial after 1 year on a case-by-case basis after discussion with 
the Medical Monitor and the sponsor. Day 1 of Cycle 1 is 
defined as the day when the combination of BI 754111 and BI 
754091 is administered.
Rationale for change
With the implementation of iRECIST in this protocol, patients 
will be re-consented to remain on treatment following PD per 
RECIST 1.1, until a confirmed progression per iRECIST.
Section to be changed
Flow Chart 2
Description of change
Vital Signs, Concomitant Medication, and Adverse Events 
removed from Cycle 2 Day 2 and 4, and Cycle 4 Day 4.
Footnote j was updated with the additional text: PK samples 
are also taken pre-treatment on Day 1 of all other cycles 
through Cycle 9 and then on Day 1 of every 3rd cycle.
Footnote h was updated with the addtioanl text: patients 
enrolled in protocol version 4.0 or later
Footnote k: was updated with remove of with NSCLC
Footnote l was updated: A minimum of 2 core needle biopsies 
or 1 punch biopsy must be taken between screening and the 
day before first treatment with BI 754091. Otherwise, Ttwo 
core needle biopsies or 1 punch biopsy (refer to lab manual for 
specifications) from the most recent relapse (if within 6 months 
of trial start with no subsequent therapy) are acceptable.;
otherwise, a minimum of 2 core needle biopsies or 1 punch 
biopsy must be taken between screening and the day before first 
treatment with BI 754091
Footnote o was updated: PK samples are to be collected during 
Cycles 1, 4, and 8, at the EOT visit, and the 30-day safety 
follow-up, and 
 blood samplings are to be collected…
Footnote p was added: The clinic will telephone the patients 
on Days 2 and 4 of Cycle 2 in order to check on any adverse 
events. The patients will not be required to go to the clinic 
on these days.
Rationale for change
The flow chart was updated to clarify when PK samples are to 
be collected, what tissue should be taken for biomarker testing, 
and to clarify when patients need to come to the clinic on 
Cycles 1, 2, and 4. 

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Section to be changed
Abbreviations
Description of change
Abbreviations for ALK-Anaplastic lymphoma kinase, mCRC-
Metastatic colorectal cancer, MSI-H-microsatellite instability 
high, and TMB-Tumour mutational burden were added. The 
abbreviation for FL-Follicular lymphoma was removed and 
irRECIST-Immune-Related Response Evaluation Criteria in 
Solid Tumours was changed to iRECIST-Guidelines for 
response criteria for use in trials testing immunotherapeutics
Rationale for change
To align the list of abbreviations to what is used in the 
amendment text. 
Section to be changed
2.1 Rationale for performing the trial
Description of change
Multiple immune checkpoint inhibitors have been approved 
for the treatment of patients metastatic NSCLC including 
pembrolizumab, nivolumab and atazolizumab. In second 
line NSCLC,  blockade of the PD-1 pathway with an anti-
PD-1 or anti-PD-L1 mAbs results in significant 
improvement in response rate (approximately 20 % Vs. 9%)  
and a significant improvement in overall survival 
(approximately 3 moths) compared to standard of care 
chemotherapy (R16-0878; R15-3715; R16-1875;R16-5828).
It is postulated that treating patients with immune check 
point inhibitor early in their treatment continuum, while 
there immune system is still relatively intact, may maximize 
the chance of response and prolonged survival.  To this end, 
immune checkpoint inhibitor have made remarkable 
changes to the standard of care for previously untreated 
patients with advanced NSCLC. Pembrolizumab 
monotherapy resulted in significant improvement in 
response rates, progression free survival and  overall 
survival  in previously untreated patients with NSCLC 
whose tumors express high level expression of PD-L1 of (to 
≥50%) when compared to standard of care chemotherapy
(R16-4803). As a result, pembrolizumab monotherapy is 
now a well-established  treatment of choice as the 
replacement for cytotoxic chemotherapy in the first-line 
(R16-4803). However, approximately half the patients 
treated with pembrolizumab in this setting do not respond 
(response rate of 44.8%) and will require other immune 
therapy combination to achieve clinical benefit.  Indeed, 
recent data have demonstrated that response rates in 
previously untreated NSCLC by combining pembrolizumab 
with chemotherapy can be improved (approximately 61% 
and 48%-55%) in patients with ≥50% and ≥1% PD-L1
expression, respectively, by combination pembrolizumab 
with chemotherapy (R16-4804; P18-03589).  However, the 
combination of pembrolizumab with chemotherapy is 
associated with a significant increase in toxicity, owing to 
the chemotherapy component, than checkpoint inhibitor 
monotherapy (R16-4804; P18-03589). Therefore, finding 
more tolerable, less toxic checkpoint inhibitor combination 
to treat previously untreated NSCLC patients is of immense 
interest. 

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Checkpoint inhibitor therapy has also proven effective 
(approximately 30-40% of patients achieved objective 
response) in a subset of patients with MSI-H or DNA 
mismatch repair deficient metastatic colorectal cancer 
(mCRC) which tend to be highly immunogenic cancers 
(R16-1497; R18-1746). However, these characteristics occur 
only in a small fraction of mCRC (~5%).  The majority of 
mCRC patients are microsatellite stable for whom single 
agent immunotherapy has not been successful. As such, this 
trial will evaluate the utility of the combination BI754091 
(anti-PD-1 mAb) with BI754111 (anti-LAG-3 mAb) in this 
microsatellite stable mCRC population who have 
progressed on the standard of care, a population with very 
high unmet medical need. 
The trial will also include a cohort of patients with solid 
tumours whose disease progressed while taking an anti-PD-
1 or anti-PD-L1 regimen and who’s tumours have high 
tumour mutational burden (TMB; defined as ≥10 
mutations/megabase of DNA) or high microsatellite 
instability MSI-H. Both TMB-high and MSI-H are good 
predictive biomarkers of immunogenic tumours and 
response to immune checkpoint inhibitor therapy (R18-
1492). As outlined above, the objective of this cohort is to 
explore the ability of the checkpoint inhibitor combination 
to restore immunotherapy responsiveness in this subset of 
anti-PD-1 or anti-PD-L1 resistant (both primary and 
acquired) with good predictive markers for response. If 
successful, such a regimen may provide a second 
immunotherapy treatment option with the potential for 
durable clinical benefit and possibly delay the need to 
initiate chemotherapy in some patients. 
While LAG-3 is not expressed on peripheral T-cells in healthy 
volunteers or most patients with solid tumours, it appears to be 
expressed on T-cells of patients with B-cell malignancies (R16-
5218). Hence we will include patients with follicular lymphoma 
(FL) in order to measure LAG-3 receptor occupancy in that 
patient population.
Rationale for change
Background information was added for the new patient 
populations to be studied in this amendment.
Section to be changed
Section 2.1
Rationale for Performing the Trial
Description of change
This 2-part trial is the first study with BI 754111 in humans and 
the second with BI 754091. The first part will include dose-
escalation cohorts to determine the maximum-tolerated dose 
(MTD) and/or the selected expansion doserecommended Phase 
II dose (RPIID). The second part includes expansion cohorts at 
the selected expansion doseRPIID that will further evaluate the 
safety, tolerability, PK, biomarkers and the preliminary efficacy 
of the BI 754111 plus BI 754091 combination. The dose-
escalation portion of the trial will enrol patients with advanced 
and/or metastatic solid tumours and FL, while the dose-
expansion portion will enrol patients with advanced and/or 
metastatic NSCLC, previously treated microsatellite stable 

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metastatic colorectal cancer (mCRC), or any anti-PD-1 or 
anti-PD-L1 pretreated solid tumour with high tumour 
mutational burden (TMB ≥10 mut/MB) and/or 
microsatellite instability high (MSI-H) and/or DNA 
mismatch repair deficient (MMRd).
Rationale for change
The rationale was updated to more accurately describe the study 
with the changes made in this amendment and to provide a 
rationale for these changes. 
Section to be changed
Section 2.2
Trial Objectives
Description of change
The following changes were made to the Part I (dose-
escalation) trial objectives:
∀
Investigate the safety, tolerability, and PK of escalating 
doses of BI 754111 as monotherapy for 2 cycles (2 doses 
administered via i.v. infusion q3w) in patients with 
relapsed/refractory FL
∀
Investigate the safety, tolerability, and PK of escalating 
doses of BI 754111 in combination with BI 754091 
(administered via i.v. infusion q3w), with BI 754091 added 
on to BI 754111 starting at Cycle 3 in patients with 
relapsed/refractory FL
∀
Determine the MTD through monitoring dose-limiting 
toxicities (DLTs) and/or to determine the doseRPIID of the 
combination of BI 754111 plus BI 754091 to be used in 
the expansion phase (Part II).
∀
Assess LAG-3 receptor occupancy (RO) in peripheral 
blood in patients with FL.
The objectives of the Part II (dose-expansion) portion of the 
trial are to:
∀
Further investigate the safety, tolerability, and PK of the
RPIID selected expansion dose of the combination of 
BI 754111 plus BI 754091 in patients with NSCLC),
microsatellite stable (MSS) metastatic colorectal cancer 
(mCRC), or any PD-1 or PD-L1 pretreated solid 
tumour with high tumour mutational burden (TMB) 
and/or microsatellite instability high (MSI-H) and/or 
DNA/MMRd, (as defined in the entry criteria [see 
Section 3.3].)
∀
Explore the efficacy of the combination in patients with 
NSCLC, mCRC, or any solid tumour with high TMB 
and/or MSI-H and/or DNA/MMRd and/or MMRd (as 
defined in the entry criteria).
Rationale for change
The trial objectives were updated to more accurately describe 
the study focus with the changes made in this amendment.

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Section to be changed
Section 2.3
Benefit-Risk Assessment
Description of change
BI 754091 monotherapy is currently being tested in patients 
in the BI 1381.1 clinical trial. As of 27-Mar-2018, 36 patients 
with advanced/metastatic solid tumors have been treated 
with BI 754091 monotherapy.  Nine patients were treated in 
the dose escalation phase of trial 1381.1 with 3 patients 
treated at each of 80mg, 240mg and 400mg dose levels, all 
administered Q3W. The remaining 27 patients were treated 
in the dose expansion phase of the same trial with 240 mg BI 
754091 (the RPIID) Q3W.   BI 745091 was well tolerated 
with no reported dose limiting toxicities (DLTs), treatment 
related SAE or treatment related deaths.  The most 
frequently reported AEs (reported in >10% of the patients) 
were fatigue (47.2%), nausea (30.6%), decreased appetite 
(22.2%), constipation (19.4%), abdominal pain (16.7%) 
cough (16.7%), diarrhea (13.9 %), arthralgia (13.9%), 
vomiting (11.1%), and hypokalaemia (11.1%), headache 
(11.1%) and dyspnea (11.1%).  The majority of these AEs 
were CTCAE grade 1 and 2.  Grade 3 and 4 AEs were 
reported in 47.2% and 5.6% of patients, respectively. Of the 
grade 3 events, only the AST elevation is reported as related 
to trial drug.  The reported grade 4 AEs were disease 
progression and sepsis, neither of which was deemed 
treatment related.  Immune-related AEs included 1 Grade 2 
hypothyroidism, 1 Grade 2 ALT increased, 1 Grade 3 AST 
increased, 2 Grade 1 rash, 2 Grade 1 rash maculo-papular 
and 1 Grade 1 pruritus.
Preliminary efficacy analyses indicate that there are 5 
patients with partial response (PR) and approximately 10 
patients with disease stabilization on BI 754091 
monotherapy in the 1381.1.  The PRs were reported in two 
patients with triple negative breast cancer, one patient with 
ovarian cancer, one patient with renal cancer, and one 
patient with stomach cancer.  All of these PRs occurred in 
patients receiving the 240 mg q3w dose of BI 754091.  
Pharmacokinetic data of BI 754091 are available from 9 
patients in the dose escalation part of the ongoing clinical 
phase I study 1381.1 in which three dose levels (80, 240 and 
400 mg) of BI 754091 as monotherapy have been tested 
(each in 3 patients).  The details of the preliminary analysis 
are provided in section 6.2 of the BI 754091 IB.
BI 754111 has not been tested in humans thus far.
Rationale for change
To better describe the current status of BI 754091 in patients. 

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Section to be changed
Section 2.3
Benefit-Risk Assessment
Description of change
BI 754111 has only been administered to human subject in 
the dose escalation part of this trial.  Six dose levels of BI 
754111 (4mg, 20mg, 80mg, 200mg, 400mg and 600mg) have 
been tested during this trial in combination with 240 mg BI 
754091 q3w.  Thus far (27-Mar-2018 data lock point), the 
combination treatment is well tolerated with no DLTs, or 
treatment related deaths reported.  One case of CTCAE 
Grade 3 ALT and Grade 2 AST elevation has been reported 
as treatment-related SAE.  The most frequently reported 
AEs in patients treated with combination BI 754091 and BI 
754111 are Nausea (23.7%), Fatigue (23.7%), decreased 
appetite (10.5%), hypokalaemia (10.5%) Pyrexia (10.5%) 
and cough (10.5%).  The majority of these events were 
CTCAE Grades 1 and 2. Grade 3 AEs occurred at a 
frequency of 18.4% and no grade 4 events were reported.  
Of the grade 3 AEs, infusion related reaction, 
maculopapular rash and ALT elevation were reported as 
possibly related to study drugs.  The only Grade 5 event was 
respiratory failure, occurring in the context of pneumonia 
and sepsis and progressive disease.  These events were 
unrelated to trial drugs.  The pattern of immune-related 
AEs for the combination treatment was similar to that 
observed for BI 754091 monotherapy.  Thus far, 2 Grade 2 
hypothyroidism, 1 Grade 3 rash maculopapular, 1 Grade 3 
ALT increase and 1 Grade 3 infusion related reaction have 
been reported as immune related AEs.
BI 754091 is currently being tested in patients in the BI 1381.1 
clinical trial. Preliminary clinical safety information is not yet 
available, but will be closely monitored during the conduct of 
this trial. Repeat-dose administrations of BI 754091 at 0, 3, 30, 
or 100 mg/kg (via i.v. injection) once per week for 13 weeks in 
the cynomolgus monkey were well tolerated. No test article 
related adverse changes in body weight, food consumption, 
respiratory rate, ECGs, or clinical observations were noted at 
any doses. There was no BI 754091-related mortality during 
that study. Administration of BI 754091 had no adverse effects 
on clinical pathology parameters including haematology, 
immune-phenotyping, and clinical chemistry. No BI 754091-
related neurologic or ophthalmic physical examination findings, 
or changes in any haematology, coagulation, clinical chemistry, 
or urinalysis parameters were observed. BI 754091 was not 
associated with any gross or organ weight findings.
Based on these pre-clinical data, as well as preliminary clinical 
data obtained with BI 754091 and other anti-PD-1 mAbs, as 
well as the combination of BI 754091 and BI 754111, the 
inhibitory effects of the combination of BI 754111 and 
BI 754091 may translate into a clinical benefit in cancer 
patients. The dose-escalation scheme for BI 754111 is guided 
by a Bayesian 2-parameter Logistic Regression Model (BLRM) 
(de-escalation of dose is possible in case of insufficient 
tolerability of a dose level) and is designed to escalate the dose 
quickly and minimise the risk of undue tolerability issues.

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Rationale for change
To better describe the current status of BI 75411 and the 
combination of BI 75411 plus BI 754091 in patients.
Section to be changed
Sections 2.3
Benefit-Risk Assessment; Section 4.1.3 Dose-
escalation scheme; Section 5.3 Assessment of Safety; Section 
5.3.6.6 Severity of adverse events; and Synopsis
Description of change
Adverse event will be coded and graded per the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0
4.03. 
Rationale for change
A new CTCAE has been release and will now be used for this 
study. 
Section to be changed
Section 3.1
Overall Trial Design and Plan and Figure 
3.1.1. and Table 3.1.1. 
Description of change
All descriptions of the FL cohort was removed from this 
section. 
Rationale for change
The FL cohort was removed from the study.
Section to be changed
Section 3.1
Overall Trial Design and Plan
Description of change
Following determination of the MTD and (or) the RPIID
selected expansion dose of the combination of BI 754111 and 
BI 754091, Part II will commence to further characterise the 
combination at the doses determined in Part I in patients with 
NSCLC, mCRC, or any solid tumour with high TMB and/or 
MSI-H and/or MMRd. 
Rationale for change
The overall trial design and plan was updated to more 
accurately describe the study with the changes made in this 
amendment. Specifically, the patient populations to be enrolled 
on the study have been updated. 
Section to be changed
Table 3.1.1
Possible Cohort Scenarios for Solid Tumour 
Cohorts
Description of change
3 additional possible cohorts were added to the study
Cohort H: Selected expansion dose in ≥ 2nd line 
microsatellite stable anti-PD-1 and anti-PD-L1 treatment-
naïve mCRC.
Cohort I Selected expansion dose in patients with any solid 
tumour with high TMB or MSI-H and/or MMRd solid 
tumours who have received 1 prior PD-1 or PD-L1 
treatment regimen.
Rationale for change
The table of possible cohorts has been updated to include the 
cohorts to be added with this amendment. 

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Section to be changed
Section 3.1
Overall Trial Design and Plan
Description of change
Following determination of the MTD and/or the RPIID dose
from the Part I portion, 3 dose-expansion cohorts (2nd and 3rd
line NSCLC, anti-PD-1 and anti-PD-L treatment –naïve 
mCRC, and any solid tumour with high TMB and/or MSI-
H), a cohort of 30 patients with NSCLC (as defined in the entry 
criteria) will be enrolled into Part II.
Rationale for change
The overall trial design and plan was updated to more 
accurately describe the study with the changes made in this 
amendment. Specifically, the new cohorts to be added with this 
amendment have been described. 
Section to be changed
Section 3.1
Overall Trial Design and Plan
Description of change
Patients will continue study treatment until disease progression 
(PD) according to the Response Evaluation Criteria in Solid 
Tumours (RECIST) and the Guidelines for Response criteria 
for use in trials testing immunotherapeutics (iRECIST) 
(R17-0923) and/or Immune-Related Response Evaluation 
Criteria in Solid Tumours (irRECIST) or response criteria for 
malignant lymphoma (R14-3387) for patients with FL,
withdrawal of patient consent, an unacceptable…
Rationale for change
iRECIST will replace irRECIST
Section to be changed
Section 3.3.2
Inclusion Criteria and Synopsis
∀
Part I (dose escalation):
∀
Patients with a confirmed diagnosis of 
advanced, unresectable, and/or metastatic 
solid tumours (any type) and patients with 
histologically confirmed relapsed/refractory 
FL.
∀
Patients with solid tumours:
o
For whom no therapy of proven 
efficacy exists, or who are not 
amenable to standard therapies.
o
Must have measurable lesions 
according to RECIST v1.1
o
Previous treatment with an anti-PD-1 
mAb is allowed as long as the last 
administration of the anti-PD-1 mAb 
on the previous treatment is a 
minimum of 60 days prior to starting 
treatment in this trial.
∀
Patients with FL:
o
Patients with histologically 
confirmed, relapsed or refractory FL 
for whom there are no treatment 
options available known to provide 
clinical benefit.
Description of change
o
Must have at least one measurable 
lesion of at least 1.5 cm in long 
diameter as defined in the Revised 
Response Criteria for Malignant 
Lymphoma (R10-1462; R14-3387).
o
Must be anti-PD-1 and anti-PD-L1 
naïve.

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o
Autologous stem cell transplantation 
(SCT) is allowed as long as the 
transplant was completed ≥100 days 
prior to starting treatment in this 
trial.
o
Allogeneic SCT is not allowed.
∀
Part II (dose expansion):
∀
Second and 3rd line NSCLC patients who 
progressed on anti-PD-1 or anti-PD-L1 
treatment after having achieved radiologically 
confirmed benefit (minimum of stable 
disease) with a minimum treatment duration 
of 6 months on the previous anti-PD-1 or anti-
PD-L1 treatment. The anti-PD-1- or anti-PD-
L1-containing treatment (excluding anti-PD-1 
or anti-PD-L1 in combination with 
chemotherapy) must have been the latest 
treatment regimen prior to enrolling in this 
trial with >4 and <12 weeks between the 
latest treatment and their first dose in this 
trial. Patients who have had anti-PD-1 or anti-
PD-L1 as their first-line NSCLC treatment 
regimen must have a PD-L1 expression level 
of ≥50% at baseline (local confirmed 
testing).Patients must have measurable 
disease per RECIST v1.1 criteria, must have 
at least 1 tumour lesion amenable to biopsy, 
and must be medically fit and willing to 
undergo a biopsy before first treatment (if 
adequate archival tissue is not available) and, 
unless clinically contraindicated, after 6 
weeks on therapy.
∀
Dose Expansion Cohorts:
o
Second and 3rd line NSCLC 
patients: 

Must have progressed on 
anti-PD-1 or anti-PD-L1 
treatment after having 
achieved radiologically 
confirmed benefit 
(minimum of stable 
disease) 

Must have had a 
minimum duration of 
benefit of 6 months and 
minimum treatment 
duration of 2 months on 
the previous anti-PD-1 or 
anti-PD-L1 treatment 
without experiencing 
disease progression 
during that period.  

The anti-PD-1- or anti-
PD-L1-containing 
treatment must have been 

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the latest treatment 
regimen prior to enrolling 
in this trial

Must be within >4 and 
<12 weeks since the latest 
treatment and their first 
dose in this trial. Patients 
who have had anti-PD-1 
or anti-PD-L1 
monotherapy as their 
first-line NSCLC 
treatment regimen must 
have a PD-L1 expression 
level of ≥1% at baseline 
(local validated testing).
o
Anti-PD-1 or anti-PD-L1 
treatment-naïve patients with 
microsatellite stable mCRC 
patients:

Patients must have had ≥ 
1 line treatment 

Must have microsatellite 
stable disease (identified 
using any validated test) 

Must be anti-PD-1 and 
anti-PD-L1 treatment 
naïve 
o
Anti-PD-1 or anti-PD-L1 
pretreated patients with any high 
TMB (≥10 mutations/Mb) and/or 
MSI-H and/or DNA MMRd solid 
tumours 

Patients must have high 
TMB (≥ 10 mutations/Mb) 
and/or MSI-H and/or 
DNA mismatch repair 
deficient (MMRd) 
(measured using any 
validated test).
Rationale for change
The inclusion criteria have been updated to more accurately 
describe the study with the changes made in this amendment. 

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Section to be changed
Section 3.3.2
Exclusion Criteria and Synopsis
Description of change
1.
Any investigational or anti-tumour treatment within 4 
weeks or within 5 half-life periods (whichever is 
shorter) prior to the initiation of trial treatment. FL 
patients on chemotherapy immediately prior to current 
study may initiate treatment in this trial within 15 days 
of last chemotherapy dose following sponsor 
agreement.
1.
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. Known central nervous system (CNS) 
involvement in patients with FL (i.e., current clinical 
CNS symptoms deemed by the Investigator to be 
related to lymphoma CNS involvement [clinical 
assessment per Investigator’s judgement is 
sufficient]) is excluded.
2.
Lymphoma in transformation or transformed
1.
Immunosuppressive corticosteroid doses (>10 mg 
prednisone daily or equivalent) within 4 weeks prior to 
the first dose of study treatment. Corticosteroids used 
for symptom control in patients with FL is allowed 
(upon discussion with sponsor). In such cases the 
patient must be on >10 mg prednisone daily or 
equivalent 2 weeks prior to starting treatment in this 
trial.
2.
Rationale for change
The exclusion criteria have been updated to remove FL-related 
criteria
Section to be changed
Table 3.3.3.1
Description of change
Laboratory values demonstrating inadequate organ function for 
FL patients has been removed.
Rationale for change
The FL cohort has been removed from this study.
Section to be changed
Section 4.1.2.1
Description of change
The recommended Phase II dose of BI 754091 to be used in 
combination with BI 754111 is 240mg every 3 weeks. Theis
starting dose of BI 754091 was in this study will be determined 
by the SRC using the most recent safety information from 
another ongoing study, BI 1381.1. In the BI 1381.1 study, 
80 mg was the starting dose of BI 754091 and escalating doses 
are selected by the SRC (informed by a BLRM with overdose 
control design).
Based on emerging safety information in the 1381.1 and 1381.2 
studies, the SRC may amend the dose of BI 754091 used in this 
study. The SRC will determine the selected dose of BI 754091 
for each cohort of this study and communicate it to the 
investigators.

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Rationale for change
The recommended Phase II dose of BI 754091 has been 
identified. 
Section to be changed
Section 5.3
Description of change
For combination therapy, DLTs observed during the MTD 
evaluation period (the first cycle of BI 754111 plus BI 754091
combination treatment) will be considered for MTD 
determination. However, all DLTs observed in all treatment 
cycles will be collected and will be considered for determining 
an RPIIDexpansion . The BLRM will be re-run to include the 
DLT information from all combination treatment cycles. Based 
on both estimates, the recommended dose for further 
development will be selected. 
For BI 754111 monotherapy, DLTs observed during the 2 
cycles of the BI 754111 treatment will be analyzed by the 
monotherapy BLRM described in Section 7.1.1.2 with 
recommendations provided to support the decision of next dose 
escalation.
Rationale for change
Text revised since FL population, and therefore monotherapy 
treatment, was removed. 
Section to be changed
Section 5.4.2
Methods of sample collection for 
pharmacokinetic analyses
Description of change
After completion of the trial, Pplasma samples may be used for 
further methodological investigations (e.g., stability testing), 
hHowever only data related to the analyte or bioanalytical assay 
will be generated by these additional investigations.
Rationale for change
The PK sample collection has been updated to allow for 
collection of plasma samples that may be needed for validation 
exercises needed prior to completion of the trial. 
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change

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Rationale for change
Section to be changed
Section 7.1.2 
Statistical design- Part II (dose expansion 
cohorts)
Description of change
Part II (dose expansion cohorts) of the trial will be designed as
multiplesingle arm open-label cohorts. CA cohorts of 
approximately 40 patients with 2nd or 3rd line NSCLC, 40 
patients with mCRC, and 40 patients with any solid tumour 
with high TMB and/or MSI-H (as defined in the entry criteria, 
see Section 3.3) at the dose and schedule recommended by the 
SRC.
Rationale for change
The statistical design section has been updated to include the 
new cohorts added in this amendment.
Section to be changed
Section 7.7.2
Determination of sample size for Part II
Description of change
For Part II Cohorts G and I, it is assumed that the combination 
of BI 754111 and BI 754091 will have an ORR of at least 25%. 
For a cohort wWith 30 40 evaluable patients per cohort, an 
ORR of 20% or more would be observed with a probability of 
approximately 8082% assuming a true response rate of 25%. 
The probability of observing a false positive signal, e.g., to 
observe at least an ORR of 20% if the underlying true ORR is 
10%, is around 74%.
Rationale for change
The sample size description has been updated to include the 
new cohorts added in this amendment.

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Section to be changed
Section 7.7.2
Determination of sample size for Part II
Description of change
For Cohort H, it is planned that 40 patients will be enrolled. 
Based on the current literature, it is considered clinically 
meaningful if the combination of BI 754111 and BI 754091 
will achieve an underlying ORR of 20%. With 40 evaluable 
patients, an ORR of 15% or more would be observed with a 
probability of approximately 84% assuming a true response 
rate of 20%. The probability of observing a false positive 
signal, e.g., to observe an ORR of at least 15% if the 
underlying true ORR is 5%, is around 1%. Table 7.7.2.2
summarises the probability of observing certain ORRs 
based on different assumptions of the underlying ORR.
Rationale for change
The text has been added to provide the statistical information 
for the newly added Cohort I (≥ 2nd line microsatellite stable 
PD-1 and PD-L1 treatment- naïve mCRC patients).
Section to be changed
Table 7.7.2.3
Probabilities of observing certain objective 
response rates in Cohort H
Description of change
The table was added to show the probabilities to observe 
defined changes in ORR when 40 patients are enrolled into this 
cohort.
Rationale for change
The table has been added to provide the statistical probabilities 
in the newly added Cohort H (≥ 2nd line microsatellite stable 
PD-1 and PD-L1 treatment- naïve mCRC patients).
Section to be changed
Section 9.1 Published references 
Description of change
R16-1875
Borghaei H, et al. Nivolumab versus 
docetaxel in advanced nonsquamous non-
small-cell lung cancer. N Engl J Med 
2015;373:1627-1639.
R16-4803
Reck M, Rodriguez-Abreu D, Robinson 
AG, Hui R, Csoszi T, Fulop A, et al, 
KEYNOTE-024 Investigators 
Pembrolizumab versus chemotherapy for 
PD-L1-positive non-small-cell lung cancer. 
N Engl J Med 2016;375:1823-1833. 
R16-4804
Langer CJ, Gadgeel SM, Borghaei H, 
Papadimitrakopoulou VA, Patnaik A, 
Powell SF, et al, KEYNOTE-021 
Investigators Carboplatin and pemetrexed 
with or without pembrolizumab for 
advanced, non-squamous non-small-cell 
lung cancer: a randomised, phase 2 cohort 
of the open-label KEYNOTE-021 study. 
Lancet Oncol, 2016; 17: 1497-1508.
R16-4925
American Cancer Society. Cancer facts & 
figures 2016. 
http://www.cancer.org/acs/groups/content/
@research/documents/document/acspc-
0470 79.pdf (access date: 20 October); 
Atlanta: American Cancer Society 2016.
R16-5828
Rittmeyer A, Barlesi F, Waterkamp D, 
Park K, Ciardiello F, Pawel J von, et al 
Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung 

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cancer (OAK): a phase 3, open-label, 
multicentre randomised controlled trial. 
Lancet 2017;389:255-265.
R17-0923
Seymour L, Bogaerts J, Perone A, Ford R, 
Schwartz LH, Mandrekar S, et al. RECIST 
Working Group iRECIST: guidelines for 
response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 
2017;18(3):e143-e152.
P18-03589
Gandhi L, Rodriguez-Abreu D, Gadgeel S, 
Esteban E, Felip E, Angelis F de, et al, 
KEYNOTE-189 Investigators 
Pembrolizumab plus chemotherapy in 
metastatic non-small-cell lung cancer. N 
Engl J Med. 2018 
doi:10.1056/NEJMoa1801005 [Epub ahead 
of print].
R18-1492
Hellmann MD, Ciuleanu TE, Pluzanski A, 
Lee JS, Otterson GA, Audigier-Valette C, 
et al. Nivolumab plus ipilimumab in lung 
cancer with a high tumor mutational 
burden.  N Engl J Med., (2018) Apr 16. 
doi: 10.1056/NEJMoa1801946.  [Epub 
ahead of print]
R18-1746
Overman MJ, McDermott R, Leach JL, 
Lonardi S, Lenz HJ, Morse MA, Desai J, et 
al., Nivolumab in patients with metastatic 
DNA mismatch repair-deficient or 
microsatellite instability-high colorectal 
cancer (CheckMate 142): an open-label, 
multicentre, phase 2 study. Lancet Oncol. 
2017 Sep;18(9):1182-1191. doi: 
10.1016/S1470-2045(17)30422-9.
Rationale for change
To provide the relevant references for iRECIST assessments 
and the updated tumour mutational burden cut-off are added. 
Section to be changed
Table 10.4.1: 1
Time schedule for PK and 
 
 sampling - Part I dose-escalation cohorts (Cycles 1, 2, 
and 4 for solid tumour cohorts)
Table 10.4.1: 2
Time schedule for PK, 
 
 sampling - Part I dose-
escalation cohorts (Cycles 1 & 2 for FL cohorts)
Table 10.4.1: 3
Time schedule for PK, 
 
 sampling - Part I dose-
escalation cohorts (Cycle 3 FL cohorts only)
Table 10.4.2: 1
Time schedule for PK, 
 
blood 
samplings - Part II dose-expansion cohorts
Description of change
A window of ±1 day has been added to PK collection on days 8 
and 15, and the following footnotes have been added to the 
tables:
∀
24 and 72 hours post SOI (PTM 24:00 to 
72:00): ±1 hour
∀
168 and 336 hours post SOI (PTM 168:00 to 
336:00): ±24 hour.

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The following tables were removed
Table 10.4.1: 2
Time schedule for PK, 
 
 sampling - Part I dose-
escalation cohorts (Cycles 1 & 2 for FL cohorts)
Table 10.4.1: 3
Time schedule for PK, 
 
sampling - Part I dose-
escalation cohorts (Cycle 3 FL cohorts only)
Rationale for change
The PK tables have been updated to provide more flexibility 
and better defined windows for the collection of PK samples. 
Number of global 
amendment
5
Date of CTP revision
3 July 2018
EudraCT number
2017-005042-29
BI Trial number
BI 1381.2
BI Investigational 
Product(s)
BI 794111 and BI 754091
Title of protocol 
(previous - see below 
for title update)
An open label, Phase I dose-finding study of BI 754111 in 
combination with BI 754091 in patients with advanced solid 
cancers followed by expansion cohorts at the selected dose of 
the combination in patients with non-small cell lung cancer 
and other solid tumors
To be implemented 
only after approval 
of the IRB / IEC / 
Competent 
Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / 
Competent Authority 
to be notified of 
change with request 
for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative 
aspects only

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Additions to the text are bolded and deletions from the text are crossed-off. Only the parts 
of sections with changes are presented. Please note that formatting changes and minor 
changes to punctuation, spelling, and abbreviations that do not affect meaning are not 
noted in this summary.
Section to be changed
No. of patients:
Description of change
Part I (Dose-Escalation Cohorts):  Approximately 15 to 50 patients
Part II (Dose-Expansion Cohorts): 120160 patients total
Rationale for changes
The number of patients was updated to include Cohort J in the dose 
expansion part of the amendment. 
Section to be changed
Total entered:
Description of change
Approximately 135175 to 170210 patients are planned to be enrolled in 
this trial.
Rationale for changes
The number of patients was updated to include Cohort J in the dose 
expansion part of the amendment.
Section to be changed
Each treatment:
Description of change
Part I: a minimum of 3 patients with solid tumours per dose-escalation 
cohort
Part II: 120160 patients
Rationale for changes
The number of patients was updated to include Cohort J in the dose 
expansion part of the amendment.
Section to be changed
Synopsis-Diagnosis
Description of change
Part I (Dose-Escalation Cohorts):
Patients with a confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours 
Part II (Dose Expansion Cohorts):
∀
Second and 3rd line NSCLC patients who progressed on anti-PD-1 or 
anti-PD-L1 treatment after having achieved radiologically confirmed 
benefit (minimum of stable disease).
∀
Anti-PD-1 and anti-PD-L1 naïve second line or greater microsatellite 
stable mCRC. 
∀
Anti-PD-1 or anti-PD-L1 pretreated (can include BI 754091) patients 
with any solid tumour with TMB high (≥10 mutations/Mb) and/or 
MSI-H and/or DNA MMRd
First line NSCLC patients with wildtype (wt) epidermal growth factor 
receptor [EGFR] and anaplastic lymphoma kinase [ALK] tumors of 
squamous or non-squamous origin.

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Rationale for changes
A 1st-line NSCLC expansion cohort was added and the description of 
diagnoses was updated. 
Section to be changed
Synopsis-Main Criteria for Inclusion
Description of change
All Cohorts:
∀
Adult patients at least 18 years-of-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
Part I (Dose-Escalation Cohorts):
∀
Patients with a confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours (any type) 
∀
For patients in Part I with solid tumours:
-
For whom no therapy of proven efficacy exists, or who are 
not amenable to standard therapies.
-
Must have measurable lesions according to Revised Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
and iRECIST
-
Previous treatment with an anti-PD-1 mAb is allowed as long 
as the last administration of the anti-PD-1 mAb on the 
previous treatment is a minimum of 60 days prior to starting 
treatment in this trial.
Part II (Dose-Expansion Cohorts):
All patients must have measurable disease according to RECIST 
Version 1.1, must have at least 1 tumour lesion amenable to biopsy, and 
must be medically fit and willing to undergo a biopsy before first 
treatment (if adequate archival tissue is not available) and, unless 
clinically contraindicated, after 6 weeks on therapy.
All patients must not have had previous LAG-3 targeted treatment
∀
2nd or 3rd-line NSCLC patients:
-
Must have progressed on anti-PD-1 or anti-PD-L1 treatment 
after having achieved radiologically confirmed benefit 
(minimum of stable disease) 
-
Must have had a minimum duration of benefit of 68 months 
for non-squamous NSCLC patients who received 
immunotherapy plus chemotherapy in a first line setting, 
or 6 months for all other patients, and minimum treatment 
duration of 2 months on the previous anti-PD-1 or anti-PD-L1 
treatment without experiencing disease progression during 
that period.  
-
The anti-PD-1- or anti-PD-L1-containing treatment must have 
been the latest treatment regimen prior to enrolling in this trial
-
Latest treatment must be within >4 and <12 weeks before 
their first dose in this trial. Patients who have had anti-PD-1 
or anti-PD-L1 monotherapy as their first-line NSCLC 
treatment regimen must have a PD-L1 expression level of 
≥1% at baseline (local validated testing).
∀
Anti-PD-1 or anti-PD-L1 treatment naïve patients with microsatellite 
stable mCRC 
-
Patients must have had ≥1 lines of systemic treatment 
∀
Anti-PD-1 or anti-PD-L1 pretreated patients with high TMB (≥10 
mutations/Mb) and/or MSI-H and/or DNA MMRd solid tumours

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∀
1st-line squamous or non-squamous NSCLC patients:
-
Patients must be treatment naïve
-
Must be EGFR WT and ALK WT
-
Any PD-L1 expression level.  However, the number of 
patients with high level of PD-L1 expression (≥50% PD-
L1) will be limited to a maximum of 10 (local validated 
testing) 
Rationale for changes
A 1st-line NSCLC expansion cohort was added.  Therefore, the inclusion 
criteria was updated. 
Additionally, the definition of stable disease now requires 8 months for 
non-squamous NSCLC patients who received immunotherapy plus 
chemotherapy in a first line setting, or 6 months for all other patients, 
instead of 6 months duration of benefit
Section to be changed
Synopsis-Doses
Description of change
Increasing doses of BI 754111 starting with 4 mg in combination with 
BI 754091 at the RPIID (240 mg q3w) or a lower dose selected by the 
1381.2 Safety Review Committee upon review of evolving data from 
Study 1381.1 (an ongoing study of of BI 754091 using a BLRM with 
overdose control in patients with advanced solid tumours).
Rationale for changes
Typographical error corrected
Section to be changed
Section 2.1-Rationale for Performing Trial
Description of change
To this end, immune checkpoint inhibitorinhibitors have made 
remarkable changes to the standard of care for previously untreated 
patients with advanced NSCLC
Rationale for changes
A typographical error was corrected.
Section to be changed
Section 2.1-Rationale for Performing Trial
Description of change
Therefore, finding more tolerable, less toxic checkpoint inhibitor 
combination to treat previously untreated NSCLC patients is of immense 
interest. As such, this trial aims to test the safety and efficacy of 
chemotherapy-sparing combination of BI 754091 with BI 754111 in 
patients with previously untreated NSCLC.  The combination of BI 
754091 with BI 754111 has the potential to be less toxic than 
chemotherapy containing regimens and would reserve chemotherapy 
as a subsequent line of treatment for patients whose disease 
progresses.
Rationale for changes
A 1st-line NSCLC expansion cohort was added.  Therefore, additional text 
was added to provide the rationale. 

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Section to be changed
Table 3.1: 1 Possible Cohort Scenarios for Solid Tumour Cohorts
Description of change
The following cohort was added to this table:
Cohort J
Selected expansion dose in patients with 1st
line epidermal growth factor receptor 
[EGFR] wildtype [WT] and  anaplastic 
lymphoma kinase [ALK] WT NSCLC. 
Patients may have any level of PD-L1 
expression, but only a maximum of 10 
patients with PD-L1 high expression 
(≥50% PD-L1) will be enrolled. 
Rationale for changes
A 1st-line NSCLC expansion cohort was added to the list of cohorts in this 
table.
Section to be changed
Section 3.1-Overall Trial Design
Description of change
Following determination of the dose from the Part I portion, 4 dose-
expansion cohorts (2nd and 3rd line NSCLC, , anti-PD1 and anti-PD-L1 
treatment–naïve mCRC, and any solid tumour with high TMB and/or 
MSI-H, and 1st-line NSCLC), will be enrolled into Part II.
Rationale for changes
A 1st-line NSCLC expansion cohort was added to the study design 
description.
Section to be changed
Section 3.3.2 -Selection of Trial Population
Description of change
Part II (dose expansion):
∀
Patients must have measurable disease per RECIST v1.1 
criteria, must have at least 1 tumour lesion amenable to 
biopsy, and must be medically fit and willing to undergo 
a biopsy before first treatment (if adequate archival tissue 
is not available) and, unless clinically contraindicated, 
after 6 weeks on therapy.
∀
Dose Expansion Cohorts:
- Second and 3rd line NSCLC patients: 
•
Must have progressed on anti-PD-1 or 
anti-PD-L1 treatment after having 
achieved radiologically confirmed 
benefit (minimum of stable disease) 
•
Must have had a minimum duration of 
benefit of 86 months for non-
squamous NSCLC patients who 
received immunotherapy plus 
chemotherapy in a first line setting,
or 6 months for all other patients, and 
minimum treatment duration of 2 
months on the previous anti-PD-1 or 
anti-PD-L1 treatment without 
experiencing disease progression 
during that period.  
•
The anti-PD-1- or anti-PD-L1-
containing treatment must have been 
the latest treatment regimen prior to 
enrolling in this trial

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•
Must be within >4 and <12 weeks since 
the latest treatment and their first dose 
in this trial. Patients who have had anti-
PD-1 or anti-PD-L1 monotherapy as 
their first-line NSCLC treatment 
regimen must have a PD-L1 expression 
level of ≥1% at baseline (local 
validated testing).
- Anti-PD-1 or anti-PD-L1 treatment-naïve 
patients with microsatellite stable mCRC:
•
Patients must have had ≥ 1 line 
treatment 
•
Must have microsatellite stable disease 
(identified using any validated test) 
•
Must be anti-PD-1 and anti-PD-L1 
treatment naïve 
- Anti-PD-1 or anti-PD-L1 pretreated patients 
with any high TMB (≥10 mutations/Mb) and/or 
MSI-H and/or DNA MMRd solid tumours 
•
Patients must have high TMB (≥ 10 
mutations/Mb) and/or MSI-H and/or 
DNA mismatch repair deficient 
(MMRd) (measured using any 
validated test).
•
Patients must have received 1 prior 
anti-PD-1 or anti-PD-L1 treatment 
regimen.
- 1st-line squamous or non-squamous NSCLC 
patients:
•
Patients must be treatment naïve
•
Must be EGFR wild type
•
Must be ALK wild type
•
Any PD-L1 expression level.  
However, the number of patients 
with high level of PD-L1 expression 
(≥50% PD-L1) will be limited to a 
maximum of 10 patients 
Rationale for changes
A 1st-line NSCLC expansion cohort was added. Therefore, inclusion 
criteria for this cohort was added to this section.
Additionally, the definition of stable disease now requires 8 months for 
non-squamous NSCLC patients who received immunotherapy plus 
chemotherapy in a first line setting, or 6 months for all other patients, 
instead of 6 months duration of benefit.
Section to be changed
Section 5.2.1
Description of change
Digital copies of disease evaluation scans are to be collected and stored 
centrally for future analysis 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.
Rationale for changes
To provide information regarding the planned use of scans.

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Section to be changed
Section 7.1.2-Statistical design-Part II (dose expansion cohorts)
Description of change
Part II (dose expansion cohorts) of the trial will be designed as multiple 
open-label cohorts. Cohorts of approximately 40 patients with 2nd or 3rd
line NSCLC, 40 patients with mCRC, and 40 patients with any solid 
tumour with high TMB and/or MSI-H (as defined in the entry criteria, see 
Section 3.3), and 40 patients with 1st line NSCLC (this cohort will 
include up to 10 patients with PD-L1 expression ≥50%) at the dose and 
schedule recommended by the SRC.
Rationale for changes
A 1st-line NSCLC expansion cohort was added and the summary of the 
number of patients on each cohort has been updated.
Section to be changed
Section 7.7.2-Determiniation of sample size for Part II
Description of change
The following text was added:
For Cohort J, it is planned that a total of 40 patients will be enrolled, 
with a maximum of 10 patients with PD-L1 high expression (≥ 50% 
PD-L1). Based on the current literature, it is deemed clinically 
meaningful if the underlying ORR for the combination of BI 754111 
and BI 754091 will be 40% for patients with PD-L1 < 50%. With 
approximately 30 patients with PD-L1 <50%, an ORR of 35% or 
more would be observed with a probability of approximately 71% 
assuming a true response rate of 40%. The probability of observing a 
false positive signal, e.g., to observe at least an ORR of 35% if the 
underlying true ORR is 20%, is around 3%. Table 7.7.2: 3 
summarizes the probability of observing certain ORRs based on 
different assumptions of the underlying ORR.
Table 7.7.2: 3 Probabilities of observing certain objective response 
rates in Cohort J
True underlying 
OR rate
Patients with 
PD-L1 <50%
Probability to observe at least
ORR ≥ 35%
(≥ 11 patients 
with OR)
ORR ≥ 40%
(≥ 12 patients 
with OR)
50%
30
95.1%
90.0%
45%
30
86.5%
76.7%
40%
30
70.9%
56.9%
35%
30
49.2%
34.5%
30%
30
27.0%
15.9%
25%
30
10.6%
5.1%
20%
30
2.6%
0.9%
Rationale for changes
A 1st-line NSCLC expansion cohort was added and the statistical 
summary of for the cohort was added. 

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Number of global 
amendment
6
Date of CTP revision
26 Feb 2019
EudraCT number
2017-005042-29
BI Trial number
BI 1381.2
BI Investigational 
Product(s)
BI 754111 and BI 754091
Title of protocol 
(previous - see below 
for title update)
An open label, Phase I dose-finding study of BI 754111 in 
combination with BI 754091 in patients with advanced solid 
cancers followed by expansion cohorts at the selected dose of 
the combination in patients with non-small cell lung cancer 
and other solid tumors
To be implemented 
only after approval 
of the IRB / IEC / 
Competent 
Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / 
Competent Authority 
to be notified of 
change with request 
for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative 
aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts 
of sections with changes are presented. Please note that formatting changes and minor 
changes to punctuation, spelling, and abbreviations that do not affect meaning are not 
noted in this summary.

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Section to be changed
Flow Chart 1
Description of change
A new row “Administration of Pre-Treatment Medicationp “and 
footnote “p- Pre-treatment medications (antihistamine and 
acetaminophen or paracetamol) should be administered at sufficient 
time prior to initiation of infusion to allow the agents to exert their 
influence.” was added. 
Rationale for changes
Pre-treatment medication has been added to the study prior to 
administration of the study treatment in order to reduce the risk of 
infusion related reactions.
Section to be changed
Flow Chart 1 footnote a
Description of change
In addition, patients benefiting clinically and without PD may stay on 
trial after 1 year on a case-by-case basis after discussion with the 
Medical Monitor and the sponsor. Day 1 of Cycle 1 is defined as the 
day when the combination of BI 754111 and BI 754091 is 
administered.
Rationale for changes
Language explaining how long patients can receive study treatment have 
been aligned throughout the protocol in order to clarify that as long as the 
investigator determines a patient is clinically benefiting from study drug 
(regardless of RECIST status), they can continue on study drug if sponsor 
and Medical Monitor agree.
Section to be changed
Flow Chart 2
Description of change
A new row “Administration of Pre-Treatment Medicationq“and 
footnote “q- Pre-treatment medications (antihistamine and 
acetaminophen or paracetamol) should be administered at sufficient 
time prior to initiation of infusion to allow the agents to exert their 
influence.” was added. 
Rationale for changes
Pre-treatment medication has been added to the study prior to 
administration of the study treatment in order to reduce the risk of 
infusion related reactions.
Section to be changed
Flow Chart 2
Description of change
Footnote “p” has been marked on Expansion Cycles 1, 2, and 4 Days 2 
and 4. 
Rationale for changes
The footnote has been added to correct portion of the flow chart. 
Section to be changed
Flow Chart 2 footnote a
Description of change
a
In addition, patients benefiting clinically and without PD may stay 
on trial after 1 year on a case-by-case basis after discussion with the 
Medical Monitor and the sponsor. Day 1 of Cycle 1 is defined as the day 
when the combination of BI 754111 and BI 754091 is administered.

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Rationale for changes
Language explaining how long patients can receive study treatment have 
been aligned throughout the protocol in order toclarify that as long as the 
investigator determines a patient is clinically benefiting from study drug 
(regardless of RECIST status), they can continue on study drug if sponsor 
and Medical Monitor agree.
Section to be changed
Flow Chart 2 footnote p
Description of change
p
The clinic will telephone the patients on Days 2 and 4 of Cycle 2 
and Day 2 of Cycle 4 in order to check on any adverse events. The 
patients will not be required to go to the clinic on these days.  
Rationale for changes
Additional text has been added to clarify that patients do not need to go to 
the clinic on Day 2 of Cycle 4. This was previously communicated to sites 
in a protocol clarification letter dated 20 November 2018. 
Section to be changed
2.3
BENEFIT-RISK ASSESSMENT
Description of change
As of 18 April 2019, a total of 106 patients were treated with the
combination of BI 754091 and BI 754111 in this study.  The currently 
available clinical data indicate that BI 754111 in combination with BI 
754091 is well tolerated.  The most common AEs were reported in the 
GI disorders and general disorders and administration site conditions 
system organ classes. The majority of reported events were mild to 
moderate in severity (Grade1 and 2).  The benefit/risk ratio continues 
to be considered positive for patients with advanced cancers.  Please 
refer to the current version of the BI 754111 Investigator Brochure 
for further details.
As of 30-November-2018, 50 patients with advanced/metastatic solid 
tumors have been treated with BI 754091 as monotherapy in the 1381.1 
trial. 
The most frequently reported AEs (reported in >10% of the patients) were 
fatigue (40%), nausea (28.0%), decreased appetite (18.0%), arthralgia 
(16.0%), cough (16.0%), abdominal pain (14.0%), constipation (14.0%), 
diarrhea (14.0 %), vomiting (14.0), back pain (12.0%) and dyspnea 
(12.0%). Headache, hypokalaemia, muscular chest pain, myalgia, pruritis 
and rash, each occurred at a frequency of 10.0%.  The majority of these 
AEs were CTCAE grade 1 and 2.
Grade 3 and 4 AEs were reported in 38.0% and 4.0% of patients, 
respectively. Of the grade 3 events, only the AST elevation event was 
reported as related to trial drug.  The reported grade 4 AEs were 1 (2.0%) 
case of disease progression and 1 (2.0%) case of sepsis, neither of which 
was deemed treatment related. 
Consistent with the similar drug class labels, most immune-related 
(irAEs) were reported in the GI, Skin and Endocrine SOCs. The majority 
of the irAEs were Grades 1 and 2, the only Grade 3 irAE was AST 
increase.

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Preliminary efficacy analyses for study 1381.1 indicate that there have 
been 6 patients with partial response (PR) and 20 patients with stable 
disease as best response on BI 754091 monotherapy in the 1381.1 trial.  
The PRs were reported in two patients with triple negative breast cancer, 
one patient with fallopian tube cancer, one patient with renal cancer, one 
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.
A similar safety profile of BI 754091 monotherapy was observed in 6 
Japanese patients with solid tumors evaluated in the Asian trial 1381.4. 
The details of the preliminary analysis are provided in section 6.2 of the 
BI 754091 IB.
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 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 240mg BI 754091 in combination with 200 mg BI 754111, 1 
patient with microsatellite stable rectal cancer treated with 240mg BI 
754091 in combination with 600 mg BI 754111 and 1 patient with TNBC 
treated with 240mg BI 754091 in combination with 600 mg BI 754111. 

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Based on these pre-clinical data, as well as preliminary clinical data 
obtained with BI 754091 as well as the combination of BI 754091 and BI 
754111, the inhibitory effects of the combination of BI 754111 and 
BI 754091 may translate into a clinical benefit in cancer patients. 
Rationale for changes
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. 
Section to be changed
3.3.3
Exclusion criteria
Description of change
4.
Any investigational or anti-tumour treatment, except BI 754091,
within 4 weeks or within 5 half-life periods (whichever is shorter) prior to 
the initiation of trial treatment.
Rationale for changes
Additional text has been added to clarify that prior use of BI 754091 is not 
exclusionary.  This was previously communicated to sites in a protocol 
clarification letter dated 09 January 2019.
Section to be changed
4.2.2.1 Permitted concomitant medications
Description of change
∀
Pre-medication will not be required, but may be utilised 
following the first dose of BI 754111 or the first dose of 
combination therapy, as appropriate. This includes medications 
for the management of nausea, diarrhoea, and vomiting for 
which the patient must be treated according to institutional 
standards.
∀
To reduce the risk of infusion related reactions, patients are to be 
pre-treated with an antihistamine and acetaminophen or 
paracetamol.  Pre-treatment should be administered at sufficient 
time prior to initiation of infusion to allow the agents to exert their 
effect.
Rationale for changes
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.

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Section to be changed
Description of change
Rationale for changes
Section to be changed
5.3.4.2 Biochemistry
Description of change
In case the criteria for hepatic injury are fulfilled, a number of 
additional measures will be performed (please see section 5.3.6.5.4 
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. 
Rationale for changes
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.
Section to be changed
5.3.6.5 Adverse events of special interest (AESIs)
Description of change
For this trial, DLTs, infusion-related AEs, potential DILI events, hepatic 
injury, and qualifying irAEs, as defined in Appendix 10.2, are AESIs (see 
Section 5.3.6.5.2, Section 5.3.6.5.3, and Section 5.3.6.5.4).
Rationale for changes
Language about drug-induced liver injury has been updated per BI revised 
template text to clarify that all liver elevations meeting potential Hy’s 
Law criteria require expedited reporting as an AESI on the SAE form
Section to be changed
5.3.6.5.3
Infusion-related reactions
Description of change
To reduce the risk of infusion-related reactions, patients are to be 
pre-treated with an antihistamine and acetaminophen or 
paracetamol.  Pre-treatment should be administered at sufficient time 
prior to initiation of infusion to allow the agents to exert their effect.  

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In the event of an infusion-related reaction ≤ Grade 2, treat the 
symptoms accordingly with antihistamine or corticosteroids if 
needed.  Tthe infusion rate of BI 754111 and/or the 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).
Rationale for changes
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. In addition, more detail has been provided on 
what to do in the event of a Grade 3 or higher infusion related reaction. 
Section to be changed
5.3.6.5.4
Hepatic injury and drug-induced liver injury (DILI)
Description of change
5.3.6.5.4
Hepatic injury and potential drug-induced liver injury 
(DILI)
Rationale for changes
The section has been expanded to include potential DILIs. 
Section to be changed
5.3.6.5.4
Hepatic injury and potential drug-induced liver injury 
(DILI)
Description of change
Hepatic injury definition:
A hepatic injury is defined by the following alterations of hepatic 
laboratory parameters: 
∀
an elevation of AST (Aspartate Aminotransferase) and/or 
ALT (Alanine Aminotransferase) ≥3 fold ULN combined with 
an elevation of total bilirubin ≥2 fold ULN measured in the 
same blood draw sample, or 
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN. 
In patient with normal baseline hepatic function, hepatic injury is defined 
by the following alterations in hepatic laboratory parameters:
An elevation of AST and/or ALT ≥3 times the ULN combined with an 
elevation of total bilirubin ≥2 times the ULN measured in the same blood 
draw sample, and/or
•
Marked peak AST and/or ALT elevation ≥10 times the ULN.
These lab findings constitute a hepatic injury alert and the patients 
showing these lab abnormalities need to be followed up according to 
the “Potential 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 “Potential DILI Checklist” should be followed. 

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Rationale for changes
Language about drug-induced liver injury has been updated to clarify the 
criteria for liver abnormalities which prompt reporting as AESI and 
completion of the Potential DILI Checklist.
Section to be changed
5.3.6.5.4
Hepatic injury and potential drug-induced liver injury 
(DILI)
Description of change
Lab values meeting the hepatic injury definition will need to be 
reported as AESI. Please follow the flowchart below for reporting 
hepatic injury / potential DILI cases.
Rationale for changes
A decision tree is provided to illustrate when the Potential DILI Checklist 
is initiated and wen it can be considered complete.
Section to be changed
5.3.6.9 Pregnancy
Description of change
Similarly, potential drug exposure during pregnancy must be 
reported if a partner of a male trial participant becomes pregnant. 
This requires a written consent of the pregnant partner; in the event 
that consent cannot be obtained, information will be collected and 
reported in accordance with regulatory requirements. 
Rationale for changes
Pregnancy risk language has been updated to provide guidance for 
partners of male trial participants. 
Section to be changed
5.3.6.10
Exemptions to SAE Reporting
Description of change
5.3.6.10
Exemptions to AE/SAE Reporting
Rationale for changes
The header has been corrected to reflect the section content. 

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Section to be changed
7.1
INTERIM ANALYSES
Description of change
An interim futility analysis will be performed for Cohort G, I, and J in 
Part II. Until a decision from the futility analysis is made, the enrolment 
for that cohort will not be stopped. The two-stage design is planned to 
stop further enrolment if the defined efficacy boundary (see Table 7.7.2: 1 
and Table 7.7.2: 3) is not met at the first stage.
The interim analysis for Part II will be conducted when:
•
The last patient contributing to the interim analysis has completed 
the third on-treatment imaging assessment (i.e. end of cycle 6).
If the last patient contributing to the interim analysis discontinues earlier 
than the third on-treatment imaging, the interim futility analysis will be 
done at approximately 4 months after the first administration of that 
patient.
Rationale for changes
The text provides detail about interim futility analyses added to the study 
for Cohorts G, I , and J. 
Section to be changed
7.7.2
Determination of sample size for Part II
Description of change
For Cohorts G and I, it is considered clinically meaningful based on the 
current literature for the combination of BI 754111 and BI 754091 to 
achieve an underlying ORR of 25%. A futility boundary of an ORR 
of 10% will be used for the interim analysis. Assuming an underlying 
ORR of 25%, the probability of observing <2 responders out of 20 
patients and stopping at the interim is 2%, and the probability of 
observing an ORR ≥20% at the final analysis is 81%. Alternatively, 
assuming an underlying ORR of 5%, the probability of stopping at 
the interim is 74% and the probability of observing an ORR ≥20% at 
the final analysis is 0%. Table 7.7.2: 1 summarizes the early stopping 
criteria and probabilities of observing certain ORRs based on 
different assumptions of the underlying ORR. it is assumed that the 
combination of BI 754111 and BI 754091 will have an ORR of at least 
25%. With 40 evaluable patients per cohort, an ORR of 20% or more 
would be observed with a probability of approximately 82% assuming a 
true response rate of 25%. The probability of observing a false positive 
signal, e.g., to observe at least an ORR of 20% if the underlying true ORR 
is 10%, is around 4%. Table 7.7.2: 1 summarizes the probability of 
observing certain ORRs based on different assumptions of the underlying 
ORR.
Table 7.7.2: 1 Early stopping criteria and probabilities of the two-
stage approach Probabilities of observing certain objective response rates 
in Cohorts G and I
Assumed 
underlying 
ORR
Early stopping 
criterion 
(observed 
ORR)
Early 
stopping 
probability
Observed 
ORR at final
analysis
Probability of 
observed ORR 
at final
analysis
5%
<10% (<2 out 
of 20)
74%
≥20% (≥8 out 
of 40)
0%
10%
<10% (<2 out 
of 20)
40%
≥20% (≥8 out 
of 40)
4%

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15%
<10% (<2 out 
of 20)
18%
≥20% (≥8 out 
of 40)
24%
20%
<10% (<2 out 
of 20)
7%
≥20% (≥8 out 
of 40)
55%
25%
<10% (<2 out 
of 20)
2%
≥20% (≥8 out 
of 40)
81%
30%
<10% (<2 out 
of 20)
1%
≥20% (≥8 out 
of 40)
95%
True 
underlying 
OR rate
Patients 
in each 
cohort
Probability to observe at least
ORR ≥ 20%
(≥ 8 patients 
with OR)
ORR ≥ 25%
(≥ 10 patients 
with OR)
ORR ≥ 30%
(≥ 12 patients 
with OR)
40%
40
99.8%
98.4%
92.9%
35%
40
98.8%
93.6%
79.5%
30%
40
94.5%
80.4%
55.9%
25%
40
81.8%
56.0%
28.5%
20%
40
56.3%
26.8%
8.8%
15%
40
24.4%
6.7%
1.2%
10%
40
4.2%
0.5%
0.0%
For Cohort H, it is planned that 40 patients will be enrolled and no 
interim futility analysis will be performed.
Rationale for changes
The text provides detail about interim futility analyses added to the study 
for Cohorts G and I and clarifies that there will not be an interim futility 
analysis added for Cohort H.
Section to be changed
7.7.2
Determination of sample size for Part II
Description of change
For Cohort J, it is planned that a total of 40 patients will be enrolled, with 
a maximum of 10 patients with PD-L1 high expression (≥ 50% PD-L1). 
In CheckMate 026, the ORR was 21% with nivolumab (N=101) 
compared with 26% in the chemotherapy group (N=81) for 1st line 
NSCLC patients with 1%≤ PD-L1 <50% (R19-0527). In KEYNOTE-
189, the ORR was 48.4% (95% CI, 39.5-57.4) with pembrolizumab 
plus chemotherapy (N=128) compared with 20.7% (95% CI, 11.2-
33.4) with chemotherapy alone (N=58) for patients with 1%≤ PD-L1 
<50%; the ORR was 32.3% (95% CI, 24.3-41.2) with pembrolizumab 
plus chemotherapy (N=127) compared with 14.3% (95% CI, 6.7-25.4) 
with chemotherapy alone (N=63) for patients with PD-L1 <1% (P18-
03589). Based on the above current literature, it is deemed clinically 
meaningful if the underlying ORR for the combination of BI 754111 and 
BI 754091 will be 40% for patients with PD-L1 < 50%., and a futility 
boundary of 20% will be used for the interim analysis of this 
population in Cohort J. With 30-40 evaluable patients and assuming 
an underlying ORR of 40%, the probability of observing <4 
responders out of 17 patients and stopping at the interim is 5%, and 

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the probability of observing an ORR ≥35% at the final analysis is 
between 70% to 77%. Alternatively, assuming an underlying ORR of 
15%, the probability of stopping at the interim is 76% and the 
probability of observing an ORR ≥35% at the final analysis is 0%. 
Table 7.7.2: 3 summarizes the early stopping criteria and 
probabilities of observing certain ORRs based on different 
assumptions of the underlying ORR. With approximately 30 patients 
with PD-L1 <50%, an ORR of 35% or more would be observed with a 
probability of approximately 71% assuming a true response rate of 40%. 
The probability of observing a false positive signal, e.g., to observe at 
least an ORR of 35% if the underlying true ORR is 20%, is around 3%. 
Table 7.7.2.: 3 summarizes the probability of observing certain ORRs 
based on different assumptions of the underlying ORR.
Table 7.7.2.: 3 Early stopping criteria and probabilities of the two-
stage approach Probabilities of observing certain objective response rates 
in Cohort J
Assumed 
underlying 
ORR
Early 
stopping 
criterion 
(observed 
ORR)
Early 
stopping 
probability
Observed 
ORR at 
final
analysis
Probability 
of 
observed 
ORR at 
final
analysis
Assuming 30 patients with PD-L1 <50%
15%
<20% 
(<4 out of 
17)
76%
≥35% 
(≥11 out 
of 30)
0%
20%
<20% 
(<4 out of 
17)
56%
≥35% 
(≥11 out 
of 30)
2%
25%
<20% 
(<4 out of 
17)
36%
≥35% 
(≥11 out 
of 30)
10%
30%
<20% 
(<4 out of 
17)
20%
≥35% 
(≥11 out 
of 30)
26%
35%
<20% 
(<4 out of 
17)
11%
≥35% 
(≥11 out 
of 30)
48%
40%
<20% 
(<4 out of 
17)
5%
≥35% 
(≥11 out 
of 30)
70%
Assuming 40 patients with PD-L1 <50%
15%
<20% 
(<4 out of 
17)
76%
≥35% 
(≥14 out 
of 40)
0%
20%
<20% 
(<4 out of 
56%
≥35% 
(≥14 out 
2%

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17)
of 40)
25%
<20% 
(<4 out of 
17)
36%
≥35% 
(≥14 out 
of 40)
10%
30%
<20% 
(<4 out of 
17)
20%
≥35% 
(≥14 out 
of 40)
29%
35%
<20% 
(<4 out of 
17)
11%
≥35% 
(≥14 out 
of 40)
54%
40%
<20% 
(<4 out of 
17)
5%
≥35% 
(≥14 out 
of 40)
77%
True 
underlying 
OR rate
Patients 
with 
PD-L1 
<50%
Probability to observe at least
ORR ≥ 35%
(≥ 11 patients with 
OR)
ORR ≥ 40%
(≥ 12 patients with 
OR)
50%
30
95.1%
90.0%
45%
30
86.5%
76.7%
40%
30
70.9%
56.9%
35%
30
49.2%
34.5%
30%
30
27.0%
15.9%
25%
30
10.6%
5.1%
20%
30
2.6%
0.9%
Rationale for changes
The section is updated to outline the futility boundary for Cohort J.
Section to be changed
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT
Description of change
The Investigator or delegate must give a full explanation to trial patients 
based on the ICF information. 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 or delegate obtains written consent of the patient’s 
own free will with the ICF after confirming that the patient understands 
the contents. The Investigator or delegate must sign (or place a seal on) 
and date the ICF.
Rationale for changes
Language has been added to allow a delegate review the study with 
patients prior to consent, rather than only allowing the Investigator to do 
this.  If local laws/regulations/practice require Investigators personally 
consent patients, local laws/regulations/practice will be followed. This 
was previously communicated to sites in a protocol clarification letter 
dated 10 October 2018.

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Section to be changed
9.1 
PUBLISHED REFERENCES
Description of change
R16-4925
American Cancer Society. Cancer fact & figures 2016. 
http://www.cancer.org/acs/groups/content/@research/ 
documents/document/acspc-0470 79.pdf (access date: 20 October); 
Atlanta: American Cancer Society 2016.
Rationale for changes
A duplicate reference has been removed from the list of references.
Section to be changed
9.1 
PUBLISHED REFERENCES
Description of change
R19-0527
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, 
Steins M, et al, CheckMate 026 Investigators First-line 
nivolumab in stage IV or recurrent non-small-cell lung 
cancer. N Engl J Med 376 (25), 2415 - 2426 (2017).
Rationale for changes
A reference has been added to the study. 
Section to be changed
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE 
EVENTS
Description of change
∀
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).
Rationale for changes
More detail has been provided on what to do in the event of an infusion 
related reaction.

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Number of global 
amendment
7
Date of CTP revision
05 Sept 2019
EudraCT number
2017-005042-29
BI Trial number
BI 1381.2
BI Investigational 
Product(s)
BI 754111 and BI 754091
Title of protocol 
(previous - see below 
for title update)
An open label, Phase I dose-finding study of BI 754111 in 
combination with BI 754091 in patients with advanced solid 
cancers followed by expansion cohorts at the selected dose of 
the combination in patients with non-small cell lung cancer 
and other solid tumors
To be implemented 
only after approval 
of the IRB / IEC / 
Competent 
Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / 
Competent Authority 
to be notified of 
change with request 
for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative 
aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of sections with 
changes are presented. Please note that formatting changes and minor changes to punctuation, spelling, and 
abbreviations that do not affect meaning are not noted in this summary.

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Section to be changed
Synopsis Diagnosis
Description of change
Part II (Dose Expansion Cohorts):
Patients with a confirmed diagnosis of advanced, unresectable, 
and/or metastatic solid tumours of one of the following types:
Rationale for changes
Text has been added to clarify the patient population to be enrolled.
Section to be changed
Synopsis Main criteria for inclusion
Description of change
Part II (Dose-Expansion Cohorts):
All patients must have measurable disease according to RECIST 
Version 1.1, must have at least 1 tumour lesion amenable to biopsy, and 
must be medically fit and willing to undergo a biopsy before first 
treatment (if adequate archival tissue is not available) and, unless 
clinically contraindicated, after 6 weeks on therapy.
All patients must not have had previous LAG-3 targeted treatment
∀
2nd or 3rd-line NSCLC patients:
-
Must have progressed on anti-PD-1 or anti-PD-L1 treatment 
after having achieved radiologically confirmed benefit 
(minimum of stable disease)
-
Must have had a minimum duration of benefit of 48 months
for non-squamous NSCLC patients who received 
immunotherapy plus chemotherapy in a first line setting, or 6
months for all other patients, and minimum treatment duration 
of 2 months on the previous anti-PD-1 or anti-PD-L1 
treatment without experiencing disease progression during 
that period.  
-
The anti-PD-1- or anti-PD-L1-containing treatment must have 
been the latest treatment regimen prior to enrolling in this trial
-
Latest treatment must be within >4 and <12 weeks before 
their first dose in this trial. Patients who have had anti-PD-1 
or anti-PD-L1 monotherapy as their first-line NSCLC 
treatment regimen must have a PD-L1 expression level of 
≥1% at baseline (local validated testing).
Rationale for changes
The definition of stable disease is being updated to requires 4 months of 
prior benefit (instead of 8/6 months).  The original definition was too 
restrictive resulting in patients that had experienced prior benefit from 
anti-PD-1 being excluded from the trial.
Section to be changed
Synopsis Endpoints and Section 5.1.2.2 Secondary endpoints of Part II 
(dose expansion) of the trial
Description of change
Secondary Endpoints:
∀
Duration of response is the duration from the date of first documented 
PR or CR according to RECIST Version 1.1 as assessed by the 
Investigator to the date of PD or death.
∀
Disease control (DC) (CR, PR, or stable disease [SD] according to 
RECIST Version 1.1, as assessed by the Investigator).
∀
Progression-free survival (PFS) is the duration from the date of first 
treatment to the date of PD or death.
∀
PK parameters (Cmax and AUC0-504) will be calculated for BI 754111 

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and BI 754091.
∀
Number of patients experiencing DLTs from start of treatment until end 
of treatment.
Rationale for changes
The secondary endpoints have been revised to more accurately reflect 
what endpoints are needed to meet the secondary objectives, and to clarify 
the PK parameters of the study.
Section to be changed
Flow Chart 1
Description of change
Footnote q has been added to troponin collection “q A measurement of 
troponin-I is to be performed if possible. If troponin-I cannot be 
measured, troponin-T can be measured instead as long as this is marked in 
the database. “ 
Rationale for changes
To allow for the measurement of troponin-T if the site is unable to assay 
troponin-I.
Section to be changed
Flow Chart 1 and 2
Description of change
Assessments will be performed by the Investigator at screening and every 
2 cycles (6 weeks ±53 days) for the first 6 months of treatment, once 
every 3 cycles (9 weeks ±53 days) thereafter, at the EOT visit (if not 
performed within the previous 4 weeks), and at the discretion of the 
Investigator and copies may be collected by the sponsor or designee
Rationale for changes
The window of response assessments has been broadened from 3 to 5 
days to allow more flexibility. 
Section to be changed
Flow Chart 2
Description of change
Footnote r has been added to troponin collection “r A measurement of 
troponin-I is to be performed if possible. If troponin-I cannot be 
measured, troponin-T can be measured instead as long as this is marked in 
the database. “ 
Rationale for changes
To allow for the measurement of troponin-T if the site is unable to assay 
troponin-I.
Section to be changed
Flow Chart 2 
Description of change
The “X” Vital Signs for Expansion Cycles 1, 2, and 4 Day 2 has been 
changed to X (C1). 
Rationale for changes
Per footnote “p”, “The clinic will telephone the patients on Days 2 and 4 
of Cycle 2 and Day 2 of Cycle 4…”. Therefore, vital signs would not be 
taken on Day 2 of Cycle 2 and Cycle 4. 
Section to be changed
Flow Chart 2 
Description of change
The “X” Vital Signs for Expansion Cycles 1, 2, and 4 Day 2 has been 
changed to X (C1, 4).
Rationale for changes
Per footnote “p”, “The clinic will telephone the patients on Days 2 and 4 

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of Cycle C and Day 2 of Cycle 4…”. Therefore, vital signs would not be 
taken on Day 4 of Cycle 2. 
Section to be changed
Section 3.3.2 Inclusion Criteria
Description of change
4.
Part II (dose expansion):
∀
Patients must have measurable disease per RECIST v1.1 
criteria, must have at least 1 tumour lesion amenable to 
biopsy, and must be medically fit and willing to undergo a 
biopsy before first treatment (if adequate archival tissue is not 
available) and, unless clinically contraindicated, after 6 weeks 
on therapy.
∀
Dose Expansion Cohorts:
-
Second and 3rd line NSCLC patients: 
•
Must have progressed on anti-PD-1 or 
anti-PD-L1 treatment after having 
achieved radiologically confirmed 
benefit (minimum of stable disease) 
•
Must have had a minimum duration of 
benefit of 84 months for non-squamous 
NSCLC patients who received 
immunotherapy plus chemotherapy in a 
first line setting, or 6 months for all 
other patients, and minimum treatment 
duration of 2 months on the previous 
anti-PD-1 or anti-PD-L1 treatment 
without experiencing disease 
progression during that period. 
Rationale for changes
The definition of stable disease is being updated to requires 4 months of 
prior benefit (instead of 8/6 months).  The original definition was too 
restrictive resulting in patients that had experienced prior benefit from 
anti-PD-1 being excluded from the trial.
Section to be changed
Description of change

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Rationale for changes
Section to be changed
Section 5.3.4.2 Biochemistry
Description of change
A measurement of troponin-I is to be performed if possible. If 
troponin-I cannot be measured, troponin-T can be measured instead 
as long as this is marked in the database.
Rationale for changes
To allow for the measurement of troponin-T if the site is unable to assay 
troponin-I.

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Number of global 
amendment
8
Date of CTP revision
20 May 2020
EudraCT number
2017-005042-29
BI Trial number
BI 1381.2
BI Investigational 
Product(s)
BI 754111 and BI 754091
Title of protocol 
(previous - see below 
for title update)
An open label, Phase I dose-finding study of BI 754111 in 
combination with BI 754091 in patients with advanced solid 
cancers followed by expansion cohorts at the selected dose of 
the combination in patients with non-small cell lung cancer 
and other solid tumors
To be implemented 
only after approval 
of the IRB / IEC / 
Competent 
Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / 
Competent Authority 
to be notified of 
change with request 
for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative 
aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of sections with 
changes are presented. Please note that formatting changes and minor changes to punctuation, spelling, and 
abbreviations that do not affect meaning are not noted in this summary.
Section to be changed
Synopsis, Section 3.3.2 Inclusion Criteria 4
Description of change
-
Must be EGFR WT and ALK WT (only applicable to 
patients with non-squamous NSCLC)

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
ALK WT
Rationale for changes
The Sponsor acknowledges that patients with squamous NSCLC are not 
routinely tested for EGFR and ALK alterations since these are very rare in 
this histology and EGFR and ALK TKIs are not indicated as first line 
treatment option in this setting.  The Sponsor will consider such patients 
to be included in the trial if the Investigator can document the squamous 
histology of the tumor and the standard of care at the institution does not 
include sequencing of such patients.  
Section to be changed
Synopsis, Section 3.3.2 Inclusion Criteria 4
Description of change
Regardless of Any PD-L1 expression level.  
Rationale for changes
This is to clarify that “any” PD-L1 expression includes 0%
Section to be changed
Flowchart 2, Footnote f and Section 5.3.3 Electrocardiograms
Description of change
Single digitalised ECGs (or analog ECG if digital not available) must 
be done….
Rationale for changes
With the addition of sites in EU, it is possible that some sites don’t have 
digitized ECGs and in this case, analog ECG could be used
Section to be changed
Section 2.3 Benefit-Risk Assessment
Description of change
As of 30-November-2018, 50 patients with advanced/metastatic solid 
tumors have been treated with BI 754091 as monotherapy in the 1381.1 
trial. 
The most frequently reported AEs (reported in >10% of the patients) were 
fatigue (40%), nausea (28.0%), decreased appetite (18.0%), arthralgia 
(16.0%), cough (16.0%), abdominal pain (14.0%), constipation (14.0%), 
diarrhea (14.0 %), vomiting (14.0), back pain (12.0%) and dyspnea 
(12.0%). Headache, hypokalaemia, muscular chest pain, myalgia, pruritis 
and rash, each occurred at a frequency of 10.0%.  The majority of these 
AEs were CTCAE grade 1 and 2.
Grade 3 and 4 AEs were reported in 38.0% and 4.0% of patients, 
respectively. Of the grade 3 events, only the AST elevation event was 
reported as related to trial drug.  The reported grade 4 AEs were 1 (2.0%) 
case of disease progression and 1 (2.0%) case of sepsis, neither of which 
was deemed treatment related. 
Consistent with the similar drug class labels, most immune-related 
(irAEs) were reported in the GI, Skin and Endocrine SOCs. The majority 
of the irAEs were Grades 1 and 2, the only Grade 3 irAE was AST 
increase.
Preliminary efficacy analyses for study 1381.1 indicate that there have 
been 6 patients with partial response (PR) and 20 patients with stable 

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disease as best response on BI 754091 monotherapy in the 1381.1 trial.  
The PRs were reported in two patients with triple negative breast cancer, 
one patient with fallopian tube cancer, one patient with renal cancer, one 
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.
A similar safety profile of BI 754091 monotherapy was observed in 6 
Japanese patients with solid tumors evaluated in the Asian trial 1381.4. 
The details of the preliminary analysis are provided in section 6.2 of the 
BI 754091 IB.
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 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 240mg BI 754091 in combination with 200 mg BI 754111, 1 
patient with microsatellite stable rectal cancer treated with 240mg BI 
754091 in combination with 600 mg BI 754111 and 1 patient with TNBC 
treated with 240mg BI 754091 in combination with 600 mg BI 754111. 
Please refer to the current version of the BI 754111 Investigator Brochure 

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for further details the latest information on patients treated with BI 
754111/BI 754091.
Based on these pre-clinical data, as well as preliminary clinical data 
obtained with BI 754091 as well as the combination of BI 754091 and BI 
754111, the inhibitory effects of the combination of BI 754111 and BI 
754091 may translate into a clinical benefit in cancer patients.
Therefore, treatment with BI 754111 and BI 754091 is expected to 
provide patients with clinical benefit at an acceptable risk.  The 
benefit/risk ratio continues to be considered positive for patients with 
advanced cancers.  
Rationale for changes
The text was updated to include the most recent clinical data on the study 
drugs. 
Section to be changed
Section 3.3.3 Exclusion Criteria 7
Description of change
(only applicable to patients with non-squamous NSCLC)
Rationale for changes
This additional text aligns exclusion criteria 5 with inclusion criteria 4
Section to be changed
Section 6.2.1.2 Medical history
Description of change
For first line NSCLC cohort, in medical history, last tumor size 
measurements taken prior to screening in the trial will be collected 
where available.
Rationale for changes
Collecting historical tumor size measurements to understand tumor 
growth kinetics in this patient population.
Section to be changed
Section 7.4 Interim Analyses
Description of change
Data from 1381-0002 and 1381-0004 may be pooled for the interim 
futility decision making, if applicable. If considered necessary, an 
evaluation of the efficacy and safety aspects will be performed. 
Results of this evaluation will be documented and archived. If 
applicable, such an analysis will be defined in more detail in the 
TSAP .
Rationale for changes
This provides an opportunity for pool analysis. 

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
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