An Open Label, Phase I Study of BI 754091 Monotherapy and Combination Therapy of BI 754091 and BI 754111 in Asian Patients With Advanced Solid Tumours
Phase: EARLY_PHASE1
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c16323837-07
BI Trial No.:
1381-0004
BI Investigational 
Product(s):
BI 754091 and BI 754111
Title:
An open label, Phase I study of BI 754091 monotherapy and 
combination therapy of BI 754091 and BI 754111 in Asian
patients with advanced solid tumours
Lay Title:
This study aims to find a safe and effective dose of BI 754091. 
The study also aims to find safe and effective doses of BI 
754091 and BI 754111 in combination. This study is done in 
Asian patients with different types of cancer
Clinical Phase:
I
Clinical Trial 
Leader:
Telephone: 
, Fax: 
Coordinating
Investigator
Telephone: 
Status:
Final Protocol (Revised Protocol based on global amendment 5)
Version and Date:
Version: 6.0
Date: 21 Apr 2021
Page 1 of 145
Proprietary confidential information.
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Finished product name
NA
Active ingredient name:
BI 754091 and BI 754111
Protocol date
15 Dec 2017
Revision date
21 Apr 2021
Trial number
1381-0004
Title of trial:
An open label, Phase I study of BI 754091 monotherapy and 
combination therapy of BI 754091 and BI 754111 in Asian patients 
with advanced solid tumours
Coordinating 
Investigator
Telephone: 
Trial site(s):
Multi-centre trial conducted in Asia
Clinical phase:
I
Objective(s):
The main objectives of the dose-finding parts (Parts I and II) of the 
trial are to investigate the following in patients with advanced solid 
tumours:
•
Part I: Safety, tolerability, and pharmacokinetics (PK) of BI 
754091 as monotherapy.
•
Part II: Safety, tolerability, and PK of escalating doses of BI 
754111 when administered with BI 754091, and PK of BI 
754091 when administered with escalating doses of BI 754111.
•
Parts I and II: Maximum tolerated dose (MTD) and/or 
recommended dose (RD) of BI 754091 monotherapy and the 
combination of BI 754091 and BI 754111.
The main objectives of the expansion part (Part III) of the trial are:
•
To further investigate the safety, tolerability, and PK of the RD 

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of the combination of BI 754091 and BI 754111 in patients with 
gastric/esophagogastric junction cancer, esophageal cancer, 
hepatocellular cancer, or non-small cell lung cancer (NSCLC)
•
To explore the efficacy of the combination of BI 754091 and BI 
754111 at RD in patients with gastric/esophagogastric junction 
cancer, esophageal cancer, hepatocellular cancer, or NSCLC
Methodology:
Part I (BI 754091 monotherapy dose-finding part): Open-label, single 
arm dose-finding
Part II (Combination dose-finding part): Open-label, single arm 
dose-finding
Part III (Combination dose- expansion part): Open-label, single arm
Number of patients
entered: 
Approximately 179 patients
Number of patients on 
each treatment:
Part I: approximately 6 to 12 patients (Japanese patients)
Part II: approximately 12 to 18 patients (Japanese patients)
Part III: Approximately 155 patients (Asian patients)
Diagnosis :
Part I and II: Patients with a confirmed diagnosis of advanced, 
unresectable, and/or metastatic solid tumours
Part III: Patients with advanced and/or metastatic disease of following 
tumour types:
Cohort A: Patients with gastric/esophagogastric junction cancer,
with no prior treatment with anti-PD-1/PD-L1 antibody, and who 
received at least one line of systemic medical treatment excluding 
adjuvant therapy
Cohort B: Patients with esophageal cancer with no prior 
treatment with anti-PD-1/PD-L1 antibody, and who received at 
least one line of systemic medical treatment excluding adjuvant 
therapy
Cohort C: Patients with hepatocellular cancer with no prior 
treatment with anti-PD-1/PD-L1 antibody, who received at least 
one line of systemic medical treatment excluding adjuvant 
therapy, and whose Child-Pugh score is 7 or less
Cohort D: Patients with gastric/esophagogastric junction cancer, 
esophageal cancer, or hepatocellular cancer with a prior treatment 
with anti-PD-1/PD-L1 antibody
Cohort E: First line NSCLC patients with wildtype (wt) 
epidermal growth factor receptor [EGFR] and anaplastic 
lymphoma kinase [ALK] tumours of squamous or non-squamous 
origin
Main in- and exclusion 
criteria
Part I and II: 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, with measurable disease according to RECIST 

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Version 1.1.
Part III: Patients with advanced and/or metastatic disease of selected 
tumour types, who have measurable disease according to RECIST 
Version 1.1, with at least 1 tumour lesion amenable to biopsy, and are
willing to undergo paired biopsies during the trial.
Additional specific criteria for the individual expansion cohorts 
include:
Cohort A: Patients with gastric/esophagogastric junction cancer,
with no prior treatment with anti-PD-1/PD-L1 antibody, and who 
received at least one line of systemic medical treatment excluding 
adjuvant therapy
Cohort B: Patients with esophageal cancer with no prior 
treatment with anti-PD-1/PD-L1 antibody, and who received at 
least one line of systemic medical treatment excluding adjuvant 
therapy
Cohort C: Patients with hepatocellular cancer with no prior 
treatment with anti-PD-1/PD-L1 antibody, who received at least 
one line of systemic medical treatment excluding adjuvant 
therapy, and whose Child-Pugh score is 7 or less
Cohort D: Patients with gastric/esophagogastric junction cancer, 
esophageal cancer, or hepatocellular cancer with a prior treatment 
with anti-PD-1/PD-L1 antibody
Cohort E: First line squamous or non-squamous NSCLC patients:
Without EGFR mutations or ALK rearrangements
PD-L1 expression level <50%
Test product(s):
BI 754091 and BI 754111
dose:
Part I: BI 754091 starting with 240 mg once every 3 weeks, the BI 
754091 RD established in the 1381-0001 trial in Caucasian patients. 
Dose-finding of BI 754091 will be guided by Bayesian logistic 
regression model (BLRM) with overdose control.
Part II: The starting dose of BI 754111 will be 400 mg, based on the 
safety information from another ongoing trial, 1381-0002. BI 754111 
will be administered once every 3 weeks in combination with BI 
754091 at the RD (Part I). Dose-finding of BI 754111 in combination 
with BI 754091 will be guided by BLRM with overdose control.
Part III: The RD of the combination determined in the combination
dose-finding part (Part II)
mode of 
administration:
Intravenous infusion
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Not applicable

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Duration of treatment:
Administration will continue until progressive disease (PD),
unacceptable toxicity, other withdrawal criteria, 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
sponsor.
Endpoints
Part I
Primary:
-
Number of patients experiencing DLTs graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE
Version 4.03) observed in the MTD evaluation period (first cycle 
of treatment; 3 weeks) 
-
MTD of BI 754091
Secondary:
-
PK parameters for BI 754091: Cmax and area under the curve 
(AUC)0-504
-
Objective Response (OR): confirmed CR or PR according to 
RECIST v1.1 assessed by the Investigator 
Part II
Primary:
-
Number of patients experiencing DLTs graded according to 
CTCAE Version 4.03 observed in the MTD evaluation period 
(first cycle of treatment; 3 weeks)
-
MTD of the BI 754091 plus BI 754111 combination
Secondary:
-
PK parameters for BI 754091 and for BI 754111: Cmax and 
AUC0-504
-
OR: confirmed complete response (CR) or partial response (PR)
according to RECIST v1.1 assessed by the Investigator
Part III
Primary:
-
OR: confirmed CR or PR according to RECIST Version 1.1 as
assessed by the Investigator
Secondary:
-
Duration of response: 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.
Safety criteria:
Adverse events (AEs) according to CTCAE (Version 4.03 in Parts I 
and II, Version 5 in Part III), incidence of DLTs for determination of 
the MTD (dose-finding parts only), results of physical examinations, 
laboratory evaluations, vital signs, and electrocardiograms (ECGs)

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Statistical methods:
Part I
Descriptive statistics.
Dose-finding will be guided by BLRM with overdose control that will 
be fitted to binary toxicity outcomes. The estimate of parameters will 
be updated as data are accumulated using BLRM. At the end of dose 
finding, the toxicity probability at each dose level will be calculated 
to determine an estimate of the MTD of BI 754091.
Part II
Descriptive statistics.
Dose escalation will be guided by BLRM with overdose control that 
will be fitted to binary toxicity outcomes. The estimate of parameters 
will be updated as data are accumulated using BLRM. At the end of 
dose escalation, the toxicity probability at each dose (combination) 
level will be calculated to determine an estimate of the MTD of the 
combination of BI 754111 plus BI 754091.
Part III
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
Flow Chart
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Cycles 1, 2, and 4
Cycles 3, 5+
End-of-
Treatmentp
(EOT) Visit
30-Day 
Safety 
Follow-upr
FU for 
PFS/OS
h
Assessments (Days)
-28 to -1
1
(±2 C2+)
2
3s
4s
8 (±1)
15 (±1)
1 (±2)
within 7 
days of 
(+7)
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
X
12-Lead Digital Electrocardiogramd, f,t
X
X
X
Xt
(C3,5,6,8,10, 
12, etc and 
C3D15)
Xt
(X)t
Haematology and Clinical Chemistry Labsd
X
X
X
X
X
X
Troponin
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
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X

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Flow Chart
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Cycles 1, 2, and 4
Cycles 3, 5+
End-of-
Treatmentp
(EOT) Visit
30-Day 
Safety 
Follow-upr
FU for 
PFS/OS
h
Assessments (Days)
-28 to -1
1
(±2 C2+)
2
3s
4s
8 (±1)
15 (±1)
1 (±2)
within 7 
days of 
(+7)
Progression/Survivalh
X
Blood Samples for Anti-Drug Antibodiesi,q,t
X
Xq,t
Xq,t
Xq,t
(Part I, II) PK Blood Samples j,q
X
X
X
X
X
X
Xq
Xq
Xq
(Part III) PK Blood Samplesj,q,t
X
X
(C1&4)
X
(C1&4)
X
(C1&4)
Xq,t
Xq
Xq,t
(Part II and III, only if feasible at study site) 
Blood Samples and extraction of PBMC for 
Biomarkers (PBMC [extract])k,t
X
(C1&2)
X (C1)
X (C1)
X
(C3&5)
Xt
(Part III cohort E only) Blood Samples for 
Biomarkers (PBMC [blood])k
X
(C1&2)
X(C1)
X(C1)
X
(Part III only) Plasma Samples for 
Biomarkers (Cytokines)k,t
X
X
(C1&4)
X
(C1&4)
X (C3D1 
only)
Xt
(Part III only) Biopsyl,t
X
X (C3D1 
only)
(X)t
Tumour Assessmentsd, m
X
Every 2 cycles ±5 days for 6 months (then every 3 cycles ±5 days thereafter)
Study Drug Infusionn
X
X
DLT Assessmento
X
X
X
X
X
X
X
X

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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 provides an additional consent. In 
addition, patients without PD may stay on trial after 1 year on a case-by-case basis after discussion with the sponsor. Day 1 of Cycle 1 is defined as the day 
when the study medication is first 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, clinical biochemistry, and urinalysis will be performed locally (Free T3, Troponin I, and venous HCO3
will be measured at a central laboratory if study site cannot measure it locally). The screening medical history and demographics, physical examination and 
Eastern Cooperative Oncology Group (ECOG) performance status (PS), vital signs, ECG, haematology, clinical chemistry (sodium, potassium, phosphate, 
chloride, creatinine, calcium, venous bicarbonate HCO3 (if the local lab test is available at the study site), albumin, total protein, aspartate aminotransferase
[AST], alanine aminotransferase [ALT], alkaline phosphatase, bilirubin, lactate dehydrogenase, glucose, creatine phosphokinase [CPK: if CPK is elevated, then 
CPK-MB, troponin (either I or T), and myoglobin should be reactively tested], urea [or blood urea nitrogen (BUN)], 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. 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 PS, an abbreviated physical 
examination, vital signs (pre- and post-infusion), and a single ECG required prior to first trial dose. Hepatitis B virus (HBV), hepatitis C virus (HCV), and 
human immunodeficiency virus (HIV) testing should be performed at screening unless test results obtained in routine diagnostics within 14 days before the 
informed consent date are available (For patients with hepatocellular cancer in Part III Cohorts C and D, if a patient is known to have HBV and/or HCV 
infection, the diagnostic testing for that item does not need to be repeated). Additionally, amylase and lipase should be analysed in case of symptoms of 
pancreatitis. 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 5.2 for additional details. Vital signs are checked at every visit. At the visit for the first treatment, vital signs are checked before and after 
infusion. At subsequent visits for administration, vital signs are checked only before infusion.
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.
f
Single digitalised ECGs must be done before blood sampling or other procedures after 5 minutes of rest at screening, on Day 1 of every cycle 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 5.2.5).
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 5.2.4.4).
h
Patients enrolled in Part III Cohort E: 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 (in person or by telephone) until death, loss to follow-up, withdrawal of consent, or end of the whole trial.

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All other patients: Additional follow-up visits for PFS after the 30-day safety follow-up visit will only be performed in Part III for patients who did not 
progress on treatment. The follow-up visits for PFS will be performed once every 12 weeks at least (in person or 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.
i
Blood samples for anti-drug antibodies (ADAs) will be collected from all patients as presented in Tables 10.4: 1 and 10.4: 2 in Appendix 10.4 .
j
Pharmacokinetic (PK) blood sampling: there is extensive PK sampling during Cycles 1, 2, and 4. It is strongly recommended that the visit days and sampling 
time points outlined in Tables 10.4: 1 and 10.4: 2 in Appendix 10.4 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 754091 and BI 754111 in Part II and III. Therefore, when PK 
samples are drawn during combination dosing, 2 tubes must be drawn at each time point.
k
Blood samples for biomarkers – following blood samples are taken for biomarker analysis:
-
Cytokine: samples will be taken in Part III on Days 1 (pre-treatment only), 2, and 8 of Cycles 1, and 4, on Day 1 (pre-treatment only) of Cycle 2 & 3, 
and at the 30-day follow-up visit for quantification of cytokines (e.g., IL-2 and IFN-γ) in plasma samples (see Section 5.4.2.2 and Appendix 10.4).
-
PBMC (extract): Blood samples will be taken and peripheral blood mononuclear cells (PBMC) will be extracted during Part II and Part III only at study 
sites in which the sample preparation is possible, on Day 1 (pre-treatment), 2, 8 of Cycle 1, on Day 1 (pre-treatment) of Cycle 2, 3 and 5, and at the 
30-day safety follow-up visit.
-
PBMC (blood): Blood samples for biomarker PBMC (blood) will be taken only in Part III cohort E 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-treatment visit. Kits will be provided from a designated laboratory logistics vendor. If the 
kits are not ready at study sites at the time of patient recruitment, this blood sampling will not be performed.
l
All patients in Part III must have tissue samples (fresh or archived [see requirements]) available for retrospective central biomarker testing. The following will 
be required (see Section 5.4.2.3 for details):
-
If available and taken within 6 months of study start and no anti-tumour treatment has been given after the sample is taken, at least 20 (4-5 µm) sections 
from an archival FFPE block should be collected. If adequate archival tissue is not available, 2 core-needle biopsies must be taken between screening 
and the day before the first study drug treatment. 
-
Two core-needle biopsies 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 or iRECIST), if possible. SD over 4 months would also be qualified as a 
response, and a biopsy (optional) would be taken at that time point. Subjects with PR will also be asked for biopsies upon confirmation of the response.

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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 5.1.1 for more 
detail). Assessments will be performed by the Investigator at screening and every 2 cycles (meaning every 6 weeks ±5 days if there are no delays in cycles but as 
close as possible to the end of the second of the 2 cycles of treatment if there was a delay) for the first 6 months of treatment, once every 3 cycles (meaning every 
9 weeks ±5 days if there are no delays in cycles but as close as possible to the end of the third of the 3 cycles of treatment if there was a delay) 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
Dosing of BI 754111 and BI 754091 will be determined by the SMC 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. 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.
o
Dose-limiting toxicities (DLTs) will be collected as adverse events of special interest (AESIs) throughout the trial and will be assessed for dose-finding. (see 
Section 4.1.5).
p
If the decision is made to permanently discontinue study treatments during a scheduled visit, the EOT visit should be performed instead of the scheduled visit
assessments. In the combination treatment parts (Part II and III), both BI 754091 and BI 754111 should be discontinued together if necessary.
q
PK and ADA blood samplings are to be collected during Cycles 1 through 12, Cycle 14, Cycle 17, at every 3 cycle after Cycle 17 at the EOT visit, and the 
30-day safety follow-up (see the tables in Appendix 10.4 for specifics).
r
30-day safety follow-up visit takes place 30 days after EOT visit.
s
Visits on days 3 and 4 are to be performed in Part I and Part II only.
t
After an interim database lock in 2021, the following procedures are not required: 12-lead ECG (could be performed if clinically indicated with significant 
abnormalities recorded as AEs), blood samples for Anti-Drug Antibodies, PK blood samples, blood samples and extraction of PBMC for biomarkers (PBMC 
[extract]), plasma samples for biomarkers, and biopsy
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........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................17
1.
INTRODUCTION...............................................................................................20
1.1
MEDICAL BACKGROUND.............................................................................20
1.2
DRUG PROFILE................................................................................................22
1.2.1
BI 754091 .............................................................................................................22
1.2.2
BI 754111 .............................................................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................23
1.4
BENEFIT - RISK ASSESSMENT.....................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoints...............................................................................................27
2.1.3
Secondary endpoints...........................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................30
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................32
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................33
3.3.3
Exclusion criteria ................................................................................................34
3.3.4
Withdrawal of patients from therapy or assessments .....................................36
3.3.4.1
Withdrawal from trial treatment ...........................................................................36
3.3.4.2
Withdrawal of consent for trial participation........................................................37
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................37
4.
TREATMENTS...................................................................................................39
4.1
INVESTIGATIONAL TREATMENTS ...........................................................39
4.1.1
Identity of the Investigational Medicinal Products..........................................39
4.1.1.1
BI 754091..............................................................................................................39
4.1.1.2
BI 754111..............................................................................................................39
4.1.2
Selection of doses in the trial..............................................................................40
4.1.2.1
Starting dose of BI 754091 ...................................................................................40
4.1.2.2
Starting dose of BI 754111 ...................................................................................41
4.1.3
Dose-finding scheme ...........................................................................................41

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4.1.4
Dose modifications and premedications............................................................42
4.1.5
Definition of dose-limiting toxicity ....................................................................43
4.1.6
Definition of maximum-tolerated dose..............................................................45
4.1.7
Definition of evaluable patient...........................................................................45
4.1.8
Method of assigning patients to treatment groups...........................................45
4.1.9
Drug assignment and administration of doses for each patient......................46
4.1.10
Blinding and procedures for unblinding...........................................................46
4.1.11
Packaging, labelling, and re-supply...................................................................46
4.1.12
Storage conditions...............................................................................................46
4.1.13
Drug accountability.............................................................................................47
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................47
4.2.1
Other treatments and emergency procedures..................................................47
4.2.2
Concomitant medications...................................................................................47
4.2.2.1
Permitted concomitant medications......................................................................48
4.2.2.2
Prohibited concomitant medications.....................................................................48
4.2.3
Restrictions ..........................................................................................................49
4.2.3.1
Restrictions on diet and life style..........................................................................49
4.2.3.2
Restrictions regarding women of childbearing potential ......................................49
4.3
TREATMENT COMPLIANCE........................................................................50
5.
ASSESSMENTS..................................................................................................51
5.1
ASSESSMENT OF EFFICACY........................................................................51
5.1.1
Tumour assessments ...........................................................................................51
5.2
ASSESSMENT OF SAFETY.............................................................................51
5.2.1
Physical examination ..........................................................................................52
5.2.2
ECOG performance status.................................................................................52
5.2.3
Vital signs.............................................................................................................52
5.2.4
Safety laboratory parameters ............................................................................52
5.2.4.1
Haematology.........................................................................................................53
5.2.4.2
Biochemistry.........................................................................................................53
5.2.4.3
Urinalysis ..............................................................................................................53
5.2.4.4
Pregnancy test .......................................................................................................53
5.2.5
Electrocardiogram ..............................................................................................54
5.2.6
Other safety parameters.....................................................................................54
5.2.7
Assessment of adverse events.............................................................................54
5.2.7.1
Definitions of adverse event .................................................................................54
5.2.7.2
Definition of adverse reaction...............................................................................54
5.2.7.3
Definition of serious adverse event.......................................................................55
5.2.7.4
Adverse events considered “Always Serious”......................................................55
5.2.7.5
Adverse events of special interest (AESIs)...........................................................56
5.2.7.6
Severity of adverse events.....................................................................................58
5.2.7.7
Causal relationship of adverse events ...................................................................58
5.2.7.8
Adverse event collection and reporting ................................................................59
5.2.7.9
Pregnancy..............................................................................................................61
5.2.7.10
Exemptions from AE/SAE reporting....................................................................61

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................62
5.3.1
Assessment of pharmacokinetics .......................................................................62
5.3.2
Methods of sample collection .............................................................................62
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................63
5.4
ASSESSMENT OF BIOMARKERS.................................................................63
5.4.1
Methods of sample collection .............................................................................64
5.4.3
Biobanking...........................................................................................................65
5.5
OTHER ASSESSMENTS...................................................................................66
5.5.1
Plasma sampling for anti-drug antibodies (ADAs)..........................................66
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................67
6.
INVESTIGATIONAL PLAN.............................................................................68
6.1
VISIT SCHEDULE.............................................................................................68
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................68
6.2.1
Screening period..................................................................................................69
6.2.1.1
Baseline Conditions ..............................................................................................69
6.2.1.2
Medical History.....................................................................................................69
6.2.1.3
Concomitant medications......................................................................................69
6.2.2
Treatment period(s)............................................................................................70
6.2.3
Follow up period and trial completion..............................................................70
6.2.3.1
End-of-treatment visit ...........................................................................................70
6.2.3.2
30-day safety follow-up visit ................................................................................70
6.2.3.3
Follow up visits for PFS (extended follow-up period) .........................................70
6.2.3.4
Follow up visits for overall survival (OS) ............................................................71
6.2.3.5
Study procedures modification after an interim database lock.............................71
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................72
7.1
STATISTICAL DESIGN - MODEL.................................................................72
7.1.1
Statistical design – Part I (BI 754091 monotherapy dose finding part).........72
7.1.2
Statistical design – Part II (BI 754091 and BI 754111 combination dose 
finding).................................................................................................................74
7.1.3
Statistical design – Part III (expansion)............................................................79
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................79
7.3
PLANNED ANALYSES.....................................................................................79
7.3.1
Primary endpoint analyses.................................................................................79
7.3.1.1
Primary endpoint analyses for Part I and Part II...................................................79
7.3.1.2
Primary endpoint analyses for Part III..................................................................79
7.3.2
Secondary endpoint analyses .............................................................................80
7.3.2.1
Secondary endpoint analyses for Part I and Part II...............................................80
7.3.2.2
Secondary endpoint analyses for Part III..............................................................80

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7.3.4
Safety analyses.....................................................................................................80
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................81
7.4
INTERIM ANALYSES ......................................................................................82
7.5
HANDLING OF MISSING DATA ...................................................................82
7.5.1
Plasma drug concentration - time profiles........................................................82
7.5.2
Pharmacokinetic parameters.............................................................................83
7.6
RANDOMISATION ...........................................................................................83
7.7
DETERMINATION OF SAMPLE SIZE .........................................................83
7.7.1
Determination of sample size for Part I and Part II........................................83
7.7.2
Determination of sample size for Part III.........................................................83
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........89
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................89
8.2
DATA QUALITY ASSURANCE ......................................................................90
8.3
RECORDS...........................................................................................................90
8.3.1
Source documents ...............................................................................................90
8.3.2
Direct access to source data and documents.....................................................91
8.3.3
Storage period of records ...................................................................................92
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................92
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........92
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................92
8.6
TRIAL MILESTONES.......................................................................................93
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................93
9.
REFERENCES....................................................................................................95
9.1
PUBLISHED REFERENCES............................................................................95
9.2
UNPUBLISHED REFERENCES....................................................................101
10.
APPENDICES...................................................................................................102
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST ...102
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS............105
10.3
HANDLING PROCEDURES FOR BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS .........................................107
10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA, AND 
BIOMARKER BLOOD SAMPLING.............................................................108
10.5
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS ...............................................................................110
10.6
iRECIST.............................................................................................................116
10.7
RELATIONSHIP BETWEEN VISIT NUMBER AND DATE ....................119
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................120
11.1
GLOBAL AMENDMENT 1 ............................................................................120
11.2
GLOBAL AMENDMENT 2 ............................................................................128
11.3
GLOBAL AMENDMENT 3 ............................................................................131

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11.4
GLOBAL AMENDMENT 4 ............................................................................137
11.5
GLOBAL AMENDMENT 5 ............................................................................145

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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the Curve
β-hCG
Beta human chorionic gonadotropin
BI
Boehringer Ingelheim
BLQ
below the limit of quantification
BLRM
Bayesian Logistic Regression Model
BOR
Best overall response
BUN
Blood urea nitrogen
CA
Competent authority
CEOI
Plasma concentration at the end of infusion
CKD-EPI
Chronic Kidney Disease Epidemiology
CL
Total clearance of the analyte in plasma following intravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CPK
Creatinine phosphokinase 
Cpre,N
Predose measured concentration of the analyte in plasma before the Nth 
dose
CR
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Leader
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CTR
Clinical Trial Report
DC
Disease control
DCR
Disease control rate
DILI
Drug induced liver injury
DLT
Dose Limiting Toxicity
eDC
electronic Data Capturing
ECG
Electrocardiogram
ECOG
Eastern Co-Operative Oncology Group
EF
Ejection Fraction
EGFR
Epidermal growth factor receptor

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eGFR
Estimated glomerular filtration rate
EOT
End of Treatment
EWOC
Escalation With Overdose Control
FFPE
Folmarin fixed paraffin embedded
GCP
Good Clinical Practice
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
iBOR
Best overall response according to iRECIST
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
iCPD
Confirmed progressive disease according to iRECIST
iCR
Complete response according to iRECIST
IDMS
Isotope dilution mass spectroscopy
IEC
Independent Ethics Committee
IFN
Interferon
IHC
Immunohistochemistory
IL
Interleukin
INR
International normalized ratio
IO
Immune Oncology
iPD
Progressive disease according to iRECIST
iPR
Partial response according to iRECIST
IRB
Institutional Review Board
IRT
Interactive Response Technology
iUPD
Unconfirmed progressive disease according to iRECIST
iSD
Stable disease according to iRECIST
ISF
Investigator Site File
irAEs
immune-related adverse events
iUPD
i.v.
intravenous
LAG-3
Lymphocyte-activation gene 3
LDH
Lactate dehydrogenase
LPDD
last patient drug discontinuation
mAb
Monochronal antibody
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHC-II
Major histocompatibility complex Class II
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
MUGA
Multigated acquisition
NE
Not evaluable
NK
Natural killer
NL
New lesion
NLNT
New lesion non-target
NLT
New lesion target
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result

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NOS
No sample available
NSCLC
Non-small-cell lung cancer
OPU
Operative Unit
OR
Overall response/objective response
ORR
Overall response rate/objective response reate
PBMC
Peripheral blood mononuclear cells
PD
Progressive Disease
PDc
Pharmacodynamics
PD-1
Programmed cell death protein-1
PD-L1
Programmed death ligand-1
PFS
Progression free survival
PET
Positron emission tomography
PK
Pharmacokinetics
PR
Partial response
PS
Performance status
RA
Accumulation ratio
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RD
Recommended dose
QTc
Corrected QT interval
SAE
Serious adverse event
SD
Stable disease
SMC
Safety Monitoring Committee
SOC
System organ class
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum concentration of the analyte in 
plasma
T-regs
regulatory T-cells
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state following intravascular 
administration
WHO
World Health Organization
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Despite the recent advancements in cancer treatment, cancer remains a leading cause of death
globally. In 2012, there were approximately 14 million new cancer cases, and 8.2 million 
cancer-related deaths worldwide (R15-3504). 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
LAG-3 (R16-0868, R16-5335), while the ligands for these checkpoint inhibitors (i.e., 
PDL1/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

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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).
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 
antitumour 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 anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
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 a significant 
improvement in ORR in patients with previously untreated NSCLC (39% to 47% for 
ipilimumab dosed every 6 weeks or every 12 weeks, respectively) compared to the 23% ORR 
achieved by nivolumab monotherapy (R16-5545). Unfortunately, the improved efficacy of 
combined PD-1/CTLA-4 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,
combined blockade of the co-inhibitory receptors PD-1 and LAG-3 has the potential to better

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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).
1.2
DRUG PROFILE
1.2.1
BI 754091
BI 754091 is a humanised IgG4Pro isotype mAb against PD-1 that is being developed as an
intravenous (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.
In pre-clinical studies, 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, electrocardiograms (ECGs), or clinical observations were noted at any doses. 
There was no BI 754091-related mortality during that study. 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. BI 754091 related microscopic findings 
included marginal increases in mononuclear cell infiltrates considered non-adverse and 
related to expected pharmacology.
BI 754091 is currently being tested in patients in the BI 1381-0001 and 1381-0002 clinical 
trials. In trial 1381-0001 dose escalation cohorts, 80 mg, 240 mg, and 400 mg dose levels 
were investigated and 3 patients were dosed at each dose level. No dose limiting toxicities 
(DLTs) or immune-related AEs were reported and the maximum tolerated dose MTD was not 
reached in the dose escalation cohorts. Recommended dose for further investigation was 
determined to be 240 mg.
1.2.2
BI 754111
BI 754111 is a humanised IgG4Pro mAb against LAG-3 that is being developed as an 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.
In a 13-week repeat-dose toxicity study in cynomolgus monkeys, which included a BI 
754111/BI 754091 combination arm, animals were given 0, 3, 30, or 100 mg/kg/doses of BI 

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754111 monotherapy or a 30 mg/kg/dose of both BI 754111 and BI 754091 via i.v. infusion
once per week for 13 weeks. BI 754111 monotherapy and the combination of BI 754111/BI 
754091 were well tolerated and did not cause mortality or changes to body weight, food 
consumption, respiratory rate, or ECGs. There were no neurologic, ophthalmic, or physical 
examination findings directly related to BI 754111 treatment or combined treatment with 
BI 754111/BI 754091, and no gross pathology or organ weight findings. BI 754111 and the
BI 754111/BI 754091 combination increased T-lymphocyte IFN-γ secretion in response to ex 
vivo tetanus toxoid challenge. There were no changes in haematology, coagulation, clinical
chemistry, or urinalysis parameters except for non-adverse, reversible low-grade changes in
serum triglycerides, albumin, globulin, and albumin/globulin ratio. At the end of the 13-week
dosing phase, BI 754111-monotherapy-related and combination-therapy-related microscopic
findings included marginal increases in mononuclear cell infiltrates considered non-adverse
and related to expected pharmacology.
BI 754111 is currently being tested in patients in the BI 1381-0002 trial. BI 754111 was 
administered at dose range from 4 mg to 600 mg in combination with BI 754091 240 mg. No 
DLTs were reported in these dose levels from patients who were eligible for DLT evaluation 
(see section 4.1.2.2).
The residual effect period of BI 754091 monotherapy and BI 754091/BI 754111 combination 
therapy is 30 days.
For more detailed descriptions of the BI 754091 and BI 754111profiles please refer to the 
respective Investigator’s Brochures (IBs).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Most patients with locally advanced or metastatic tumours will succumb to their disease,
justifying the substantial need for novel therapeutic strategies to improve the outcome for
patients with advanced or metastatic malignancies.
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 patient with NSCLC (R15-3696; R16-
0852; R16-0868, R16-0881; R16-2707; R16-5335; R16-5545).
New, more tolerable, combinations of immune-therapy treatments are needed to continue to
improve the outcome for patients. BI 754091 in combination with BI 754111 has the
potential to be such a combination.
Clinical trials to of BI 754091 monotherapy and combination of BI 754091 and BI 754111 
are being conducted in North America, and Asian countries are not included in those trials. 

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This trial is intended to assess the safety, efficacy and pharmacokinetics (PK) of BI 754091 
monotherapy and combination of BI 754091 and BI 754111 in Asian patients to establish a 
safe combination dose that can be explored further in later development. 
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 their 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 
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, compared to 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 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.
The therapeutic benefit or specific adverse events in patients cannot always be anticipated 
during the trial setup. Later on there may be new scientific knowledge about biomarkers and 
other factors contributing to diseases or the action of a drug. In order to address future 
scientific questions, patients will be asked to voluntarily donate biospecimens for banking. If 
the patient agrees, banked samples may be used for future drug development projects, e.g., to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event, and thereby better match patients with therapies.

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1.4
BENEFIT - RISK ASSESSMENT
The role of the immune-checkpoint inhibitors within a normal immune response is to dampen
the immune response after the trigger (antigen) is resolved, minimizing 
collateral-immune-mediated damage to healthy tissue. Immune-checkpoint inhibitors also 
play a major role in promoting and maintaining self-tolerance by inactivating auto-reactive 
T-cells. Therefore, manipulation of immune-checkpoint-inhibitor pathways unleashes the 
immune system and comes with a higher risk of inducing immune dysfunction leading to 
immune-related adverse events (irAEs). Indeed, mice deficient in PD-1 or its ligands (PD-Ll 
and PD-L2) were found to be highly prone to development of autoimmune diseases 
(R16-2362; R16-2364; R16-2968; R16-2969; R16-2970).
Data from immune-checkpoint clinical trials show that irAEs occur frequently in patients
treated with anti-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 commonly 
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, pneumonitis and myocarditis 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 steroid-refractory 
irAE (R16-0763; R16-0899).
As previously mentioned, significant improvement in checkpoint inhibitor effect has been
achieved with checkpoint inhibitor combination therapy. The combination of nivolumab and
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 754091 and BI 754111 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.
Based on the 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 754091 and BI 754111 may

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translate into a clinical benefit in cancer patients. The dose-escalation scheme is guided by a
Bayesian 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 safety issues.
In addition, dose levels which are higher than the ones investigated in preceding trials 
1381-0001 and 1381-0002 will not be investigated in this trial.
Therefore, treatment with BI 754091 and BI 754111 may provide patients with clinical 
benefit at an acceptable risk.
By the end of June 2018, 48 patients were treated with the combination therapy of BI 754091 
and BI 754111 (BI 754111 dose range: 4mg to 600mg, all in combination with BI 754091 
240mg) and the risk benefit profile from the observed data was considered positive.
The trial safety will be monitored by the Safety Monitoring Committee (SMC, see Section 
8.7) established in this trial to safeguard the patient safety.
Even so, patients should be advised of the potential risks of side effects from investigational
trial treatments. While some may be anticipated, others may be rare and unknown with
irreversible and/or life-threatening effects. Patients should also be advised that there are other
unknown risks associated with participation in a clinical trial.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.7.5, adverse events of special interest.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objectives of the BI 754091 monotherapy dose-finding part (Part I) of the trial are 
to investigate the following items in advanced solid tumours:
•
Safety, tolerability, and pharmacokinetics (PK) of BI 754091 as monotherapy.
•
Maximum tolerated dose (MTD) and/or recommended dose (RD) of BI 754091 
monotherapy.
The main objectives of the Combination dose-finding part (Part II) of the trial are to
investigate the following items in advanced solid tumours:
•
Safety, tolerability, and PK of the combination treatment of BI 754091 and BI 754111.
•
MTD and/or RD of the combination treatment of BI 754091 and BI 754111.
The main objectives of the expansion part (Part III) of the trial are:
•
To further investigate the safety, tolerability, and PK of the RD of BI 754091 and BI 
754111 combination in patients with gastric/esophagogastric junction cancer, esophageal 
cancer, hepatocellular cancer, or non-small cell lung cancer (NSCLC)
•
To explore the efficacy of the RD of the combination of BI 754091 and BI 754111 in 
patients with gastric/esophagogastric junction cancer, esophageal cancer, hepatocellular 
cancer, or NSCLC
2.1.2
Primary endpoints
The primary endpoints of Part I (BI 754091 monotherapy dose-finding) are:

Maximum tolerated dose (MTD) of BI 754091

Number of patients experiencing dose limiting toxicities (DLTs) during the MTD 
evaluation period (first cycle of treatment)
The primary endpoints of Part II (combination dose finding) are:

MTD of the BI 754091 plus BI 754111 combination

Number of patients experiencing DLTs during the MTD evaluation period (first cycle of 
treatment)
The definition of MTD is described in Section 4.1.6. For definition of DLTs, refer to Section 
4.1.5.
The primary endpoint of Part III (expansion) is:

Objective response (OR) - confirmed complete response (CR) or partial response (PR)
according to response evaluation criteria in solid tumours (RECIST) Version 1.1 
(R09-0262) as assessed by the Investigator.

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2.1.3
Secondary endpoints
The secondary endpoints of Part I are the following:

The following pharmacokinetics (PK) parameters of BI 754091 will be measured after 
single administration:
-
Cmax: maximum measured concentration of BI 754091 in plasma
-
AUC0-504: area under the concentration-time curve of BI 754091 in plasma over the 
time interval from 0 to 504 hours

Objective response (OR): confirmed CR or PR according to RECIST v1.1 as assessed by 
the Investigator.
The secondary endpoints of Part II are the following:

The following PK parameters of BI 754091 and BI 754111 will be measured after single
administration:
-
Cmax: maximum measured concentration of BI 754091 and BI 754111 in plasma
-
AUC0-504: area under the concentration-time curve of BI 754091 and BI 754111 in 
plasma over the time interval from 0 to 504 hours

Objective response (OR): confirmed CR or PR according to RECIST v1.1 as assessed by 
the Investigator.
The secondary endpoints of Part III are the following:

Duration of response: defined as 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 
progressive disease (PD) or death.

Disease control: CR, PR, or stable disease (SD) according to RECIST Version 1.1 as 
assessed by the Investigator.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I, open-label, non-randomised, multicentre trial of BI 754091 and BI 754111
that will be conducted in 3 parts. The data obtained from the trial will determine the MTD 
estimate based on a Bayesian logistic regression model with overdose control (R13-4803).
The BLRM estimates the MTD by updating estimates of the probability of observing a DLT 
in the MTD evaluation period for each dose level in the trial as patient information becomes 
available. At any time in the trial, it will not be permitted to escalate to a dose which does not 
fulfil the escalation with overdose control (EWOC) principle. 
It is planned that approximately 6 to 12 patients with advanced solid tumour will be enrolled 
in the first part of the trial, which is for dose-finding of BI 754091 administered as 
monotherapy. A cohort or successive cohorts of patients will receive doses of BI 754091 until 
the MTD is reached, or RD determined in 1381-0001 is confirmed in this trial.
Following determination of the MTD and/or RD of BI 754091 in Part I, approximately 6 to 
12 patients with advanced solid tumour will be enrolled in Part II of the trial and will receive 
BI 754091 at RD determined in Part I and escalating doses of BI 754111. Successive cohorts 
of patients will receive doses of BI 754091 and BI 754111 until MTD is reached, or RD
determined in 1381-0002 is confirmed in this trial.
The DLT information collected in trials 1381-0001 and 1381-0002 will be used to construct 
the priors for the BLRM, and therefore will be included in the dose escalation 
decision-making process. In general, it will be permitted to escalate to a dose that fulfils the 
EWOC principle (see section 7). 
At the starting dose level of Part I, patient recruitment will continue until 6 evaluable patients 
are enrolled for the review of this dose level by the SMC. The SMC may determine to stop
the recruitment and perform a safety evaluation if necessary. A cohort size of 3 patients will 
be treated at each subsequent dose level. Additional patients may be added to some 
previously evaluated cohorts to expand the safety and PK evaluation.
After all patients in a cohort have either experienced a DLT or have been observed for at least 
the MTD evaluation period (cycle 1, 21 days) without experiencing a DLT, the Bayesian 
model will be updated with the newly accumulated data. The overdose risk will then be 
calculated for each dose, and escalation will be permitted to all doses/dose combinations
which fulfil the EWOC criterion. Hypothetical data scenarios (examples in section 10.5) will 
be calculated with potential cohort sizes and provided to the SMC. Based on the model and 
on additional information (e.g. PK, PD, patient profiles), the SMC will reach a joint decision 
on the next dose level to be investigated and the size of the next cohort.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose level still fulfils the EWOC principle. Based on this information, the SMC will 

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evaluate whether the next patients will be enrolled at the same dose level, or if they will be 
enrolled at a lower dose level.
The SMC may recommend stopping the dose 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 the criterion for MTD is not fulfilled at 
the RD determined in the corresponding trial of the Parts (i.e. RD in 1381-0001 for Part I, 
RP2D in 1381-0002 for Part II), the SMC may decide to include an additional number of 
patients at the same dose level or to declare this dose as the RD from this trial. The SMC can 
declare any dose that fulfils the EWOC criterion as RD, independent of the MTD estimate.
Following determination of the MTD and/or the RD from the dose-finding parts, Part III will 
commence and approximately 155 patients with gastric/esophagogastric junction cancer, 
esophageal cancer, hepatocellular cancer, or NSCLC will be enrolled to explore the efficacy 
and further evaluate the safety, tolerability, PK profile, biomarkers of the combination of BI 
754091 and BI 754111 at RD determined in Part II. Part II may still continue for further 
safety and/or PK evaluation at any dose levels, after the start of recruitment in Part III at the 
recommended dose.
In Part III, patient will be enrolled in cohorts of approximately 35 patients, designated for 
different patient populations as follows:
Cohort A: Patients with gastric/esophagogastric junction cancer, with no prior treatment 
with anti-PD-1/PD-L1 antibody, and who received at least one line of systemic 
medical treatment excluding adjuvant therapy
Cohort B: Patients with esophageal cancer with no prior treatment with anti-PD-1/PD-L1 
antibody, and who received at least one line of systemic medical treatment 
excluding adjuvant therapy
Cohort C: Patients with hepatocellular cancer with no prior treatment with anti-PD-1/PD-L1 
antibody, who received at least one line of systemic medical treatment excluding 
adjuvant therapy, and whose Child-Pugh score is 7 or less
Cohort D: Patients with gastric/esophagogastric junction cancer, esophageal cancer, or 
hepatocellular cancer with a prior treatment with anti-PD-1/PD-L1 antibody
Cohort E:
First line NSCLC patients with wildtype (wt) epidermal growth factor receptor 
[EGFR] and anaplastic lymphoma kinase [ALK] tumours of squamous or 
non-squamous origin.
In Part I and Part II, only Japanese patients will be enrolled. From Part III, Asian patients will 
be included.
In December 2019, BI decided to close the recruitment of new patients into Cohort C, based 
on an analysis of the available data from patients enrolled in this cohort. The data showed 
less than expected clinical efficacy for the patient population studied in this indication, and 
the likelihood that the cohort will meet the protocol defined criteria to continue at the planned 
futility analysis was considered very low. This decision did not affect the recruitment of other 
cohorts, the treatment of patients who were already receiving study treatment in Cohort C, or 
the overall benefit risk assessment of the combination therapy of BI 754091 and BI 754111.

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Dose-finding and cohort size will be determined based on the recommendation of the SMC, 
guided by a BLRM with overdose control. An EWOC design will increase the chance of 
treating patients at efficacious doses while reducing the risk of overdosing. This design is
based on practical experience and is an efficient method due to its ability to identify the dose 
with a desired toxicity rate and its allocation of a greater proportion of patients to doses at or 
close to that desired dose (R13-4802; R13-4804; R13-4805). The use of Bayesian models for 
Phase I studies has also been advocated by the European Medicines Agency (EMA) guideline 
on small populations (R07-4856) and by the United States Food and Drug Administration 
(FDA) (R13-4881).
For the expansion part, cancer types which are more common in Asia than Western countries, 
or whose epidemiology is different between Asia and Western countries, will be included, to 
explore the possibilities of further clinical development in these patient populations. Data 
from clinical trials of other anti-PD-1 antibodies suggest that anti-PD-1 treatment have 
clinical activities in these cancer types.
The results from this trial will form the basis for decisions for future studies.
3.3
SELECTION OF TRIAL POPULATION
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been entered. 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the investigator site file (ISF) at the investigational site irrespective of whether 
they have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Part I and II: Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic 
solid tumours
Part III: Patients with advanced and/or metastatic disease of following tumour types:
Cohort A: Patients with gastric/esophagogastric junction cancer, with no prior treatment 
with anti-PD-1/PD-L1 antibody, and who received at least one line of systemic 
medical treatment excluding adjuvant therapy
Cohort B: Patients with esophageal cancer with no prior treatment with anti-PD-1/PD-L1 
antibody, and who received at least one line of systemic medical treatment 
excluding adjuvant therapy
Cohort C: Patients with hepatocellular cancer with no prior treatment with anti-PD-1/PD-L1 
antibody, who received at least one line of systemic medical treatment excluding 
adjuvant therapy, and whose Child-Pugh score is 7 or less
Cohort D: Patients with gastric/esophagogastric junction cancer, esophageal cancer, or 
hepatocellular cancer with a prior treatment with anti-PD-1/PD-L1 antibody
Cohort E:
First line NSCLC patients with wt EGFR and ALK tumours of squamous or 
non-squamous origin.

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Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Of full age (according to local legislation) at the time of signing of the informed consent 
form (ICF)
2. Women of childbearing potential (WOCBP)1 with negative serum pregnancy test at 
screening and men able to father a child, who agree to use highly effective methods of 
birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year 
when used consistently and correctly. A list of contraception methods meeting these 
criteria is provided in the patient information. The requirement of contraception does not 
apply to women of no childbearing potential but they must have an evidence of such at
screening
3. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
4. Patients with measurable lesions according to RECIST v1.1
5. Conditions specific to respective part of the trial:
o
Part I (BI 754091 dose-finding part):

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.

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 28 days prior to the first BI 754091 treatment.
o
Part II (Combination dose-finding part): 

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.

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 28 days prior to the first BI 754091 treatment.
o
Part III (Expansion part): 

Cohort A: Patients with gastric/esophagogastric junction cancer, with no 
prior treatment with anti-PD-1/PD-L1 antibody, and who received at least 
one line of systemic medical treatment excluding adjuvant therapy
                                                
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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
Cohort B: Patients with esophageal cancer with no prior treatment with 
anti-PD-1/PD-L1 antibody, and who received at least one line of systemic 
medical treatment excluding adjuvant therapy

Cohort C: Patients with hepatocellular cancer with no prior treatment with 
anti-PD-1/PD-L1 antibody, who received at least one line of systemic 
medical treatment excluding adjuvant therapy, and whose Child-Pugh 
score is 7 or less

Cohort D: Patients with gastric/esophagogastric junction cancer, 
esophageal cancer, or hepatocellular cancer with a prior treatment with 
anti-PD-1/PD-L1 antibody

Cohort E: First line squamous or non-squamous NSCLC patients:

Without EGFR mutations or ALK rearrangements

PD-L1 expression level <50%

All cohorts: Patients with advanced and/or metastatic disease, with at least 
1 tumour lesion amenable to biopsy, and must be medically fit for biopsy 
at screening as determined by investigator 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.
6. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance status (PS): 0 to 1
at screening
3.3.3
Exclusion criteria
1. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to study entry 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 treatment with study medications in this trial
4. Any investigational or anti-tumour treatment within 4 weeks or 5 half-life periods 
(whichever is shorter) prior to the initiation of trial treatment
5. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria 
for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the 
exception of alopecia and Grade 2 neuropathy due to chemotherapy
6. (Part II and III only) Prior treatment with anti-LAG-3 agents
7. Patients with lung cancer that have epidermal growth factor receptor (EGFR) mutations 
or anaplastic lymphoma kinase (ALK) rearrangements, unless disease has progressed 
following available EGFR or ALK targeted therapy
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 or 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 of 
PD by imaging for at least 4 weeks prior to the first dose of trial treatment, and any

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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 following 
laboratory values:
o
Absolute neutrophil count <1.5 x 109/L (<1500/mm3)
o
Platelet count <100 x 109/L (<100,000/mm3)
o
Haemoglobin <9.0 g/dL
o
Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no 
demonstrable liver lesion(s) (primary or metastases) or >5 times ULN in the 
presence of liver lesion(s)
o
Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver
lesion(s) or >5 times ULN in the presence of liver lesion(s)
o
Total bilirubin >1.5 times ULN, except for patients with Gilbert's syndrome who 
are excluded if total bilirubin >3.0 times ULN or direct bilirubin >1.5 times ULN
o
Serum creatinine (measured by enzymatic assay, Isotope dilution mass 
spectroscopy [IDMS] standardized Jaffe assay, or non-IDMS Jaffe assay) >1.5 
times ULN or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2
(Chronic Kidney Disease Epidemiology [CKD-EPI] Collaboration equation); 
confirmation of eGFR is only required when creatinine is >1.5 X ULN
o
International normalized ratio (INR) (only tested if clinically indicated) >1.5 times 
ULN (if treated with anticoagulants, prolonged INR is acceptable)
11. Any of the following cardiac criteria:
o
Mean resting corrected QT interval (QTc) >470 msec
o
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
o
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
such as heart failure, hypokalaemia, congenital long QT syndrome, family history 
of long QT syndrome or unexplained sudden death under 40 years-of-age, or any
concomitant medication known to prolong the QT interval
o
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 [ECHO], 
multi-gated acquisition scan [MUGA]). 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 (including current) of interstitial lung disease or pneumonitis within the last 5 
years
13. History of severe hypersensitivity reactions to other mAbs
14. History of severe hypersensitivity reactions to the ingredients of study drug
15. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within
4 weeks prior to the first dose of study treatment
16. Active autoimmune disease or a documented history of autoimmune disease, except
vitiligo or resolved childhood asthma/atopy, or asthma well controlled with steroids

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17. Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal
therapy) at start of treatment in this trial
18. Known history of human immunodeficiency virus (HIV) infection. Test results obtained
in routine diagnostics are acceptable if done within 14 days before the informed consent 
date
19. Any of the following laboratory evidence of hepatitis virus infection. Test results 
obtained in routine diagnostics are acceptable if done within 14 days before the informed 
consent date
o
Positive results of hepatitis B surface (HBs) antigen
o
Presence of HBc antibody together with HBV-DNA
o
Presence of hepatitis C RNA 
However, for patients with hepatocellular cancer in Part III Cohorts C and D, patients 
with HBV and/or HCV infection are allowed. Hepatocellular cancer patients in Part III 
Cohorts C and D with HBV infection must be receiving effective antiviral therapy (viral 
load <100 IU/mL)
20. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
him/her an unreliable trial patient, unlikely to complete the trial, or unable to comply with 
the protocol procedures. However, for patients with hepatocellular cancer in Part III 
Cohorts C and D, past chronic alcohol abuse are allowed
21. Women who are pregnant, nursing, or who plan to become pregnant during the trial. 
Women who are nursing can be enrolled if they stop nursing. In this case, the patient 
cannot resume nursing even after discontinuation of study treatment.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole 
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the entered patients in the trial: if possible on tretament, 
or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason 
must be documented in the patient files and case report form (CRF).
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product. Refer to Section 4.2.2.2 for permitted and prohibited concomitant medications.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy). Refer to Section 4.1.4 for AEs that require 
treatment discontinuation.

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
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.

The patient experiences unequivocal PD by RECIST v1.1 and/or iRECIST.

The patient completes 1 year of treatment. If the patient is benefiting clinically at 1 year, 
he/she may continue after a case-by-case review with the sponsor.
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 Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported.
During the dose finding part, patients withdrawn for a reason other than having a DLT or 
patients who miss more than one visit during MTD evaluation period may be replaced after 
discussion in the SMC if the information that needed to be collected during that visit is not 
available and makes the patient non-evaluable for the PK analyses or safety parameters
(including evaluation for DLTs).
Patients who come off trial due to a DLT will not be replaced.
If a patient should become pregnant during the trial, the treatment with BI 754091 and BI 
754111 must immediately be stopped. The patient will be followed up until delivery or 
termination of pregnancy (see Section 5.2.7.9 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.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore,
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk-assessment that could significantly affect the continuation of the trial

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3. Violation of GCP, the trial protocol, or the contract impairing 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 / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.4.3.1
Enrolment stopping rules in case of unacceptable toxicities
All AEs, including serious adverse events (SAEs) and deaths will be carefully analysed by 
the sponsor. Unacceptable toxicity will be defined as: 

Clinically relevant adverse events that are:
o
unexpected considering the mode of action, and are not manifestations of 
underlying disease or background events typical of the trial population 
o
and/or are debilitating, non-reversible, not manageable
o
or lead to a fatal outcome 
where evidence suggests that there was a reasonable possibility that the drug caused 
the adverse event.

Higher than expected frequency or severity of adverse events (such as irAEs) that 
indicates those events occur more frequently or with higher severity in the drug 
treatment group than would be expected in the trial population.
If one or both of the above criteria are met the enrolment to the trial will be stopped to allow 
for in-depth analysis of the safety profile of the study medications. The benefit-risk profile of 
BI 754091 and/or BI 754111 will be re-assessed by the SMC. The outcome of the analysis 
and the recommendations will be shared with all involved regulatory health authorities prior 
to a possible re-start of enrolment. In case the benefit-risk assessment is no longer considered 
to be positive, the trial will be discontinued.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
4.1.1.1
BI 754091
Details of the drug product, BI 754091 are presented in Table 4.1.1.1: 1. Additional details
are presented in the BI 754091 IB and Pharmacy Manual.
Table 4.1.1.1: 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
4.1.1.2
BI 754111
Details of the drug product, BI 754111 are presented in Table 4.1.1.2: 1. Additional details
are presented in the BI 754111 IB and Pharmacy Manual.
Table 4.1.1.2: 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

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4.1.2
Selection of doses in the trial
4.1.2.1
Starting dose of BI 754091
BI 754091 will be tested at a flat starting dose of 240 mg to be administered via infusion 
q3w. In case of DLTs, lower doses may also be explored. The dose-finding will be guided by 
the BLRM, and the final decision will be made by the SMC (see Section 8.7).
The starting dose was selected based on the data obtained in 1381-0001 dose-escalation 
cohorts, where 3 patients each received BI 754091 monotherapy at dose levels of 80, 240, 
and 400 mg and none of them experienced DLT or AESI and MTD was considered not 
reached and the RD was determined to be 240 mg. 
The results of in vitro binding experiments suggest that BI 754091 has at least similar affinity 
to PD-1 as pembrolizumab (n00250922). Therefore, determining the dose based on the 
similarity of pharmacokinetic properties between BI 754091 and pembrolizumab is 
considered appropriate. The dose of pembrolizumab for PD-L1 positive, unresectable, 
advanced or recurrent NSCLC is 200 mg per dose at intervals of 3 weeks, which is similar to 
the starting dose of BI 754091 for Part I of this trial (240 mg). A comparison of the simulated 
pembrolizumab blood concentrations over time under 240 mg q3w dosing based on the 
population PK model (R17-2460) and the actual BI 754091 blood concentrations observed in 
the trial 1381-0001 (under the same dosing schedule) showed observed concentration of BI 
754091 is mostly within the 90% prediction interval of simulated gMean of pembrolizumab. 
Hence BI 754091 240 mg appears to be appropriate and is expected to be effective in Asian
patients. The preliminary results from trial 1381-0001 further showed that the binding of BI 
754091 to the PD-1 receptors was saturated also support that the selected dose of 240mg q3w 
should be adequate.
Generally, antibody drugs, which are intravenously administered, are not metabolised via 
CYPs, and are not substrate of the transporter. Therefore, no differences in PK due to race 
and ethnicity are expected. Notable PK differences between Asian and Western patients have 
not been reported for similar drugs (anti-PD-1 antibodies including nivolumab and 
pembrolizumab). In fact, the dose and administration of similar drugs are comparable in 
Asian and non-Asian patients, which suggests that notable racial difference in PK is not 
expected with BI 754091 and justifies the determination of the starting dose in Asian patients
by extrapolating the results in Western patients.
The exposure in a 13-week repeated dose toxicity study NOAEL (100 mg/kg) in cynomolgus 
monkeys (Cmax: 6210 µg/mL, AUC0-168: 710000 µg/mL h or AUC0-504: 2130000 µg/mL h) 
and the simulated steady state BI 754091 exposure following dosing of 240 mg q3w i.v. in 
humans (Cmax: 110 µg/mL, AUC0-504: 29700 µg/mL h based on predictions of the exploratory 
population pharmacokinetic BI 754091 model) showed the safety margin based on Cmax and 
AUC0-504 to be 56-fold and 72-fold, respectively.

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4.1.2.2
Starting dose of BI 754111
BI 754111 will be tested at a starting dose of 400 mg to be administered via infusion q3w. In 
case of DLTs in 400 mg cohort, lower doses may also be explored. 
The starting dose was selected based on the data obtained in 1381-0002 dose-escalation 
cohorts. By the end of June 2018, BI 754111 was administered at dose range from 4 mg to 
600 mg in combination with BI 754091 240 mg. DLTs were not reported at any dose level 
and the MTD was not reached. 
Table 4.1.2.2: 1
Number of evaluable patients and DLTs in trial 1381-0002 (as of Jun 
2018)
Dose level
BI 754091 dose
BI 754111 dose
Number of 
evaluable patients
Number of 
DLTs
1
240 mg
4 mg
3
0
2
240 mg
20 mg
9
0
3
240 mg
80 mg
9
0
4
240 mg
200 mg
9
0
5
240 mg
400 mg
9
0
6
240 mg
600 mg
9
0
Total
-
-
48
0
4.1.3
Dose-finding scheme
The dose is planned to be tested in cohorts at pre-defined provisional dose levels. The 
provisional dose levels to be assigned to separate cohorts of patients are listed in Table 4.1.3: 
1 and 4.1.3: 2. Intermediate or lower dose levels may be investigated if agreed in the SMC, 
depending on the number of DLTs observed in the trial.
In Part II, increasing doses of BI 754111 will be administered in combination with BI 754091 
at the RD determined in Part I. The dose of BI 754091 may also be titrated based on DLTs 
and the overall safety profile of the combination.

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Table 4.1.3: 1 Example of dose titration in BI 754091 monotherapy dose finding part*
Dose level
Increment from previous 
dose
Proposed dose of BI 754091
-1
-66.6%
80 mg*
0
Starting dose
240 mg
Table 4.1.3: 2 Example of dose titration in combination dose finding part*
Dose level
Increment from previous 
dose
Proposed dose of BI 754111
-1
-50%
200 mg*
0
Starting dose
400 mg
1
50%
600 mg*
2
33.3%
800 mg*
*Actual dose assignments for individual patients will be communicated separately as
determined by the SMC.
When the last patient in each cohort completes Cycle 1, the SMC will evaluate the available 
data. The SMC will review all safety data including, but not limited to, DLTs and all CTCAE 
Version 4.03 Grade ≥2 toxicity data during cycle 1. Updated safety data on other ongoing 
patients, including data beyond cycle 1, will be discussed as well. Based on that, a decision 
on the next dose level to be tested will be made.
4.1.4
Dose modifications and premedications
There will be no dose reductions or escalations of BI 754091 or BI 754111 in any one patient. 
The dose may be delayed for up to 6 weeks because of AEs, following discussion with the 
sponsor.
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 or baseline – exceptions should be discussed and agreed with the 
sponsor) of the AE, 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 irAEs, 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 (unless 
unequivocally attributed to another cause) that do not recover to Grade 1 or less within 12 

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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.
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. 
Symptoms of infusion related reactions may include, but not limited to, flushing, rigors, 
chills, dyspnea, nausea, vomiting, hypotension, hypertension, syncope, pruritus, tachycardia, 
and back pain. 
To reduce the risk of IRRs, patients are to be premedicated with an antihistamine and 
acetaminophen or paracetamol. Premedications should be administered at sufficient time 
prior to initiation of infusion to allow the agents to exert their effect.
In the event of an infusion-related reaction ≤Grade 2, treat the symptoms accordingly with 
antihistamine or corticosteroids if needed, the infusion rate of study drug(s) may be decreased 
by 50% or interrupted until resolution of the event and re-initiated at 50% of the initial rate 
until completion of the infusion. In patients experiencing infusion-related reactions ≤ Grade 
2, subsequent infusions may be administered at 50% of the initial rate. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the study, permanently 
discontinue study drug(s) (see Section 5.2.7.5.3).
4.1.5
Definition of dose-limiting toxicity
DLTs will be recorded throughout the trial. This report should be submitted to the sponsor 
within 24 hours of first knowledge. Only DLTs occurring during cycle 1 will be used for 
MTD determination. All relevant safety information (including DLTs) will be considered 
when selecting the RD.
Previous anti-PD-l mAbs have been associated in the clinical setting with inflammatory 
adverse reactions resulting from increased or excessive immune 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 in Parts I and II, Version 
5 in Part III). Any of the following AEs will be classified as DLTs following review by the 
Investigators and the sponsor, unless unequivocally due to underlying malignancy or an 
extraneous cause.
Haematologic toxicities:

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
Any Grade 5 toxicity

Neutropenia ≥ Grade 4 lasting for >5 days

Febrile neutropenia of any duration (absolute neutrophil count <1.0 X 109 cells/L and 
fever ≥38.5°C)

Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding

Thrombocytopenia of any Grade which requires platelet transfusions

Grade 4 anaemia unexplained by underlying disease

Anaemia of any Grade which requires blood transfusions
Non-haematological toxicities:

AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without initial 
findings of cholestasis (findings consistent with Hy's law or the FDA definition of 
potential DILI)

≥ Grade 4 AST or ALT of any duration

Any ≥ Grade 3 non-haematologic toxicity with the following exceptions:
o
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with immunosuppressive 
therapy within 2 weeks
o
Grade 3 fatigue that persists <7 days
o
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
o
Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated with 
clinical or radiographic evidence of pancreatitis
o
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical intervention
o
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention
o
Alopecia
o
Grade 3 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.
o
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 study 
medication (BI 754091 in Part I, BI 754091 and BI 754111 in Part II and III) on Cycle 2 
Day 1.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria but 
occur after the MTD evaluation period. These, as well as all toxicities, will be monitored 
throughout the trial. If any late immune-related DLT is reported during dose-finding, the 
BLRM will be rerun including the late immune-related DLT, and updated results will be 
reviewed in the SMC meeting to recommend the next dose level and cohort size.

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4.1.6
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 6 patients have been treated at the MTD in each part
4.1.7
Definition of evaluable patient
For decisions on dose escalation, an evaluable patient is defined as a patient who has received 
BI 754091 or BI 754091 plus BI 754111 and either:

has completed cycle 1 without experiencing DLT
OR

has experienced DLT during cycle 1
4.1.8
Method of assigning patients to treatment groups
There will be no randomisation in this trial, as it is a single-arm open-label trial. After 
assessment of all inclusion and exclusion criteria, each eligible patient will be assigned a dose 
of medication available at the time of enrolment.
To determine the dose or doses for subsequent cohorts, the available safety data (including
DLTs, AEs that are not DLTs, and AE information), as well as the recommendations from the
BLRM, will be evaluated by the SMC members.
The SMC must reach a consensus on whether to declare the MTD, escalate the dose any
further, or de-escalate and/or expand recruitment into particular cohorts. Dose-finding of BI 
754091 monotherapy in Part I will continue until the MTD is reached, or RD determined in 
1381-0001 is confirmed. Similarly, dose-finding of BI 754091 and BI 754111 combination in 
Part II will continue until the MTD is reached, or RD determined in 1381-0002 is confirmed.
Part II may still continue for further safety and/or PK evaluation at any dose levels, after the 
start of recruitment in Part III at the recommended dose.
To further characterise the safety (e.g., specific suspected treatment-related AEs) or PK
profiles of BI 754091 monotheraply or BI 754091 plus BI 754111 combination, one or
several doses may be expanded. Dose-finding may be terminated at any time based on
emerging safety concerns without establishing the RD or the MTD.
In the expansion part, all patients will be treated with the schedule and dose determined by 
the assessment of DLTs, available PK, and available biomarker results from the dose finding 
parts of this trial and the data from 1381-0001 and 1381-0002. 
Patient numbers will be assigned as enrolment (screening) occurs.

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4.1.9
Drug assignment and administration of doses for each patient
Patients will be assigned to their doses based on the available toxicity information (including 
DLTs, AEs that are not DLTs, and AE information post MTD evaluation period), PK, and 
anti-tumour activity information, as well as the recommendations from the SMC members 
following the dose decision meeting, please see Section 4.1.2.
BI 754091 and BI 754111 will be assigned to subjects via interactive response technology 
(IRT). BI 754091 and BI 754111 will be diluted and administered via i.v. infusion according 
to the details in the Pharmacy Manual.
Dosing will be sequential when the dose of BI 754111 is less than 80 mg, 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. When the dose of BI 754111 is 80 mg or more, the infusion will be simultaneously 
(infusion duration ~1 hour).
4.1.10
Blinding and procedures for unblinding
Not applicable as this is an 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 (GMP). 
Each site will be provided with an initial shipment of trial drug supply. Re-supply to the sites
will be managed via an IRT system, which will also monitor expiry dates of supplies 
available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.12
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.
If the storage conditions are found to be outside the specified range, the clinical monitor local 
(as provided in the list of contacts) must be contacted immediately.

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4.1.13
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the clinical trial protocol by the institutional review board (IRB) / ethics 
committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. The investigator and/or pharmacist
and/or investigational drug storage manager must maintain records of the product’s delivery 
to the trial site, the inventory at the site, the use by each patient, and the return to the sponsor
or warehouse / drug distribution centre or alternative disposal of unused products. If 
applicable, the sponsor or warehouse / drug distribution centre will maintain records of the 
disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor, the investigator / pharmacist / investigational drug storage manager must verify that 
all unused drug supplies have been returned to sponsor or destroyed on site, and partially 
used drug supplies have been destroyed on site, and that no remaining supplies are in the 
investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used or special emergency procedures to be
followed in this trial.
4.2.2
Concomitant medications
Rescue medications to reverse the action of BI 754091 or BI 754111 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

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indicated for treatment of a related AE has to be reported. If a new anti-cancer treatment is
started, it must be documented in the eCRF.
4.2.2.1
Permitted concomitant medications

If medically feasible, patients taking regular medication for their coexisting disease 
should be maintained on it throughout the trial.

To reduce the risk of IRRs, patients are to be premedicated with an antihistamine and 
acetaminophen or paracetamol. Premedications should be administered at sufficient time 
prior to initiation of infusion to allow the agents to exert their effect. This applies to all 
cycles and all patients except for cycle 1 in the dose-finding part. The patients in the 
dose-finding part should not be treated prior to cycle 1 to avoid masking the emergence 
of DLTs. 

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.
<for Japan> No erythropoietin product is approved in Japan for anaemia associated with 
cancer chemotherapy.

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-finding part of the trial, except during the first cycle as it could interfere with the
DLT evaluation for MTD/RD determination. In the expansion phase (Part III), palliative 
radiotherapy is allowed only for non-target lesions, following discussion with the 
sponsor, provided that the reason for radiotherapy does not reflect PD and does not 
interfere with response assessment. Lesions that have been exposed to radiotherapy are 
no longer evaluable, and may not be included in the assessment of the non-target lesions 
and the overall assessment. These lesions may also not be used for a trial biopsy. Unless 
in emergency situations, the sponsor should be contacted prior to the administration of 
palliative radiotherapy in the expansion phase.

Hepatocellular cancer patients in Part III Cohorts C and D with HBV infection must be 
receiving effective antiviral therapy (viral load <100 IU/mL)
4.2.2.2
Prohibited concomitant medications

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.

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
Immunosuppressive medications including, but not limited to systemic corticosteroids at
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and
tumour necrosis factor-alpha blockers are prohibited. Use of immunosuppressive
medications for the management of investigational product-related AEs or in patients
with contrast allergies is acceptable, and does not necessarily warrant immediate
treatment discontinuation. In addition, use of inhaled, topical, intranasal corticosteroids 
or local steroid injections (e.g., intra-articular injection) is permitted. Temporary uses of
corticosteroids for concurrent illnesses (e.g., food allergies, computed tomography [CT] 
scan contrast hypersensitivity) are acceptable.

Live attenuated vaccines are prohibited during the trial through 30 days after the last 
dose of investigational product.

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.

Prophylactic erythropoietin, prophylactic granulocyte colony stimulating factors, are not 
allowed during the first 3 weeks. Palliative radiotherapy is not allowed during the first 3 
weeks of the dose finding parts.
4.2.3
Restrictions
4.2.3.1
Restrictions on diet and life style
The usual restrictions on diet and life style that were already applicable for a given patient
before entry into the trial, according to his/her medical condition, have to be continued.
4.2.3.2
Restrictions regarding women of childbearing potential 
Due to the advanced stage of disease of Phase I trial patient populations and the high medical
need, women 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 Conference on Harmonisation (ICH) M3 (R2) that result in a low failure rate of
less than 1% per year when used consistently and correctly.
Examples of highly-effective methods of contraception are provided 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.

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Male patients with partners of childbearing potential must agree to use condoms and ensure
their partner is using an additional highly-effective method of birth control, during the trial
and until at least 6 months after the end of the trial treatment.
4.3
TREATMENT COMPLIANCE
BI 754091 and BI 754111 will be administered by i.v. infusion at the sites by the Investigator
and/or trained site personnel, and dosing will be recorded in the eCRF. Therefore, actual
dosing is expected to precisely follow the prescribed drug regimen. Missed or interrupted
doses will be recorded in the eCRF with the associated reasons. The method of collecting
dosing information assures that total exposure can be calculated programmatically taking into
account any missing doses.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Tumour assessments
The tumour response will be evaluated according to RECIST Version 1.1 (R09-0262) and
iRECIST (R17-0923). The overview of iRECIST will be found in Appendix 10.6.
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 ±5 days) for the first 6 months, then every 3 cycles (9 weeks ±5
days) thereafter, and at the EOT visit (if not performed within the previous 4 weeks).
If a patient discontinues trial medication 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).
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 provides an additional 
consent. If a patient is considered to be confirmed progressive disease according to iRECIST 
(iCPD), the patient may still continue to receive treatment if the Investigator and sponsor 
agree that the patient is deriving clinical benefit, and the patient provides an additional 
consent.
Copies of CT/MRI/PET scan data will be collected by the sponsor for later radiomics
assessment. It is planned to explore the potential for enhanced and improved baseline and 
on-treatment markers/ patterns of early efficacy based on comprehensive quantitative CT
metrics, i.e. radiomics features, assessed in standard-of-care medical imaging data.
5.2
ASSESSMENT OF SAFETY
The safety of BI 754091 and BI 754111 will be assessed by a descriptive analysis of
incidence and severity of AEs graded according to CTCAE (Version 4.03 in Parts I and II, 
Version 5 in Part III), 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 will be considered for MTD determination. 
However, all DLTs observed in all treatment cycles will be collected and will be considered 
for determining a RD. The BLRM will be re-run including the DLT information from all 

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cycles. Based on both estimates, the recommended dose for further development will be 
selected. At regular intervals, all available safety data including AEs qualifying as DLTs will 
be submitted to the SMC. The SMC 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, other data including PK will be taken into consideration for 
RD determination.
5.2.1
Physical examination
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.
The physical examination will include measurement of height (screening only) and of body 
weight. Weight will be measured during screening and at each full physical examination (not 
during abbreviated physical examinations).
5.2.2
ECOG performance status
The ECOG PS will be assessed at the times indicated in the Flow Chart.
5.2.3
Vital signs
Vital signs (blood pressure, body temperature, pulse rate, and arterial oxygen saturation
[SpO2] 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. Measurement of 
SpO2 is included in the vital signs check for early detection of pneumonitis.
5.2.4
Safety laboratory parameters
Blood (venous) samples will be collected at the times indicated in the Flow Chart and will be 
analysed by the sites’ local safety laboratories. For Free T3, Troponin I, and venous HCO3, 
these will be measured at a central laboratory if study site cannot measure it locally. With the 
protocol amendment to version 4, Troponin I can be substituted by Troponin T, and HCO3
does not have to be measured if not available at the study site (the central lab will not be used 
for Troponin I and HCO3 after the approval of protocol version 4). 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.

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5.2.4.1
Haematology
Red blood cell count, haemoglobin, haematocrit, mean corpuscular volume, platelets, and 
white blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils) will be measured. White blood cell differentials should be expressed in 
absolute values.
5.2.4.2
Biochemistry
The standard biochemistry panel will consist of glucose, sodium, potassium, chloride, 
calcium, phosphate, venous bicarbonate HCO3 (if the local lab test is available at the study 
site), urea (or blood urea nitrogen [BUN]), creatinine, CPK, AST, ALT, alkaline phosphatase, 
lactate dehydrogenase (LDH), bilirubin (total and direct), total protein, albumin, and uric 
acid. Troponin will be tested according to the times listed in the Flow Chart. The troponin 
measurement should be quantitative analysis and can be either Troponin I or T, according to 
the institutional standard as long as the testing method is consistent. In case of pathological 
CPK, then CPK-MB, additional tropoinin (either I or T), and myoglobin should be reactively 
tested and the findings documented.
A thyroid panel (TSH, free T4, and free T3) will be done at the time of each standard 
biochemistry panel.
HBV, HCV, and HIV testing should be performed at screening unless test results obtained in 
routine diagnostics within 14 days before the informed consent date are available (For 
patients with hepatocellular cancer in Part III Cohorts C and D, if a patient is known to have 
HBV and/or HCV infection, the diagnostic testing for that item does not need to be repeated).
Additionally, amylase and lipase should be analysed in case of symptoms of pancreatitis.
5.2.4.3
Urinalysis
Urine (pH, glucose, erythrocytes, leukocytes, protein, and nitrite) will be analysed 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.
5.2.4.4
Pregnancy test
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.

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5.2.5
Electrocardiogram
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 
must be done after 5 minutes of rest at the time points specified in the Flow Chart, 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. Dated and signed printouts of ECG with findings should be documented in 
patient’s source document.
Following assessment of safety data at the timepoint of interim database lock, it was 
determined that continued ECG monitoring would not be required (see section 6.2.3.5)
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.
5.2.6
Other safety parameters
No assessment planned.
5.2.7
Assessment of adverse events
5.2.7.1
Definitions of adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
5.2.7.2
Definition of adverse reaction
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 

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exposure. Conditions of use outside the marketing authorisation include off-label use, 
overdose, misuse, abuse and medication errors.
5.2.7.3
Definition of serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse.
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
Patients may be hospitalized for administrative reasons during the trial, including 
hospitalization for respite care. These as well as hospitalizations/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 hospitalization/surgical procedure has not 
changed/worsened after signing informed consent)
5.2.7.4
Adverse events considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the duration between discontinuation of the trial medication and must be 
reported as described in 5.2.7.8, subsections “AE Collection” and AE reporting to sponsor 
and timelines.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.

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The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
5.2.7.5
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs as described in Section 5.2.7.8, subsections “AE Collection” 
and AE reporting to sponsor and timelines.
In this trial, DLTs, irAEs as defined in Appendix 10.1, infusion-related AEs, potential DILI 
events, and hepatic injury are AESIs.
5.2.7.5.1
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.
5.2.7.5.2
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. The sponsor has defined a list of irAEs in Table 10.1: 1 that must be 
reported as AESIs. 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.
5.2.7.5.3
Infusion-related reactions
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of study drug(s) may 
be decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate.
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional
standard may be administered prior to subsequent infusions at the discretion of the
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related

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reaction is Grade 3 or higher in severity at any point during the study, treatment with BI 
754091 and/or BI 754111 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
sponsor within 24 hours:

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.
5.2.7.5.4
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 at any point during the trial.
Hepatic injury definition
In patient with normal baseline hepatic function, a hepatic injury is defined by the following 
alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT > 3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
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.

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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 eDC system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the Potential DILI checklist should be 
followed.
5.2.7.6
Severity of adverse events
Part I and II:
The severity of AEs should be classified and recorded in the eCRF according to the CTCAE
Version 4.03.
Part III:
The severity of AEs should be classified and recorded in the eCRF according to the CTCAE
Version 5.
5.2.7.7
Causal relationship of adverse events
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.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. 
pre-existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).

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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 weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.

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).
5.2.7.8
Adverse event collection and reporting
5.2.7.8.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the end of the 30-day safety follow-up 
visit
- all AEs (non-serious and serious) and all AESIs.
•
After the 30-day safety follow-up visit 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 report 
related SAEs and related AESIs of which the investigator may become aware of by any 
means of communication, e.g. phone call. Those AEs should however, not be reported in 
the CRF.
The rules for Adverse Event Reporting exemptions still apply. 

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Figure 5.2.7.8.1: 1
Safety follow-up schema
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):
Worsening of pre-existing conditions other than the underlying disease
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
Screening / Treatment incl. 30-day FU
30-day FU
visit

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5.2.7.9
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
<for Japan only> Pregnancy until 6 months after the last dose of study medication should be 
reported as a drug exposure during pregnancy.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for Studies 
(Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for 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.
5.2.7.10
Exemptions from AE/SAE reporting
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
progression of the underlying malignancy, the event must be reported as an SAE on the SAE
Form and on the eCRF.
Examples of exempted events of PD may be:

Progression of underlying malignancy (PD): if PD is clearly consistent with the 
suspected progression of the underlying malignancy as defined by the respective 
response criteria.

Hospitalisation/procedures due solely to the progression of underlying malignancy (PD)

Clinical symptoms and/or signs of progression (without confirmation by objective 
criteria e.g., imaging, clinical measurement): if the symptom can exclusively be 
determined to be due to the progression/relapse of the underlying malignancy and does 
meet the expected pattern of progression for the disease under study.
Exempted events are reviewed at appropriate intervals.
Lab values meeting the hepatic injury definition as defined in section 5.2.7.5.4 will need to be 
reported as AESI. PD reporting exemption does not apply to hepatic injury. Please follow the 
flowchart below for reporting hepatic injury / potential DILI cases.

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Figure 5.2.7.10: 1
Processing potential DILI cases
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
If data allow, PK parameters of BI 754091 after single and multiple doses of BI 754091
monotherapy in Part I, and PK parameters of BI 754091 and BI 754111 after single and 
multiple doses of combination of BI 754091 and BI 754111 in Part II and III will be 
evaluated as secondary 
 endpoints using non-compartmental analysis methods 
according to BI internal SOP (001-MCS-36-472). 
If deemed necessary, further PK parameters (other than those defined see Sections 2.1.3 and 
2.1.4) might be calculated. Exact date and clock time of drug administration and 
pharmacokinetic sampling will be recorded in the CRFs by the medical personnel. The actual 
sampling times will be used for determination of pharmacokinetic parameters.
5.3.2
Methods of sample collection
For quantification of analyte plasma concentrations, blood will be drawn for BI 754091 (Part 
I) and for both BI 754091 and BI 754111 (Part II and Part III) at the time points listed in 
Flow Chart under PK sampling and specified in PK time schedules in Tables 10.4: 1 and 
10.4: 2 in Appendix 10.4.

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Details on sample characteristics, collection, processing, handling, and shipment are provided
in the Laboratory Manual.
After completion of the trial, plasma samples may be used for further methodological
investigations, e.g., stability testing. However, only data related to the 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.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a PK/pharmacodynamics (PDc) relationship is planned.
Data may be used to develop PK/PDc models by using nonlinear mixed effect modelling
techniques, if feasible. For this purpose, data may also be combined with data from other
trials. Modelling activities will be planned and documented separately according to internal
and external guidelines and SOPs.
5.4
ASSESSMENT OF BIOMARKERS
The study of biomarkers will be mostly hypothesis-generating and will be used to expand our
understanding of the disease and trial drug. The following exploratory biomarkers are
planned to be examined in this trial:

Mechanism-related cytokines (e.g., IL-2, IFN-γ), as well as exploratory immune-related
cytokines during expansion cohorts (see Section 5.4.2.2)

PD-L1, PD-1, LAG-3, MHC-II, CD-8 positive cells in tumour biopsies taken before and
on treatment, if feasible (see Section 5.4.2.3). If enough formalin-fixed and 
paraffinembedded (FFPE) material is available, a gene-expression profile analysis will be 
performed. Also, genomic profiling may be performed on pre-treatment biopsies in order 
to define mutational load (unless a similar analysis has been performed beforehand).

Peripheral blood mononuclear cells (PBMC) will be characterized for the presence of 
individual cell lineages, and subsets of T cells will be further analysed for the expression 
of activation and checkpoint marker expression (PBMC [extract]).

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
In a complementary analysis to the above, PBMC (blood), myeloid-derived suppressor 
cells (MDSC), PD1+ and LAG3+ T-cells, PD-L1+ monocytes, as well as regulatory 
T-cells and activated T-effector memory cells and activated dendritic cells will be 
measured (see Section 5.4.2.1)  
As medical knowledge in this field is constantly evolving, other tissue/blood biomarkers that
may become relevant as predictive markers of treatment response may also be explored via
available tissues/blood or acquisition of additional tumour tissues/blood. The list of
biomarkers planned to be studied during the trial may change based on new information in
the literature or early analyses. The results of biomarker analysis will not be disclosed to 
patients because they are exploratory analysis which is not validated for diagnostic use.
5.4.1
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 III dose-expansion portion of the trial. In addition, 
optional biopsies could be taken after treatment discontinuation, if possible. All samples must 
be adequately labelled by the trial site personnel. Details about tumour tissue and blood 
sample collection, plasma/serum preparation, required tubes, labelling of tubes, storage and 
shipment (frequency and addresses) will be provided in the ISF.

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5.4.3
Biobanking
Participation in biobanking is voluntary and not a prerequisite for participation in the trial.
Biobanking will be realized only after a separate biobanking informed consent has been given
in accordance with local ethical and regulatory requirements. Banked samples may be
analysed in the future for scientific evaluations or to further, for example, the mechanistic

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understanding of drug effects and/or to identify genetic or other factors associated with
response to therapy or the risk of adverse drug reactions.
Measures are in place to comply with the applicable rules for the collection, biobanking and
future use of biological samples and clinical data, in particular:

Sample and data usage has to be in accordance with the separate biobanking informed
consent.

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples
collected in clinical trials.

An appropriate sample and data management system, including an audit trail for clinical 
data and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report)
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF.
The leftovers of the following biomarker samples as specified in Section 5.4 (‘Assessment of 
Biomarkers’) will be banked:

FFPE blocks of pre- and on-treatment biopsies.
The samples for biobanking will be stored at Boehringer Ingelheim at room temperature for 
maximum 30 years after the end of the clinical trial. If a patient withdraws the consent for 
biobanking, the samples will be destroyed. However, the results that have been obtained
before the withdraw of consent will not be discarded.
5.5
OTHER ASSESSMENTS
5.5.1
Plasma sampling for anti-drug antibodies (ADAs)
All patients: for ADA assessments, the specified blood volume will be drawn into 
blood-drawing tubes at the time points listed in Flow Chart, and Tables 10.4: 1 and 10.4: 2 in 
Appendix 10.4.
Details on sample characteristics, processing, handling, and shipment are provided in the
Laboratory Manual.
After completion of the trial, plasma samples may be used for further methodological
investigations, e.g., stability testing. However, only data related to the ADAs will be
generated by these additional investigations. The trial samples will be discarded after
completion of the additional investigations, but not later than 5 years after the final trial
report has been signed.

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Note that for some disease indications, it may be necessary to use plasma samples collected
prior to administration of study treatments in order to assess the performance of the ADA
assay.
5.6
APPROPRIATENESS OF MEASUREMENTS
All assessments except for iRECIST have been planned in accordance with traditional 
oncology Phase I trial methodology.
iRECIST is a new guideline for response assessment and still to be validated, so this 
guideline will be used as an exploratory efficacy assessment in this trial.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients that have met 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 Flow Chart. If a patient misses a scheduled 
visit, and reports to the Investigator between the missed visit and the next scheduled visit, the 
assessments for the missed visit must be done with the actual date and the reason must be 
given for the delayed visit. 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 BI 754091 or 
the combination of BI 754091 plus BI 754111, an EOT visit must occur as soon as possible 
(preferably within 7 days). After the EOT visit, the patient must undergo a follow-up 
evaluation 30 (+2) days after EOT.
Additional follow-up visits for progression after the 30-day safety follow-up visit will only be 
performed in Part III for patients who did not progress on treatment. The follow-up visits for 
progression will be performed once every 12 weeks at least (in person or 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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The procedures required at each trial visit in all portions of the trial are presented in the Flow 
Chart of this protocol. The key procedures required include:

PK samples throughout the trial

Reporting of all AEs occurring after the ICF has been signed

Baseline and on-treatment blood samplings for 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 study medications 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 a period of 28 days (period within the trial and before the
first administration of study medication). For the detailed description of the tests to be 
performed during this period and their timing, please refer to the Flow Chart.
6.2.1.1
Baseline Conditions
Demographics (sex, birth date, race, and ethnicity where allowed), information on tobacco
and alcohol use, and baseline conditions will be collected during the screening visit.
6.2.1.2
Medical History
6.2.1.2.1
Medical history of cancer
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumour site will 
be reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumour, (lymph) 
node, and metastasis (TNM) classification will be provided as obtained at diagnosis and at 
trial screening. Previous surgeries will be reported.
Previously administered chemotherapy, tyrosine kinase inhibitor treatment, vaccine therapy, 
antibodies therapy, immune therapy, and hormone therapy will be reported, including start 
and end dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
lines of treatment will be recorded, if known.
Baseline information relevant to the disease history such as PD-L1 expression level, 
microsatellite instability (MSI), and tumour mutation burden (TMB) information will be 
collected in eCRF where available.
6.2.1.2.2
Other medical history
Past diseases and/or concomitant diagnoses relevant to patient's safety during the trial as 
judged by the Investigator will be recorded in eCRF.
6.2.1.3
Concomitant medications
Past medications relevant to patient's safety during the trial as judged by the Investigator will 
be recorded in eCRF. From the date of signature of the ICF, all concomitant medications will 
be recorded (see Section 4.2.2 for details on concomitant medications).

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6.2.2
Treatment period(s)
Please refer to the Flow Chart for a detailed presentation of each visit during the treatment
period.
6.2.3
Follow up period and trial completion
6.2.3.1
End-of-treatment visit
The EOT visit will be performed as soon as possible but no later than 7 days after permanent 
discontinuation of the trial medication for any reason or e.g. when the Investigator decided 
with the patient to permanently discontinue the trial medication or became aware that the trial 
medication had been terminated.
The assessments of the EOT visit will then be performed instead of at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of EOT, unless it has been done within the past 4 weeks.
6.2.3.2
30-day safety follow-up visit
The safety follow-up visit is performed 30 (+7) days after the EOT visit. The information 
collected at this visit must include all new AEs that occurred after the EOT visit, and a 
follow-up of AEs ongoing at EOT.
A patient will be considered as having completed the trial if he/she discontinues because of
PD and has performed the safety follow-up visit 30 days after EOT, or was lost to follow up,
or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for any 
other reason, he/she will be considered as withdrawn.
6.2.3.3
Follow up visits for PFS (extended follow-up period)
Additional follow-up visits for PFS after the 30-day safety follow-up visit will only be 
performed for patients in Part III who did not progress on treatment. These will be performed 
once every 12 weeks at least (by telephone or in person) until PD.
The follow-up period for PFS will end at the earliest if one of the following events is met:

Disease progression

Start of a new anti–cancer therapy

Death

Withdrawal of consent

Lost to follow-up

End of whole trial as specified in Section 8.6

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The following will be obtained and/or performed during the follow-up visits for PFS.

Date of contact

For each reportable serious adverse event / AESI, the investigator should provide the 
information with regard to concomitant medication and the medication administered 
to treat the adverse events on the appropriate CRF pages and the SAE form including 
trade name, indication and dates of administration

Treatment and date with any subsequent anti-cancer therapy (including surgery and 
radiotherapy) including the name and type of the anti-cancer drug and/or best 
supportive care (if applicable)

Outcome (date of and reason for death [if applicable], in case the patient had PD the 
actual date of PD shall be recorded)
6.2.3.4
Follow up visits for overall survival (OS)
Additional follow-up visits after the 30-day safety follow-up visit will be performed for 
patients in Part III Cohort E. These will be performed once every 12 weeks at least (by 
telephone or in person) on the same schedule as PFS follow-up visits until death, loss to 
follow-up, or end of the whole trial as specified in Section 3.3.4.3. 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.
6.2.3.5
Study procedures modification after an interim database lock
After an interim database lock (planned in year 2021), the following study procedures do not 
need to be performed:

12-lead ECG (could be performed if clinically indicated with significant abnormalities 
recorded as AEs)

Blood samples for Anti-Drug Antibodies

PK blood samples

Blood samples and extraction of PBMC for biomarkers (PBMC [extract])

Plasma samples for biomarkers, and biopsy

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
7.1.1
Statistical design – Part I (BI 754091 monotherapy dose finding part)
Part I of the trial will be designed as an open label study. The objective of the design is to 
determine the MTD defined as the highest dose with less than 25% risk of the true DLT rate 
being equal or above 0.33 (EWOC criterion). The part I dose-finding will be guided by a 
Bayesian 2-parameter logistic regression model with overdose control (R13-4806; 
R13-4803).
The model is given as follows:
logit(πd) = log(α) + β*log(d/d*), 
where logit(π) = log(π/(1-π)).
πd represents the probability of having a DLT in the MTD evaluation period at dose d, d* = 
400 mg is the reference dose, allowing for the interpretation of α as the odds of a DLT at dose 
d*, and θ = (log(α), log(β)) with α, β > 0 is the parameter vector of the model.
The estimated probability of a DLT at each dose level from the model will be summarized 
using the following intervals:
Underdosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM-recommended dose for the next cohort is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the doses 
fulfilling EWOC. Applying the EWOC criterion it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will exceed 0.33.
The MTD may be considered reached if one of the following criteria is fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.5, OR
2.
At least 6 patients have been treated at the MTD in each part
The SMC may recommend stopping the dose finding phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm this MTD estimate. If no DLT is 
observed at a dose of which the efficacy is considered sufficient, the SMC may decide to 
include additional number of patients at this dose level and to declare this dose as the dose 
recommended for further testing.
Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified.

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The prior distribution for θ will be specified as a mixture of two bivariate normal 
distributions, 
f(θ) = a1f1(θ) + a2f2(θ)
with
ai, i = 1, 2 the prior mixture weights (a1+ a2 = 1)
and
fi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Prior derivation:
To determine the prior distribution for θ, a meta-analytic predictive (MAP) approach will be 
used. Toxicity information on BI 754091 from the 1381-0001 dose-finding part is available. 
Exact details on the derivation of the prior distributions and on the evaluation of the model 
using hypothetical data scenarios and operating characteristics are provided in the statistical 
appendix, a brief description is given here. 
The historical data for 1381-0001 phase Ia as of 01 Jun 2017 can be found in Table 7.1.1: 1.
Table 7.1.1: 1 Historical data for BI 754091
Study
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
1381-0001(phase Ia)
80 mg
0/3
240 mg
0/3
400 mg
0/3
The following steps were performed to derive the prior distribution for θ:
-
The MAP prior was derived using the information in Table 7.1.1: 1 allowing for 
moderate to substantial between-trial heterogeneity. This mixture component was 
assigned 90% mixture weight.
-
A second, weakly informative component was added with 10% mixture weight.
The prior distributions are given in Table 7.1.1: 2. The corresponding prior probabilities of a 
DLT at different doses and the corresponding probability of underdosing, targeted dosing, 
and overdosing are shown in Table 7.1.1: 3. 

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Table 7.1.1: 2 Prior distribution
Parameter
Means, standard deviations, 
correlation
Mixture weight
θ: component 1
(-1.553, 0.269), (1.002, 
1.025), 0.1107
0.9
θ: component 2
(0.1, 0.6), (2,1), 0
0.1
Table 7.1.1: 3 Prior probabilities of DLTs
Dose
Probability of true DLT rate in
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
80 mg
0.848
0.076
0.076
0.096
0.185
0.000
0.026
0.809
240 mg
0.687
0.182
0.132
0.164
0.206
0.002
0.090
0.883
400 mg
0.424
0.319
0.257
0.257
0.216
0.031
0.190
0.916
The prior may be updated once the trial has started in case new data that can be used will be 
available. The prior that is used for each BLRM analysis for the SMC meetings will be 
documented in the SMC minutes, the prior used for the final analysis will be documented in 
the Trial Statistical Analysis Plan (TSAP).
7.1.2
Statistical design – Part II (BI 754091 and BI 754111 combination dose 
finding)
Part II of the trial will be performed as an open label single arm study. The primary objective 
of the design is also to determine the MTD in Japanese patients of BI 754091 in combination 
with BI 754111. To determine the MTD, patients are entered sequentially into escalating dose 
cohorts. The dose-finding will be guided by a Bayesian 5-parameter logistic regression model 
with overdose control. The model is defined as follows. Let π1,d1 be the probability of 
having a DLT when giving dose d1 of BI 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* and d2* are set for BI 754091 and 
BI 754111, respectively.

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Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination of dose d1, d2 is obtained as 
π012,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds
odds(π012,d1,d2)= π012,d1,d2 /(1- π012,d1,d2)
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 
between BI 754091 and BI 754111, a dose-dependent interaction term -∞<η<∞ is introduced 
to the model by the following definition:
odds(π12,d1,d2) = odds(π012,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the variable describing the observed number of DLTs from nd1,d2 patients 
at the dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
The prior distributions for θ1 and θ2 will be specified as mixtures of three multivariate normal 
distributions, i.e.
f(θk) = a1,k f1(θk) + a2,k f2(θk) + a3,k f3(θk)  
with
a1,k, a2,k the prior mixture weights, k=1,2,3 and 
fi(θk) = MVN(μik, Σik) (k=1,2,3),
the multivariate normal distribution of the i-th component with mean vector μik and 
covariance matrix Σik, where 
Σ = 
2 ,11
 ,11 ,22
 ,11 ,22
2 ,22

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
A 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 for the next cohort is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the doses 
fulfilling EWOC. Applying the EWOC criterion it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will exceed 0.33.

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As described The MTD may be considered to be reached if one of the following criteria is 
fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of 
the MTD is above 0.5, OR
2.
At least 6 patients have been treated in the study, of which at least 6 at the MTD.
The prior distributions for θ1 and θ2 are modelled as mixtures of three multivariate normal 
distributions.
Prior for combination in 1381-0004 to be derived is a mixture with 3 components. One is a 
weakly-informative one with a weight of 10%. Second one uses only the mono data from 
PD1 with a weight of 30% (based on MAP). Third one uses all available data based on the 
posterior of this approach (weight of 60%, mono is used via MAP, combo is actual data).
The following information is currently available.
•
Updated mono data for PD1 from 1381-0001
•
Updated mono data for PD1 from part I of 1381-0004
•
Updated combo data for PD1/LAG3 from 1381-0002
Table 7.1.2: 1
Historical data from 1381-0001 and part I of 1381-0004 as of 06 Jul 2018
Dose BI 754091 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
80
3
0
240
40
0
400
3
0
Table 7.1.2: 2
Historical data from 1381-0002 as of 06 Jul 2018
Dose BI 754091 (mg) / BI 
754111 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
240 / 4
3
0
240 / 20
9
0
240 / 80
9
0
240 / 200
9
0
240 / 400
9
0
240 / 600
9
0
Prior probability is calculated based on the Table 7.1.2: 1 and Table 7.1.2: 2.

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Table 7.1.2: 3
Derivation of weakly informative prior distributions both PD-1 and LAG-3
Parameter
Prior distributions
Means, standard deviations, 
correlation
Mixture weight
log(α1), log(β1): component 1
-4.855, 1.062, 2, 1, 0
0.90
log(α1), log(β1): component 2
-0.578, 0.028, 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
Table 7.1.2: 4
Derivation of prior distributions based on PD-1 mono data (1381-0001) for 
component 1 + weakly informative for the others
Parameter
Prior distributions
Means, standard deviations, 
correlation
Mixture weight
log(α1), log(β1): component 1
-3.749, -0.13, 0.758, 0.819, -0.129
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
Table 7.1.2: 5
Derivation of posterior distributions based on PD-1/LAG-3 combo data 
(1381-0002) + prior distribution obtained in step 2
Parameter
Posterior distributions
Means, standard deviations, correlation
log(α1), log(β1) 
-4.148, -0.145, 0.707, 0.781, -0.171
log(α2), log(β2) 
-4.023, -0.812, 1.292, 0.984, 0.043
η
-0.665, 0.523, n/a

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Table 7.1.2: 6
Summary of components of mixture prior distribution with their 
corresponding weights
Parameter
Obtained 
from
Prior distributions
Means, standard deviations, 
correlation
Mixture 
weight
log(α1), log(β1): 
component 1
Step1
-4.439, 0.983, 2.383, 1.050, 
-0.182
0.10
log(α1), log(β1): 
component 2
Step2
-3.565, -0.047, 1.119, 0.863, 
0.024
0.30
log(α1), log(β1): 
component 3
Step3
-4.148, -0.145, 0.707, 0.781, 
-0.171
0.60
log(α2), log(β2): 
component 1
Step1
-1.431,-0.774,
2.003,1.099,-0.037
0.10
log(α2), log(β2): 
component 2
Step2
-1.431, -0.774, 2.003, 1.099, 
-0.037
0.30
log(α2), log(β2): 
component 3
Step3
-4.023, -0.812, 1.292, 0.984, 
0.043
0.60
η: component 1
Step1
-0.011, 1.125, n/a
0.10
η: component 2
Step2
0.093, 0.71, n/a
0.30
η: component 3
Step3
-0.665, 0.523, n/a
0.60
The corresponding prior probabilities of a DLT at different doses and the corresponding 
probability of underdosing, targeted dosing, and overdosing are shown in Table 7.1.2: 7.
Table 7.1.2: 7
Prior probabilities of DLTs
Dose 
(mg)
Dose 
(mg)
Probability of true DLT rate in
Descriptive statistics
BI 
754091
BI 
754111
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
SD
240
4
0.858
0.074
0.068
0.092
0.152
240
20
0.827
0.087
0.086
0.108
0.169
240
80
0.787
0.101
0.112
0.126
0.188
240
200
0.743
0.116
0.141
0.146
0.21
240
400
0.695
0.115
0.19
0.175
0.252
240
600
0.677
0.102
0.221
0.198
0.289
240
800
0.671
0.087
0.242
0.214
0.316

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7.1.3
Statistical design – Part III (expansion)
Part III (dose expansion) of the trial will be designed as open-label. 155 patients with 
advanced disease of selected tumour types (Section 3.3.2) will be enrolled. 
The analyses of the safety and efficacy for part III will be descriptive and exploratory in 
nature.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical test will be 
performed.
7.3
PLANNED ANALYSES
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
7.3.1.1
Primary endpoint analyses for Part I and Part II
In order to identify the MTD, the number of patients with DLTs during the MTD evaluation 
period of Part I and Part II at each dose level must be presented. Patients who discontinue 
during the first treatment course for reasons other than DLTs will be excluded from the 
determination of MTD. 
In addition, the number of patients with DLTs that occurred during the entire treatment 
period will be also summarised.
7.3.1.2
Primary endpoint analyses for Part III
The primary endpoint for Part III 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 
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.

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7.3.2
Secondary endpoint analyses
7.3.2.1
Secondary endpoint analyses for Part I and Part II
Objective response will be analysed in terms of 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-Peason method.
Detailes on the statistical inference for PK parameters, e.g., dose proportionality using Cmax
and AUC0-504 of BI 754111 in Part II in case of more than 3 dose level tested, will be 
specified in the TSAP.
Analyses of PK parameters, i.e., Cmax and AUC0-504 will be described in Section 7.3.5. More 
detail will be provided in TSAP.
7.3.2.2
Secondary endpoint analyses for Part III
Duration of response – for all patients with an OR, the duration of OR will be calculated as 
follows:
For patients with PD or death:
•
Duration of response [days] = date of outcome – date of first assessment indicating OR + 
1
For patients without disease progression or death:
•
Duration of response (censored) [days] = date of outcome – date of first assessment 
indicating OR + 1
The consoring 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.
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.
7.3.5
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 30 days after the last dose of trial medication, will be assigned to the on-treatment period 
for evaluation. Statistical analysis and reporting of adverse events will concentrate on 

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treatment-emergent adverse events, i.e. all adverse events occurring between start of 
treatment and end of the residual effect period. Adverse events that start before first drug 
intake and deteriorate under treatment will also be considered as ‘treatment-emergent’.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The pharmacokinetic parameters listed in Sections 2.1.3 and 2.1.4 will be calculated 
according to the relevant SOP (001-MCS-36-472). Pharmacokinetic analyses will be
performed using validated software programs, normally. Phoenix Winnonlin (Pharsight®)
with applications validated will be used for the respective purpose. Graphs and tables will be 
generated using validated customised SAS® macros or appropriate graphic software. A 
reference to the software used, e.g., name, will be indicated in the Clinical Trial Report 
(CTR).
The subject set for the evaluation 
 will include all treated patients 
(Treated set). 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
Further details on analysis will be described in the TSAP

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7.4
INTERIM ANALYSES
The sponsor will continuously monitor the safety. The dose escalation design foresees that 
the sponsor and the SMC perform regular safety evaluations. These evaluations will be 
unblinded to dose.
No formal interim analysis of PK data is planned. However, exploratory analyses of PK will 
be done during the dose finding part (Part I and Part II) and may also be done during the 
expansion part (Part III), if considered reasonable exploratory PK analyses will be based on 
planned sampling times. 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 deemed appropriate, an interim futility analysis will be performed for each cohort in part 
III. Until any decision from the futility analysis is done, the enrolment of next patient will not 
be stopped. The two-stage design is planned to stop further recruitment of patient if the 
defined efficacy boundary (see Table 7.7.2: 1) is not met at the first stage.
The interim analyses for part III will be conducted when:
•
After the 17th patients has completed the third on-treatment imaging assessment 
(i.e. end of cycle 6).
•
If the 17th patient discontinues earlier than the third on-treatment imaging, the 
interim futility analysis will be triggered at approximately 4 months after the 
first administration of the 17th patient.
For cohort E, data from 1381-0002 will 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.
7.5
HANDLING OF MISSING DATA
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 “Handling of missing and incomplete AE dates”)
7.5.1
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP
(001-MCS-36-472).

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Drug concentration data identified with no sample available (NOS), no valid result (NOR), 
not analysed (NOA), or below the limit of quantification (BLQ) will be displayed as such and 
not replaced by zero at any time point (this rule also applies also to the lag phase, including 
the predose values). 
7.5.2
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ will 
be set to zero. All other BLQ values of the profile will be ignored. The lag phase is defined as 
the period between time zero and the first time point with a concentration above the 
quantification limit. 
7.6
RANDOMISATION
No randomisation will be performed. Patients will be assigned to escalating dose groups by 
order of admission into the trial.
7.7
DETERMINATION OF SAMPLE SIZE
7.7.1
Determination of sample size for Part I and Part II
For Part I and Part II, no formal statistical power calculations of sample size were performed. 
A minimum of 6 and up to approximately 12 paients for Part I are expected. A minimum of 
approximately 12 and up to approximately 18 patients for Part II are expected. Fewer or more 
patients might be needed based on the recommendation of the SMC and the actual number of 
cohorts tested.
7.7.2
Determination of sample size for Part III
For Part III, below cohorts are assumed.
Cohort A: Patients with gastric/esophagogastric junction cancer, with no prior treatment 
with anti-PD-1/PD-L1 antibody, and who received at least one line of systemic 
medical treatment excluding adjuvant therapy
Cohort B: Patients with esophageal cancer with no prior treatment with anti-PD-1/PD-L1 
antibody, and who received at least one line of systemic medical treatment 
excluding adjuvant therapy
Cohort C: Patients with hepatocellular cancer with no prior treatment with anti-PD-1/PD-L1 
antibody, who received at least one line of systemic medical treatment excluding 
adjuvant therapy, and whose Child-Pugh score is 7 or less

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Cohort D: Patients with gastric/esophagogastric junction cancer, esophageal cancer, or 
hepatocellular cancer with a prior treatment with anti-PD-1/PD-L1 antibody
Cohort E:
Patients with first-line squamous or non-squamous NSCLC patients without EGFR 
mutations or ALK rearrangements and PD-L1 expression level < 50%
For cohort A, around 10% ORR with anti-PD-1 antibody monotherapy is assumed. In 
ONO-4538-12 (R17-3846) which is a randomized phase III trial of Nivolumab in Asian 
patients with advanced gastric or esophagogastric junction cancer who failed second or later 
line chemotherapy, the ORR in Nivolmab group was 11.2% [95%CI, 7.7-15.6] (N=330). In
KEYNOTE-059 (R17-3847) which is a phase II trial with Pembrolizumab in patients with 
advanced gastric or esophagogastric junction adenocarcinoma, the ORR in cohort 1 
(Pembrolizumab monotherapy in previously treated patients) was 11.2% [95%CI, 7.6-15.7]
(N=259). 
Based on above result, the futility boundary was set for cohort A as 15% at planned interim 
futility analysis timing. Assuming the underlying ORR of 35%, the probability of observing 
<3 responders out of 17 and stopping at interim is 3%, and the probability of observing 
>=25% ORR at final analysis 90%. If the underlying ORR is 10%, the probability of stopping 
early is 77%, and the false positive probability of observing >=25% ORR at final analysis is 
1%.
For cohort B, around 15% ORR with anti-PD-1 antibody monotherapy is assumed. In
ONO-4538-07 (R17-3828) which is an open label phase II trial of Nivolumab in Japanese 
patients with esophageal squamous-cell carcinoma, the ORR by central review was 17% 
[95%CI, 10-28] (N=64) and the ORR by investigator assessment was 22% [95%CI, 14-33]
(N=64). In KEYNOTE-028 (R17-3849) which is a phase Ib study of Pembrolizumab in
PD-L1 positive advanced solid tumour, the ORR result in esophageal cancer cohort was
30.4% [95%CI, 13.2-52.9] (N=23). In KEYNOTE-180 (R19-0167) which is a phase II study 
of Pembrolizumab in patients with metastatic esophageal cancer progressing after at least 2 
lines of prior therapy was 9.9% [95%CI, 5.2-16.7] (N=121).
Based on above result, the futility boundary was set for cohort B as 20% at planned interim 
futility analysis timing. Assuming the underlying ORR of 45%, the probability of observing 
<4 responders out of 17 and stopping at interim is 2%, and the probability of observing 
>=40% ORR at final analysis 77%. If the underlying ORR is 15%, the probability of stopping 
early is 76%, and the false positive probability of observing >=40% ORR at final analysis is 
0%.
For cohort C, around 20% ORR with anti-PD-1 andibody monotherapy is assumed. In 
Checkmate-040 (R17-3829) which is an open label phase I/II trial of Nivolumab in patients 
with advanced hepatocellular carcinoma, the ORR was 20% [95%CI, 15-26] (N=50) in dose 
expansion phase and 15% [95% CI, 6-28] (N=10) in the dose escalation phase. In 
KEYNOTE-224 (R19-0168) which is a phase 2 study of Pembrolizumab in patients with 
advanced hepatocellular carcinoma previously treated with sorafenib , the ORR was 17% 
[95% CI, 11-26] (N=104).
Based on above result, the futility boundary was for cohort C as 20% at planned interim 
futility analysis timing. Assuming the underlying ORR of 40%, the probability of observing 
<4 responders out of 17 and stopping at interim is 5%, and the probability of observing 
>=30% ORR at final analysis 87%. If the underlying ORR is 15%, the probability of stopping 

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early is 76%, and the false positive probability of observing >=30% ORR at final analysis is 
1%.
For cohort D, there is no literature available for the target patients. As there are no treatments 
of proven efficacy for this population, it is assumed around 5% ORR.
Based on above result, the futility boundary was for cohort D as 10% at planned interim 
futility analysis timing. Assuming the underlying ORR of 30%, the probability of observing 
<2 responders out of 17 and stopping at interim is 2%, and the probability of observing 
>=20% ORR at final analysis 93%. If the underlying ORR is 5%, the probability of stopping 
early is 80%, and the false positive probability of observing >=20% ORR at final analysis is 
0%.
For cohort E, around 20% ORR with antibody monotherapy is assumed. In Keynote-042
(R20-0754) which is randomised, open-label phase 3 trial of Pembrolizumab in patients with 
previously untreated locally advanced or metastatic non-small cell lung cancer without a 
sensitising EGFR mutation or ALK translocation, the ORR in the Pembrolizumab group was 
118 pts, 39%[95%CI, 34-45](N=299) in the PD-L1 tumour proportion score of 50% or greater 
and 174 pts, 27%[95%CI, 24-31](N=637) in the PD-L1 tumour proportion score of 1% or 
greater. Based on the results, the ORR in the pembrolizumab group in the PD-L1 tumour 
proportion score of 1% to 50% was 17% (56 pts/338 pts).
In part III, a total of around 155 patients will be enrolled and allocated to 5 cohorts. The 
sample size of each cohort is planned around 35 patients for cohort A to D. For cohort E, the 
30 patients is the maximum target sample size.
Table 7.7.2: 1 shows the early stopping criterion and probability for the two-stage approach. 
It has been calculated that with an earlier interim point, the probabilities of false early 
stopping or observing a false positive/negative result at the final analysis will be too high. 
With a later interim point, the false positive, false negative and false early stopping 
probabilities will be improved, but the scale of improvement is not that meaningful.
Table 7.7.2: 1 Early stopping criteria and probabilities for the two-stage approach for part III
Assumed 
underlying 
ORR
Total 
sample 
size
Stage 1 
sample 
size
Early 
stopping 
criterion 
(observed 
ORR)
Early 
stopping 
prob.*
Observed 
ORR at 
final
Probabilit
y of 
observed 
ORR at 
final**
Cohort A
10%
35
17
<15%(< 3 
out of 17)
77%
>=25%(>
= 9 out of 
35)
1%
15%
35
17
<15%(< 3 
out of 17)
53%
>=25%(>
= 9 out of 
35)
6%

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20%
35
17
<15%(< 3 
out of 17)
31%
>=25%(>
= 9 out of 
35)
24%
25%
35
17
<15%(< 3 
out of 17)
17%
>=25%(>
= 9 out of 
35)
50%
30%
35
17
<15%(< 3 
out of 17)
8%
>=25%(>
= 9 out of 
35)
74%
35%
35
17
<15%(< 3 
out of 17)
3%
>=25%(>
= 9 out of 
35)
90%
Cohort B
15%
35
17
<20%(< 4 
out of 17)
76%
>=40%(>
= 14 out of 
35)
0%
20%
35
17
<20%(< 4 
out of 17)
56%
>=40%(>
= 14 out of 
35)
1%
25%
35
17
<20%(< 4 
out of 17)
36%
>=40%(>
= 14 out of 
35)
3%
30%
35
17
<20%(< 4 
out of 17)
20%
>=40%(>
= 14 out of 
35)
13%
35%
35
17
<20%(< 4 
out of 17)
11%
>=40%(>
= 14 out of 
35)
32%
40%
35
17
<20%(< 4 
out of 17)
5%
>=40%(>
= 14 out of 
35)
55%
45%
35
17
<20%(< 4 
out of 17)
2%
>=40%(>
= 14 out of 
35)
77%
Cohort C
15%
35
17
<20%(< 4 
out of 17)
76%
>=30%(>
= 11 out of 
35)
1%
20%
35
17
<20%(< 4 
out of 17)
56%
>=30%(>
= 11 out of 
7%

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35)
25%
35
17
<20%(< 4 
out of 17)
36%
>=30%(>
= 11 out of 
35)
23%
30%
35
17
<20%(< 4
out of 17)
20%
>=30%(>
= 11 out of 
35)
46%
35%
35
17
<20%(< 4 
out of 17)
11%
>=30%(>
= 11 out of 
35)
70%
40%
35
17
<20%(< 4 
out of 17)
5%
>=30%(>
= 11 out of 
35)
87%
Cohort D
5%
35
17
<10%(< 2 
out of 17)
80%
>=20%(>
= 7 out of 
35)
0%
10%
35
17
<10%(< 2 
out of 17)
49%
>=20%(>
= 7 out of 
35)
5%
15%
35
17
<10%(< 2 
out of 17)
25%
>=20%(>
= 7 out of 
35)
25%
20%
35
17
<10%(< 2 
out of 17)
12%
>=20%(>
= 7 out of 
35)
55%
25%
35
17
<10%(< 2 
out of 17)
5%
>=20%(>
= 7 out of 
35)
79%
30%
35
17
<10%(< 2 
out of 17)
2%
>=20%(>
= 7 out of 
35)
93%
Cohort E#
15%
30
17
<20%(< 4 
out of 17)
76%
>=35%(>
= 11 out of 
30)
0%
20%
30
17
<20%(< 4 
out of 17)
56%
>=35%(>
= 11 out of 
30)
2%

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25%
30
17
<20%(< 4 
out of 17)
36%
>=35%(>
= 11 out of 
30)
10%
30%
30
17
<20%(< 4 
out of 17)
20%
>=35%(>
= 11 out of 
30)
26%
35%
30
17
<20%(< 4 
out of 17)
11%
>=35%(>
= 11 out of 
30)
48%
40%
30
17
<20%(< 4 
out of 17)
5%
>=35%(>
= 11 out of 
30)
70%
*the probability is stopping due to meeting the futility boundary at interim analysis.
**the probability is not meeting the futility boundary at interim analysis and meeting the 
observed ORR specified at final analysis.
#the futility analysis will be done with 1381.2 data, if conduct.

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

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The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.13.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s Clinical Research Associate (CRA) or auditor must be 
granted access to the original patient file (see Section 8.3.2). The investigator must ensure 
that all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 

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number) have properly been removed or redacted from any copy of the patients’ source 
documents before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, 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 adverse events (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.

Technical information collected on PK sampling days (e.g., PK sampling times, repeated 
vital signs linked with PK) may be collected on specific paper PK logs, which will be 
considered as source data for related entries in eCRF and are considered part of the ISF.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and 
in-house data quality review. The frequency of 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 site trial-related monitoring, audits, IRB/IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.

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8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
Exemptions from expedited reporting are described in Section 5.2.7.10, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted 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 WHO 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, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples 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 Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/135/95)

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 Boehringer Ingelheim 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 informed consent is available.

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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient 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 (SUSARs) 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.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
The target group of Principal Investigators will be oncologists who have experiences in 
clinical trials of immune-oncology products and working at centres where physicians who are 
experts of oncology phase 1 trials are available. Tasks and responsibilities will be defined in a 
contract. Relevant documentation on the participating (Principal) Investigators (e.g. their 
curricula vitae) will be filed in the ISF. The investigators will have access to the BI clinical 
trial portal (Clinergize) to facilitate document exchange and maintain electronic ISF. 
A Safety Monitoring Committee (SMC) will be established in this trial. 
Members of the SMC will include:
•
An investigator representative or delegate
•
BI safety physician or delegate
•
BI Team Member Medicine
•
BI Project or Trial Statistician
•
BI Clinical Trial Leader (CTL)
Other BI and non-BI subject matter experts may also be invited, as appropriate. The SMC
documentation for this trial will define the exact membership and who should be present for 
decisions to be made.
The SMC will be responsible for making dose-selection decisions for BI 754091 and BI 
754111, making decisions on the next cohort size, and recommending to the sponsor whether 
to continue, modify, or stop the trial. 

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The tasks and responsibilities of the SMC will be documented. The SMC will maintain 
written records of all its meetings.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
Central laboratory services, a central imaging archiving service, and an IRT vendor will be 
used in this trial. Details will be provided in the Central Laboratory Manual, the imaging 
manual, and the IRT manual available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 1982. 5: 649-55.
R07-4856
European Medicines Agency (EMEA). Committee for Medicinal Products for 
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Francisco LM, Sage PT, Sharpe AH. The PD-I Pathway in Tolerance and 
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Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
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Nishimura N, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like 
autoimmune diseases by disruption of the PD-1 gene encoding an ITIM 
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novel member of the immunoglobulin gene superfamily, upon programmed 
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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, Eder JP, 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 
Oncology, Published Online: 04 June 2016, doi: 
10.1016/S1470-2045(16)30098-5; 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.
R16-3547
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.
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.

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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. 
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Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination 
With Nivolumab to Patients With Hematologic and Solid Malignancies. Paper 
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(SITC), National Harbor, 9-13 Nov 2016 
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Targets Lymphocyte Activation Gene (LAG)–3, Alone and in Combination 
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presented at: 31st Ann Sci Mtg of the Society of Immunotherapy of Cancer 
(SITC), National Harbor, 9-13 Nov 2016
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upregulation of PD-1, LAG-3 and CTLA-4 limits the efficacy of single agent 
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RECIST Working Group. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017. 18 (3): 143-152 
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Model-based characterization of the pharmacokinetics of pembrolizumab: a 
humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT 
Pharmacometrics Syst Pharmacol. 2017. 6 (1): 49-57
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Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 
040): an open-label, non-comparative,phase 1/2 dose escalation and expansion 
trial
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Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or 
later-line chemotherapy for advanced gastric or gastro-esophageal junction 
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KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) 
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Updated results for the advanced esophageal carcinoma cohort of the phase Ib 
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Esophagus The Phase 2 KEYNOTE-180 Study
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treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 
2 trial

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(KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet.
2019. 393 (10183): 1819-30
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics
n00250922
 Prediction of BI 754091 Human 
Pharmacokinetics and Therapeutic Dose. (Report in Preparation)
001-MCG-156
Handling of missing and incomplete AE dates

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

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

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

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

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

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o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with i.v. or oral corticosteroids
o
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 and BI 754111 should be permanently discontinued for any recurrent 
Grade 3-4 AE, transaminase increases >5 times ULN or total bilirubin >3 times 
ULN (unless unequivocally attributably to another cause), inability to taper 
steroids to 10 mg or less prednisone or equivalent within 12 weeks, or persistent 
Grade 2-3 AEs that do not recover to Grade 1 or less within 12 weeks.

Renal failure or nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 and BI 754111 should be permanently discontinued for any recurrent 
Grade 3-4 AE, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.

Adrenal insufficiency:
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 3-4 
adrenal insufficiency or persistent Grade 2 AEs that do not recover to Grade 1 or 
less within 12 weeks.

Rash:
o
BI 754091 and BI 754111 should be permanently discontinued for Grade 4 rash, 
any recurrent Grade 3 AE or persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.

Encephalitis:
o
BI 754091 and BI 754111 should be permanently discontinued for any grade 
encephalitis.

Infusion reactions:
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.
10.3
HANDLING PROCEDURES FOR BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS
Handling procedures for blood samples are presented in the Laboratory Manual.

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10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA, AND 
BIOMARKER BLOOD SAMPLING
Table 10.4: 1
Time schedule for PK, ADA, and biomarker blood sampling during 
treatment (Parts I and II)
Treat
ment
Cycle
Visit
Day
CRF Time
/PTM
Event
PK
ADA
PBMC2)
(frozen)
1, 2, 4
1
1
-0:05 (Just 
before drug 
admin)
Blood
X
X
X
(C1&2)
0:00
Drug 
admin
1:00
(Immediately 
before end of 
infusion)
Blood
X
1:30
Blood
X
2:00
Blood
X
4:00
Blood
X
7:00
Blood
X
2
2
24:00
Blood
X
X (C1)
3
3
48:00
Blood
X
4
4
72:00
Blood
X
5
8 ±1
168:00
Blood
X
X (C1)
6
15±1
336:00
Blood
X
3, 5-12,  
14, 171)
1
1
-0:05 (Just 
before drug 
admin)
Blood
X
X
X (C3&5)
0:00
Drug 
admin
EOT
Blood
X
X
FU
Blood
X
X
X
1)
every 3 cycles after Cycle 17
2)
PBMC sample will be taken in Part II (only if feasible)

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Table 10.4: 2
Time schedule for PK, ADA, and biomarker blood sampling during 
treatment (Part III)
Treat
ment
Cycle
Visit
Day
CRF Time
/PTM[hh:mi
n]
Event
PK
ADA
PBMC
(extract)
PBMC
(blood)
Cytokine
1, 4
1
1
-0:05 (Just 
before drug 
admin)
Blood
X
X
X (C1)
X (C1)
X
0:00
Drug 
admin
1:00
(Immediately 
before end of 
infusion)
Blood
X
2
2
24:00
Blood
X
X (C1)
X
3
8 ±1
168:00
Blood
X
X (C1)
X (C1)
X
4
15±1
336:00
Blood
X
X (C1)
2, 3, 
5-12, 
14, 171)
1
1
-0:05
(Just before 
drug admin)
Blood
X
X
X (C2, 3, 
and 5)
X (C2)
X
(C2, C3)
0:00
Drug 
admin
EOT2)
Blood
X
X
X
FU2)
Blood
X
X
X
X
1)
every 3 cycles after Cycle 17
2)
blood samples for PK, ADA, PBMC and cytokines are not required after the interim database lock

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10.5
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS
A Bayesian logistic regression model with overdose control will be used to guide 
dose-finding in this study. The BLRM is introduced in Section 7.1, which also specifies the 
prior for the model. After patients in each cohort have completed at least one cycle of 
treatment, 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 present 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 summarized in 
Table 10.5: 3. In addition, recommendations of the next dose level by the BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios in 
early cohorts to show how it facilitates on-study dose-finding decisions (see Table 10.5: 1).
At 1st SMC, 6 patients will be evaluated in part 1. After that, a cohort size of 3 patients who 
are all evaluable is assumed. Though the simulation results are showed, the next dose level 
decision will be done by the SMC. The simulations for scenarios and operating characteristics 
were produced using RStudio version 3.3.2 in conjunction with WinBUGS 1.4.3. 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5: 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model. For each scenario, 
the probability of overdose for the current dose, as well as the next potential dose and related 
probabilities of under-dosing, target dose, and over-dosing are shown.
For example, scenario 1 represents the case that no DLT is observed in the first 6 patients at 
the starting dose of 240 mg. In this case, the next dose recommended by BLRM is 240 mg. 
And the SMC may conclude the completion of part 1.
Scenario 2 and 3 represents that the case that 1 or 2 DLTs are observed in the first 6 patients 
at the starting dose of 240 mg. In this case, the next dose level recommended by BLRM is 
240 mg. 
Scenario 4 and 5 represents that the case that 1 DLT is observed in the first 6 patients at the 
starting dose of 240 mg, and the next dose level is kept the same where 0 or 1 DLT occurred. 
Scenario 6 and 7 represents that the case that 2 DLTs are observed in the first 6 patients at the 
starting dose of 240 mg and the next dose level is different based on the SMC decision.

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Table 10.5: 1 
Hypothetical data scenarios
Scenario
Dose 
(mg)
# 
Patients
# 
DLT
Current 
Dose : 
P(OD)
Next 
recommended 
dose (mg)
Next dose:
P(UD)
P(TD)
P(OD)
1
240
6
0
0.005
240
0.926
0.069
0.005
2
240
6
1
0.043
240
0.686
0.271
0.043
3
240
6
2
0.173
240
0.367
0.460
0.173
4
240
240
6
3
1
0
0.015
240
0.795
0.195
0.015
5
240
240
6
3
1
1
0.071
240
0.519
0.410
0.071
6
240
80
6
3
2
0
0.010
240
0.452
0.435
0.112
7
240
240
6
3
2
1
0.207
240
0.255
0.537
0.207
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose with true DLT rate in the target 
interval can be approximated via simulation. Table 10.5: 2 describes 4 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. 
The scenario setting was referred to 1381-0001 trial assumptions. These scenarios reflect a 
wide range of possible cases as follows:

Scenario 1: aligned with prior means

Scenario 2: low-toxicity scenario

Scenario 3: high-toxicity scenario

Scenario 4: low-toxicity followed by high-toxicity
Table 10.5: 2 
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
80
240
400
1: Prior
P(DLT)
0.096
0.164
0.257
2: Low Tox
0.001
0.009
0.028
3: High Tox
0.100
0.200
0.300

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4: Low-High
0.001
0.180
0.360
For each of these scenarios, 1000 trials were simulated. The each cohort consisted of 3 
patients and the MTD was considered reached if at least 6 patients have been evaluated at a 
dose level which is the model’s recommendation for the next dose cohort and for which the 
posterior probability of targeted toxicity was at least 50%.
It was then assessed how often a dose was declared as MTD with true DLT rate in the under-, 
targeted-, or over-dose range. Furthermore, the average, minimum and maximum number of 
patients per trial and the average number of DLTs per trial are reported. Results are shown in 
Table 10.5: 3.
Table 10.5: 3 
Simulated operating characteristics
Scenario
% of trials declaring a MTD with true DLT rate 
in
# Patients
# DLTs
Underdose
Target 
dose
Overdose
Stopped
Before 
MTD
Mean 
(Min-Max)
Mean
(Min-Max)
1: Prior
44.2
53.4
0
2.4
10.1
(3-33)
1.59
(1-6)
2: Low 
Tox
76.9
0
0
23.1
34.8
(6-60)
0.8
(0-2)
3: High 
Tox
50.7
45.5
0
3.8
9.56
(3-33)
1.67
(1-6)
4: 
Low-High
48.9
42.3
8.0
0.8
9.78
(3-30)
1.39
(1-6)
In scenario 1 (Prior), which reflects the case that the true dose-toxicity is aligned with prior 
means, 53.4% of the simulated trials that have found a MTD declared the MTD with true 
toxicity rate in the target interval. Few simulated trials (2.4%) have been stopped before 
declaring a MTD. 
In scenario 2 (Low-toxicity scenario), since none of the assumed true dose-toxicity scenarios 
were beyond 16%, 76.9% of the simulated trials declared a dose as MTD with true DLT rate 
in the under dose range. 23.1% of the trials stopped before MTD was reached.
In scenario 3 (High-toxicity scenario) illustrate a behaviour similar to scenario 1 because of 
the similar setting dose toxicity scenarios. 
In scenario 4 (Low-High scenario) shows 42.3% of the simulated trials declared a dose as 
MTD with true DLT rate in the targeted dose range. 8.0% of the simulated trials declared a 
dose as MTD in the overdose range. This is because the assumed true dose-toxicity rate at 
400 mg was above 33%.

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The mean patients numbers range from 9 to 10 patients except for scenario 2 (Low-toxicity 
scenario). The mean patients number was around 35 patients at scenario 2. But in case low 
toxicity and no safety concern at RD level (i.e. 240 mg), the SMC may recommend stopping 
the dose finding phase.
In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.
Part II
The purpose of this statistical appendix is to present 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 summarized in 
Table 10.5: 6. In addition, recommendations of the next dose level by the BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios in 
early cohorts to show how it facilitates on-study dose-finding decisions (see Table 10.5: 4).
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5: 4. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model. For each scenario, 
the probability of overdose for the current dose, as well as the next potential dose and related 
probabilities of under-dosing, target dose, and over-dosing are shown.
For example, scenario 1 represents the case that no DLT is observed in the first 3 patients at 
the starting dose of 240/400 mg. In this case, the next dose recommended by BLRM is 
240/600 mg.
Scenario 2 represents that the case that 1 DLT is observed in the first 3 patients at the starting 
dose of 240/400 mg. In this case, the next dose level is 240/400 mg. 
Scenario 3 represents that the case that 1 DLT is observed in the first 3 patients at the starting 
dose of 240/400 mg. And no DLTs is observed at next dose level 240/400 mg. In this case, 
the next dose level is 240/600 mg.
Scenario 4 represents that the case that 1 DLT is observed in the first 3 patients at the starting 
dose of 240/400 mg. And 1 DLT is observed at next dose level 240/400 mg. In this case, the 
next dose level is 240/200 mg.
Scenario 5 represents the case that no DLT is observed in the first 3 patients and next 3 
patients. In this case, the next dose recommended by BLRM is 240/800 mg.

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Table 10.5: 4 
Hypothetical data scenarios
Scenario
Dose
comb.
BI754091/
BI754111
(mg/mg)
# 
Patients
# 
DLT
Current 
Dose : 
P(OD)
Next dose 
comb.
BI754091/
BI754111
(mg/mg)
Next dose:
P(UD)
P(TD)
P(OD)
1
240/400
3
0
0.024
240/600
0.874
0.077
0.048
2
240/400
3
1
0.279
240/200
0.562
0.251
0.186
3
240/400
240/400
3
3
1
0
0.084
240/600
0.631
0.203
0.166
4
240/400
240/400
3
3
1
1
0.333
240/200
0.214
0.219
0.163
5
240/400
240/600
3
3
0
0
0.008
240/800
0.934
0.044
0.022
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose with true DLT rate in the target 
interval can be approximated via simulation. Table 10.5: 5 describes 4 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. 
These scenarios reflect a wide range of possible cases as follows:

Scenario 1: aligned with prior means

Scenario 2: low-toxicity scenario

Scenario 3: high-toxicity scenario

Scenario 4: low-toxicity followed by high-toxicity
Table 10.5: 5 
Assumed true dose-toxicity scenarios
Scenario
BI 754091 / BI 754111 (mg / mg)
240 / 200
240 / 400
240 / 600
240 / 800
1: Prior
P(DLT)
0.146
0.175
0.198
0.214
2: Low Tox
0.001
0.009
0.028
0.160
3: High Tox
0.100
0.200
0.300
0.600
4: Low-High
0.001
0.180
0.360
0.720

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For each of these scenarios, 1000 trials were simulated. The each cohort consisted of 3 
patients and the MTD was considered reached if at least 6 patients have been evaluated at a 
dose level which is the model’s recommendation for the next dose cohort and for which the 
posterior probability of targeted toxicity was at least 50%.
It was then assessed how often a dose was declared as MTD with true DLT rate in the under-, 
targeted-, or over-dose range. Furthermore, the average, minimum and maximum number of 
patients per trial and the average number of DLTs per trial are reported. Results are shown in 
Table 10.5: 6.
Table 10.5: 6 
Simulated operating characteristics
Scenario
% of trials declaring a MTD with true DLT rate 
in
# Patients
# DLTs
Underdose
Target 
dose
Overdose
Stopped
Before 
MTD
Mean 
(Min-Max)
Mean
(Min-Max)
1: Prior
14.0
69.3
0
16.7
27.41
(9-60)
1.24
(0-4)
2: Low 
Tox
21.0
72.8
0
6.2
11.97
(3-42)
2.161
(1-7)
3: High 
Tox
8.6
75.4
1.5
14.5
11.5
(3-30)
2.5
(1-9)
4: 
Low-High
5.5
66.9
18.2
9.4
11.7
(3-42)
2.57
(1-9)
In scenario 1 (Prior), which reflects the case that the true dose-toxicity is aligned with prior 
means, 69.3% of the simulated trials that have found a MTD declared the MTD with true 
toxicity rate in the target interval. 
In scenario 2 (Low-toxicity scenario), almost all simulated trials (93.8%) are declared as 
MTD in underdose or target dose. The resut is similar to scenario 1.
In scenario 3 (High-toxicity scenario), 75.4 % of the simulated trials are declared te MTD 
with true toxicity rate in the target intervals. Though overdose toxicity is assumed but the 
only 1.5% is declared as MTD in overdose.
In scenario 4 (Low-High scenario) shows 66.9% of the simulated trials declared a dose as 
MTD with true DLT rate in the targeted dose range. 18.2% of the simulated trials declared a 
dose as MTD in the overdose range. This is because the assumed true dose-toxicity rate at 
240/600 mg and 240/800 mg was above 33%.
The mean patients numbers range is from 3 to 60 patients and the DLT numbers range is 
from 0 to 9. 

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In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.
10.6
iRECIST
Immunotherapeutics may result in infiltration of immune cells leading to transient increase in 
the size in malignant lesions, or undetectable lesions becoming detectable. The criteria are 
identical to those of RECIST 1.1 in many respects but have been adapted to account for 
instances where an increase in tumour burden, or the appearance of new lesions, does not 
reflect true tumour progression. Key differences are described below. All responses defined 
using iRECIST criteria are designated with a prefix. iRECIST time-point and best overall 
responses will be recorded separately.
Confirming progression
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD.
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is 
seen as evidenced by one or more of the following:

Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions
o
Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum
o
Continued unequivocal progression in non-target disease with an increase in tumour 
burden
o
Increase in size of previously identified new lesion(s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions

RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). The prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response 
(BOR) providing that iCPD is not documented at the next assessment after iUPD.
New lesions
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in 
short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New 

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Lesion-Non-Target (NLNT) to allow clear differentiation from baseline target and non-target 
lesions.
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the sum of measures 
of original target lesions identified at baseline. Rather, these measurements will be collected 
on a separate table in the case record form.
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at 
least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression from 
iUPD with either an increase of at least 5 mm in the absolute value of the sum of NLT OR an 
increase (but not necessarily unequivocal increase) in the size of NLNT lesions OR the 
appearance of additional new lesions
Table 10.6: 1 Time-point (TP) iResponse
Target 
Lesions*
Non-Target 
Lesions*
New
Lesions
*
Time Point Response
No prior 
iUPD**
Prior iUPD**; ***
iCR
iCR
No
iCR
iCR
iCR
Non-iCR/Non-iU
PD
No
iPR
iPR
iPR
Non-iCR/Non-iU
PD
No
iPR
iPR
iSD
Non-iCR/Non-iU
PD
No
iSD
iSD
iUPD with 
no change 
OR decrease 
from last TP
iUPD with no 
change OR 
decrease from last 
TP
Yes
NA
NLs confirms iCPD if NLs were 
previously identified and increase in 
size (≥5 mm in SOM for NLT or
any increase for NLNT) or number.
iSD
iUPD
No
iUPD
Remains iUPD unless iCPD 
confirmed based in further increase 
in size of NT disease (need not meet 
RECIST 1.1 criteria for unequivocal 
PD)
iUPD
Non-iCR/Non-iU
PD
No
iUPD
Remains iUPD unless iCPD 
confirmed based on:
o further increase in SOM of at least 
5 mm, otherwise remains iUPD
iUPD
iUPD
No
iUPD
Remains iUPD unless iCPD 
confirmed based on further increase 
in:
o previously identified T lesion 
iUPD SOM ≥5 mm and / or
o NT lesion iUPD (prior assessment 
- need not be unequivocal PD)

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iUPD
iUPD
Yes
iUPD
Remains iUPD unless iCPD 
confirmed based on further increase 
in:
o previously identified T lesion 
iUPD ≥5 mm and / or
o previously identified NT lesion 
iUPD (need not be unequivocal) and 
/or
o size or number of new lesions 
previously identified
Non-iUPD/P
D
Non-iUPD/PD
Yes
iUPD
Remains iUPD unless iCPD 
confirmed based on
o increase in size or number of new 
lesions previously identified
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, 
PR and SD would be the same. ** in any lesion category. *** previously identified in assessment 
immediately prior to this TP.
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below.
Table 10.6: 2 iRECIST Best Overall Response (iBOR)
TPR1
TPR2
TPR3
TPR4
TPR5
iBOR
iCR
iCR
iCR, iPR, 
iUPD, NE
iUPD
iCPD
iCR
iUPD
iPR, iSD, NE
iCR
iCR
iCR, iPR, 
iSD, iUPD, 
NE
iCR
iUPD
iPR
iPR
iPR, iSD, 
iUPD, NE
iPR, iSD, 
iUPD, NE, 
iCPD
iPR
iUPD
iSD, NE
iPR
iPR
iPR, iSD, 
iUPD, NE
iPR
iUPD
iSD
iSD, iUPD, 
NE
iSD, iUPD, 
iCPD, NE
iSD, iUPD, 
iCPD, NE
iSD
iUPD
iCPD
Anything
Anything
Anything
iCPD
iUPD
iUPD
iCPD
Anything
Anything
iCPD
iUPD
NE
NE
NE
NE
iUPD
•
NE = not evaluable that cycle.
•
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation.
•
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be 

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assigned at each TPR but is not shown in the table for ease of presentation.
10.7
RELATIONSHIP BETWEEN VISIT NUMBER AND DATE
Table 10.7: 1 Relationship between visit number and date in Part I and II
Cycle
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
1, 2, 4
Day 1
Day 2
Day 3
Day 4
Day 8
Day 15
3
Day 1
Day 15
5 onward
Day 1
Table 10.7: 2 Relationship between visit number and date in Part III
Cycle
Visit 1
Visit 2
Visit 3
Visit 4
1, 4
Day 1
Day 2
Day 8
Day 15
2
Day 1
Day 8
Day 15
3
Day 1
Day 15
5 onward
Day 1

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
1
Date of CTP revision
14 Aug 2018
EudraCT number
Not applicable
BI Trial number
1381-0004
BI Investigational Product(s)
BI 754091 and BI 754111
Title of protocol (previous - see 
below for title update)
An open label, Phase I study of BI 754091 
monotherapy and combination therapy of BI 754091 
and BI 754111 in Asian patients with advanced 
solid tumours
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
Cover page and Synopsis – Coordinating investigator
Description of change
Added:
Telephone: 
Rationale for change
Coordinating investigator was appointed for the expansion of 
the trial from single-centre to multi-centre.
Section to be changed
General
Description of change
The term "recommended phase 2 dose (RP2D)" was replaced 
with "recommended dose (RD)".

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Rationale for change
The recommended dose for phase 2 trials may change based on 
the data from the expansion part.
Section to be changed
Synopsis - dose
Description of change
Part II: The starting dose of BI 754111 will be 80 400 mg, 
based on the safety information from another ongoing trial, 
1381-0002. BI 754111 will be administered once every 3 
weeks in combination with BI 754091 at the RP2D RD (Part 
I).
Rationale for change
Starting dose of BI 754111 was changed based on the latest 
safety data from a preceding trial 1381-0002
Section to be changed
Flow chart footnote d and section 5.2.4.2
Description of change
Added:
Heaptitis B virus (HBV), hepatitis C virus (HCV), and 
human immunodeficiency virus (HIV) testing should be 
performed at screening unless test results obtained in 
routine diagnostics within 14 days before the informed 
consent date are available (In Part III Cohort C, if a 
patient is known to have HBV and/or HCV infection, the 
diagnostic testing for that item does not need to be 
repeated).
Rationale for change
To clarify these tests are required at the screening to check the 
eligibility
Section to be changed
1.2.2
BI 754111
Description of change
BI 754111 is currently being tested in patients in the BI 
1381-0002 trial. BI 754111 4 mg and 20 mg were was
administered at dose range from 4 mg to 600 mg in 
combination with BI 754091 240 mg at the first and second 
dose levels of this trial. No DLTs were reported in these dose 
levels from patients who were eligible for DLT evaluation (see 
section 4.1.2.23 patients at each dose level).
Rationale for change
Update based on the latest safety data from a preceding trial 
1381-0002
Section to be changed
1.2.2
BI 754111
Description of change
Added:
The residual effect period of BI 754091 monotherapy and 
BI 754091/BI 754111 combination therapy is 30 days.
Rationale for change
Clarification
Section to be changed
1.4 Benefit – Risk assessment
Description of change
In addition, dose levels which are higher than the 
recommended phase II doses (RP2Ds) determined ones 
investigated in preceding trials 1381-0001 and 1381-0002 will 
not be investigated in this trial.
Rationale for change
Clarification, as a dose level higher than RD may be 
investigated in 1381-0002 and that dose level may also be 
investigated in 1381-0004.
Section to be changed
3.1 Overall trial design and plan
Description of change
Following determination of the MTD and/or the RP2D RD 
from the dose-finding parts, Part III will commence and 
approximately 140 patients with gastric/esophagogastric 

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junction cancer, esophageal cancer, or hepatocellular cancer 
will be enrolled to explore the efficacy and further evaluate the 
safety, tolerability, PK profile, biomarkers of the combination 
of BI 754091 and BI 754111 at RP2D RD determined in Part 
II. Part II may still continue for further safety and/or PK 
evaluation at any dose levels, after the start of recruitment 
in Part III at the recommended dose.
Rationale for change
Clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
2.
Patients who must or wish to continue the intake of 
restricted medications (see Section 4.2.2.14.2.2.2) or any drug 
considered likely to interfere with the safe conduct of the trial
Rationale for change
Correction of error
Section to be changed
4.1.2.2
Starting dose of BI 754111
Description of change
BI 754111 will be tested at a starting dose of 80400 mg to be 
administered via infusion q3w. In case of DLTs in 80400 mg 
cohort, lower doses may also be explored. 
The starting dose was selected based on the data obtained in 
1381-0002 dose-escalation cohorts. By the end of November 
2017June 2018, BI 754111 4 mg, 20 mg, and 80 mg were was 
administered at dose range from 4 mg to 600 mg in 
combination with BI 754091 240 mg. In these dose levels, 
three patients were evaluable for DLT in each dose level and 
none of them experienced DLT.DLTs were not reported at 
any dose level and the MTD was not reached.
Rationale for change
Starting dose of BI 754111 was changed based on the latest 
safety data from a preceding trial 1381-0002
Section to be changed
4.1.2.2
Starting dose of BI 754111
Description of change
Table 4.1.2.2: 1 was added
Rationale for change
To summarise the number of evaluable patients and DLTs in 
trial 1381-0002 as a rationale for the change in the starting 
dose.
Section to be changed
4.1.3
Dose-finding scheme
Description of change
Table 4.1.3.2 Example of dose titration in combination dose 
finding part*:
Dose level
Increment from 
previous dose
Proposed dose of 
BI 754111
-1
-50%
200 mg*
0
Starting dose
80 400 mg
1
150 50%
200 600 mg*
2
100 33.3%
400 800 mg*
3
50%
600 mg*
Rationale for change
Starting dose of BI 754111 was changed based on the latest 
safety data from a preceding trial 1381-0002. The example of 
dose levels was updated accordingly.
Section to be changed
4.1.8
Method of assigning patients to treatment groups

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Description of change
Added:
Part II may still continue for further safety and/or PK 
evaluation at any dose levels, after the start of recruitment 
in Part III at the recommended dose.
Rationale for change
Clarification
Section to be changed
4.2.2.1
Permitted concomitant medications
Description of change
Added:
Patients in Part III Cohort C with HBV infection must be 
receiving effective antiviral therapy (viral load <100 
IU/mL)
Rationale for change
Clarification
Section to be changed
5.1.1
Tumour assessments
Description of change
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 provides an 
additional consent. Following PD, a If a patient is 
considered to be confirmed progressive disease according 
to iRECIST (iCPD), the patient may still continue to receive 
treatment for a maximum of a year if the Investigator and 
sponsor agree that the patient is deriving clinical benefit, and 
the patient provides an additional consent.
Rationale for change
Clarification
Section to be changed
5.1.1
Tumour assessments
Description of change
Added:
Copies of CT/MRI/PET scan data will be collected by the 
sponsor for later radiomics assessment. It is planned to
explore the potential for enhanced and improved baseline 
and on-treatment markers/ patterns of early efficacy based 
on comprehensive quantitative CT metrics, i.e. radiomics 
features, assessed in standard-of-care medical imaging 
data.
Rationale for change
Clarification
Section to be changed
5.2.7.8.1
AE collection
Description of change
The following must be collected and documented on the 
appropriate CRF(s) by the investigator:
•
From signing the informed consent onwards until the end 
of treatment (including the Residual Effect Period [REP]; 
a period of 30 days after the last dose of trial medication 
period between EOT visit and the 30-day follow up 
visit) 

all AEs (non-serious and serious) and all AESIs.
•
After the end of treatment (including the REP) 30-day 
safety follow-up visit until the individual patient’s end of 
trial:

all related SAEs and all related AESIs.
Rationale for change
Clarification
Section to be changed
7.1.2
Statistical design – Part II (BI 754091 and BI 
754111 combination dose finding)
Description of change
The following information is currently available.
•
Updated mono data for PD1 from 1381-0001
•
Updated mono data for PD1 from part I of 1381-0004

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•
Updated combo data for PD1/LAG3 from 1381-0002
Table 7.1.2: 1
Historical data from 1381-0001 as of 06 
Dec 2017 06 Jul 2018 and part I of 1381-0004 as of 20 Jun 
2018
Dose BI 754091 
(mg)
N of patients 
treated
N of patients with 
DLTs during MTD 
evaluation period
80
3
0
240
25 40
0
400
3
0
Table 7.1.2: 2
Historical data from 1381-0002 as of 06 
Dec 2017 Jul 2018
Dose BI 754091 
(mg) / BI 754111 
(mg)
N of patients 
treated
N of patients with 
DLTs during MTD 
evaluation period
240 / 4
3
0
240 / 20
39
0
240 / 80
39
0
240 / 200
9
0
240 / 400
9
0
240 / 600
9
0
Rationale for change
Prior information to be used for DLT rate estimate was 
updated based on the latest data.
Section to be changed
7.1.2
Statistical design – Part II (BI 754091 and BI 
754111 combination dose finding)
Description of change
Table 7.1.2: 4
Derivation of prior distributions based on 
PD-1 mono data (1381-0001) for component 1 + weakly 
informative for the others
Parameter
Prior distributions
Means, standard 
deviations, correlation
Mixture 
weight
log(α1), log(β1): 
component 1
-3.541, -0.123, 0.778, 
0.816, -0.126-3.749, 
-0.13, 0.758, 0.819, 
-0.129
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 7.1.2: 5
Derivation of posterior distributions 
based on PD-1/LAG-3 combo data (1381-0002) + prior 
distribution obtained in step 2
Parameter
Posterior distributions
Means, standard deviations, 
correlation
log(α1), log(β1) 
-3.730, -0.115, 0.752, 0.796, 
-0.140 -4.148, -0.145, 0.707, 
0.781, -0.171
log(α2), log(β2) 
-2.745, -0.406, 1.578, 1.154, 
0.265 -4.023, -0.812, 1.292, 
0.984, 0.043
η
-0.032, 0.698 -0.665, 0.523, n/a
Table 7.1.2: 6
Summary of components of mixture prior 
distribution with their corresponding weights
Parameter
Obtained 
from
Prior distributions
Means, standard 
deviations, 
correlation
Mixture 
weight
log(α1), 
log(β1): 
component 
1
Step1
-4.439, 0.983, 2.383, 
1.050, -0.182
0.10
log(α1), 
log(β1): 
component 
2
Step2
-3.378,-0.040, 
1.100,0.859, 0.010
-3.565, -0.047, 
1.119, 0.863, 0.024
0.30
log(α1), 
log(β1): 
component 
3
Step3
-3.730, -0.115, 
0.752, 0.796, -0.140
-4.148, -0.145, 
0.707, 0.781, -0.171
0.60
log(α2), 
log(β2): 
component 
1
Step1
-1.431,-0.774,
2.003,1.099,-0.037
0.10
log(α2), 
log(β2): 
component 
2
Step2
-1.431,-0.774, 
2.003,1.099,-0.037
-1.431, -0.774, 
2.003, 1.099, -0.037
0.30
log(α2), 
log(β2): 
component 
3
Step3
-2.745, -0.406, 
1.578, 1.154, 0.265
-4.023, -0.812, 
1.292, 0.984, 0.043
0.60
η: 
component 
1
Step1
-0.011, 1.125, n/a
0.10
η: 
component 
Step2
0.093, 0.710, n/a
0.30

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2
η: 
component 
3
Step3
-0.032, 0.698
-0.665, 0.523, n/a
0.60
The corresponding prior probabilities of a DLT at different 
doses and the corresponding probability of underdosing, 
targeted dosing, and overdosing are shown in Table 7.1.2: 7.
Table 7.1.2: 7
Prior probabilities of DLTs
Dose 
(mg)
Dose 
(mg)
Probability of true DLT rate in
Descriptive 
statistics
BI 
754091
BI 
754111
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
SD
80
4
0.884
0.059
0.057
0.074
0.142
80
20
0.837
0.082
0.081
0.098
0.164
80
80
0.750
0.124
0.125
0.139
0.193
80
200
0.599
0.184
0.217
0.207
0.229
80
400
0.459
0.180
0.360
0.307
0.295
80
600
0.401
0.166
0.433
0.364
0.326
240
4
0.824
0.100
0.076
0.109
0.154
240
20
0.773
0.125
0.102
0.132
0.173
240
80
0.668
0.174
0.158
0.175
0.202
240
200
0.503
0.205
0.292
0.256
0.251
240
400
0.400
0.150
0.450
0.375
0.336
240
600
0.376
0.115
0.509
0.438
0.378
400
4
0.700
0.155
0.145
0.168
0.209
400
20
0.647
0.180
0.174
0.191
0.219
400
80
0.543
0.208
0.249
0.238
0.243
400
200
0.418
0.179
0.403
0.333
0.303
400
400
0.374
0.110
0.516
0.445
0.383
400
600
0.376
0.076
0.548
0.492
0.417
240
4
0.858
0.074
0.068
0.092
0.152
240
20
0.827
0.087
0.086
0.108
0.169
240
80
0.787
0.101
0.112
0.126
0.188
240
200
0.743
0.116
0.141
0.146
0.21
240
400
0.695
0.115
0.19
0.175
0.252
240
600
0.677
0.102
0.221
0.198
0.289
240
800
0.671
0.087
0.242
0.214
0.316
Rationale for change
Prior probability of DLT rate was updated based on the latest 
data.
Section to be changed
8.7
Administrative structure of the trial
Description of change
Added:

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A Coordinating Investigator is responsible to coordinate 
investigators at the different sites participating in this trial. 
Tasks and responsibilities are defined in a contract.
Rationale for change
Coordinating investigator was appointed for the expansion of 
the trial from single-centre to multi-centre.
Section to be changed
10.5
Statistical appendix including model performance 
and data scenarios 
Description of change
Hypothetical data scenarios, assumed true dose-toxicity 
scenarios, and operating characteristics were added.
Rationale for change
To present performance metrics that illustrate the precision of 
the design in estimating the MTD under various dose-toxicity 
relationships through computer simulation.

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11.2
GLOBAL AMENDMENT 2
Date of amendment
28 Sep 2018
EudraCT number
EU number
Not applicable
BI Trial number
1381-0004
BI Investigational Medicinal 
Product(s)
BI 754091 and BI 754111
Title of protocol
An open label, Phase I study of BI 754091 
monotherapy and combination therapy of BI 
754091 and BI 754111 in Asian patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis – Objective(s)
Description of change
The main objectives of the dose-finding parts (Parts I and II) 
of the trial are to investigate the following in patients with 
advanced solid tumours:
•
Part I: Safety, tolerability, and pharmacokinetics (PK) 
of BI 754091 as monotherapy.
•
Part II: Safety, tolerability, and PK of escalating doses 
of BI 754111 when administered with BI 754091, and 
PK of BI 754091 when administered with escalating 
doses of BI 754111.
•
Parts I and II: Maximum tolerated dose (MTD) and/or 
recommended dose (RD) of BI 754091 monotherapy 
and the combination of BI 754091 and BI 754111.
Rationale for change
Clarification
Section to be changed
Synopsis – safety criteria, 4.1.5 Definition of dose limiting 
toxicities, 5.2 Assessment of safety, and 5.2.7.6 Severity of 
adverse events
Description of change
The version of CTCAE to be used for the safety assessment 
in Part III was changed from 4.03 to 5. The criteria in Parts I 
and II were not changed.
Rationale for change
Boehringer Ingelheim decided to use the most updated 
criteria for the safety assessment.
Section to be changed
Flow chart and section 5.2.4.2 Biochemistry
Description of change
HBV, HCV, and HIV testing should be performed at 
screening unless test results obtained in routine diagnostics 
within 14 days before the informed consent date are available 
(For patients with hepatocellular cancer in In Part III 
Cohorts C and D, if a patient is known to have HBV and/or 
HCV infection, the diagnostic testing for that item does not 
need to be repeated).
Rationale for change
Clarification
Section to be changed
Section 1.4 Benefit risk assessment
Description of change
Added:
By the end of June 2018, 48 patients were treated with the 

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combination therapy of BI 754091 and BI 754111 (BI 
754111 dose range: 4mg to 600mg, all in combination with 
BI 754091 240mg) and the risk benefit profile from the 
observed data was considered positive.
Rationale for change
Update
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
19. *snip* However, for patients with hepatocellular 
cancer in in Part III Cohorts C and D, patients with HBV 
and/or HCV infection are allowed. Hepatocellular cancer 
patients Patients in Part III Cohorts C and D with HBV 
infection must be receiving effective antiviral therapy (viral 
load <100 IU/mL)
Rationale for change
Clarification
Section to be changed
Section 4.2.2.1
Permitted concomitant medications
Description of change
•
If medically feasible, patients taking regular medication 
for their coexisting disease should be maintained on it 
throughout the trial.
*snip*
•
Hepatocellular cancer patients Patients in Part III 
Cohorts C and D with HBV infection must be receiving 
effective antiviral therapy (viral load <100 IU/mL)
Rationale for change
Clarification
Section to be changed
Section 5.2.4.2
Biochemistry
Description of change
Added:
The regular troponin measurement should be 
quantitative analysis and can be either Troponin I or T, 
according to the institutional standard as long as the 
testing method is consistent.
Rationale for change
Clarification
Section to be changed
Section 5.2.7.8.1
AE collection
Description of change
The following must be collected and documented on the 
appropriate CRF(s) by the investigator:
•
From signing the informed consent onwards until the 
end of the 30-day safety follow-up visit end of 
treatment (including period between EOT visit and the 
30-day follow-up visit)
-
all AEs (non-serious and serious) and all AESIs.
Rationale for change
Section to be changed
Figure 5.2.7.8.1: 1
Description of change
The time point "end of treatment" was updated to "30-day FU 
visit".
Rationale for change
Clarification
Section to be changed
6.2.1.2.1   Medical history of cancer
Description of change
Added:
Baseline information relevant to the disease history such 
as PD-L1 expression level, microsatellite instability (MSI), 
and tumour mutation burden (TMB) information will be 

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collected in eCRF where available.
Rationale for change
To collect the information which is considered relevant for 
the response to the study medications.

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11.3
GLOBAL AMENDMENT 3
Date of amendment
21 Feb 2019
EudraCT number
EU number
Not applicable
BI Trial number
1381-0004
BI Investigational Medicinal 
Product(s)
BI 754091 and BI 754111
Title of protocol
An open label, Phase I study of BI 754091 
monotherapy and combination therapy of BI 
754091 and BI 754111 in Asian patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flow Chart
Description of change
d. Safety laboratory assessments including haematology, 
clinical biochemistry, and urinalysis will be performed 
locally (Free T3, Troponin I, and venous HCO3 will be 
measured at a central laboratory if study site cannot 
measure it locally). The screening medical history and 
demographics, physical examination and Eastern Cooperative 
Oncology Group (ECOG) performance status (PS), vital
signs, ECG, haematology, clinical chemistry (sodium, 
potassium, phosphate, chloride, creatinine, calcium, venous 
bicarbonate HCO3 (if the local lab test is available at the
study site), albumin, total protein, aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], alkaline 
phosphatase, bilirubin, lactate dehydrogenase, glucose, 
c-peptide [baseline only], serum cholesterol [baseline only], 
serum triglycerides [baseline only], creatine phosphokinase 
[CPK: if CPK is elevated, then CPK-MB, troponin (either I
or T), and myoglobin should be reactively tested], urea [or 
blood urea nitrogen (BUN)], 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.
Rationale for change
Clarification
Section to be changed
Flow Chart and section 5.4.2.3
Description of change
The conditions to allow archival tumor tissue was updated as 
follows:
-
If available and taken within 6 months of study 
start and no anti-tumour treatment has been 
given after the sample is taken, at least 20 (4-5 
µm) sections from an archival FFPE block should 
be collected. If adequate archival tissue is not 
available, 2 fine-needle biopsies must be taken 
between screening and the day before the first 
study drug treatment.
Rationale for change
Clarification

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Section to be changed
3.3.3
Exclusion criteria
Description of change
10.
Inadequate organ function or bone marrow reserve 
as demonstrated by the following laboratory values:
*snip*
o
Alanine aminotransferase (ALT) >2.5 times the upper 
limit of normal (ULN) if no demonstrable liver lesion(s) 
(primary or metastases) or >5 times ULN in the 
presence of liver lesion(s)metastases
o
Aspartate aminotransferase (AST) >2.5 times ULN if no 
demonstrable liver lesion(s)metastases or >5 times ULN 
in the presence of liver lesion(s)metastases
Rationale for change
Clarification
Section to be changed
3.3.3
Exclusion criteria
Description of change
20. Chronic alcohol or drug abuse or any condition that, in 
the investigator’s opinion, makes him/her an unreliable trial 
patient, unlikely to complete the trial, or unable to comply 
with the protocol procedures. However, for patients with 
hepatocellular cancer in Part III Cohorts C and D, patients 
with past chronic alcohol abuse are allowed
Rationale for change
Clarification
Section to be changed
4.1.4
Dose modifications and premedications
Description of change
Added:
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. Symptoms of infusion 
related reactions may include, but not limited to, flushing, 
rigors, chills, dyspnea, nausea, vomiting, hypotension, 
hypertension, syncope, pruritus, tachycardia, and back 
pain. 
To reduce the risk of IRRs, patients are to be 
premedicated with an antihistamine and acetaminophen 
or paracetamol. Premedications should be administered 
at sufficient time prior to initiation of infusion to allow 
the agents to exert their effect.
Updaed:
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 

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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 discontinue study drug(s)
Rationale for change
The pre-treatment is considered warranted to prevent the 
IRRs for patients' safety.
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 study medication. 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 IRRs, patients are to be premedicated 
with an antihistamine and acetaminophen or 
paracetamol. Premedications should be administered 
at sufficient time prior to initiation of infusion to 
allow the agents to exert their effect. This applies to 
all cycles and all patients except for cycle 1 in the 
dose-finding part. The patients in the dose-finding 
part should not be treated prior to cycle 1 to avoid 
masking the emergence of DLTs.
Rationale for change
The pre-treatment is considered warranted to prevent the 
IRRs for patients' safety.
Section to be changed
4.2.2.1
Permitted concomitant medications
Description of change
•
For symptom control, palliative radiotherapy is 
permitted for any lesion in the dose-finding part of the 
trial, except during the first cycle as it could interfere 
with the DLT evaluation for MTD/RD determination. 
Following the first cycle of the In the expansion phase 
(Part III), palliative radiotherapy is allowed only for 
non-target lesions, following discussion with the 
sponsor, 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 in Part III.
Rationale for change
It was concluded that the restriction of radiotherapies in the 
first cycle should be only for dose finding parts and would 
not be useful in the expansion part.
Section to be changed
4.2.2.2
Prohibited concomitant medications
Description of change
•
Prophylactic erythropoietin, prophylactic granulocyte 
colony stimulating factors, and palliative radiotherapy 
are not allowed during the first 3 weeks. Palliative 
radiotherapy is not allowed during the first 3 weeks 
of the dose finding parts.
Rationale for change
It was concluded that the restriction of radiotherapies in the 
first cycle should be only for dose finding parts and would 
not be useful in the expansion part.
Section to be changed
5.2.4
Safety laboratory parameters
Description of change
Following description was added:
For Free T3, Troponin I, and venous HCO3, these will be 
measured at a central laboratory if study site cannot 

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measure it locally. With the protocol amendment to 
version 4, Troponin I can be substituted by Troponin T, 
and HCO3 does not have to be measured if not available 
at the study site (the central lab will not be used for 
Troponin I and HCO3 after the approval of protocol 
version 4).
Rationale for change
Clarification on the use of central laboratory was added. 
HCO3 was considered to be not mandatory as blood gas tests 
according to local standard in case of medical need would be 
sufficient. Troponin T as well as Troponin I was considered 
valid to detect the cardiac AE.
Section to be changed
5.2.4.2
Biochemistry
Description of change
The standard biochemistry panel will consist of glucose, 
sodium, potassium, chloride, calcium, phosphate, venous 
bicarbonate HCO3 (if the local lab test is available at the
study site), urea (or blood urea nitrogen [BUN]), creatinine, 
CPK, AST, ALT, alkaline phosphatase, lactate 
dehydrogenase (LDH), bilirubin (total and direct), total 
protein, albumin, and uric acid. In addition, serum 
cholesterol, serum 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 Chart. The 
troponin measurement should be quantitative analysis and 
can be either Troponin I or T, according to the institutional 
standard as long as the testing method is consistent. In case of 
pathological CPK, then CPK-MB, additional tropoinin 
(either I or T), and myoglobin should be reactively tested 
and the findings documented.
Rationale for change
Clarification on the use of central laboratory was added. 
HCO3 was considered to be not mandatory as blood gas tests 
according to local standard in case of medical need would be 
sufficient. Troponin T as well as Troponin I was considered 
valid to detect the cardiac AE.
Section to be changed
5.2.7.5 and 5.2.7.5.4
Description of change
A prefix "potential" was added to the term "DILI"
Rationale for change
To indicate that the reporting requirement applies not only 
confirmed DILI cases but also potential DILI cases.
Section to be changed
5.2.7.10 Exemptions to from AE/SAE reporting
Description of change
Section title updated:
5.2.7.10 Exemptions to from AE/SAE reporting
Updated:
Exempted events are reviewed at appropriate intervals by 
sponsor following a pre-specified review plan.
Lab values meeting the hepatic injury definition as 
defined in section 5.2.7.5.4 will need to be reported as 
AESI. PD reporting exemption does not apply to hepatic 
injury. Please follow the flowchart below for reporting 
hepatic injury / potential DILI cases.
Figure 5.2.7.10: 1 was added

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Rationale for change
Clarification
Section to be changed
7.4
INTERIM ANALYSES
Description of change
No formal interim analysis is foreseen.
The sponsor will continuously monitor the safety. The dose 
escalation design foresees that the sponsor and the SMC 
perform regular safety evaluations. These evaluations will be 
unblinded to dose.
If considered necessary, an evaluation of the efficacy and 
safety aspects will be performed. Results of this evaluation 
will be documented and archived. If applicable, such an 
analysis will be defined in more detail in the TSAP.
No formal interim analysis of PK data is planned. However, 
exploratory analyses of PK will be done during the dose 
finding part (Part I and Part II) and may also be done during 
the expansion part (Part III), if considered reasonable
Exploratory PK analyses will be based on planned sampling 
times. 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.
An interim futility analysis will be performed for each 
cohort in part III. Until any decision from the futility 
analysis is done, the enrolment of next patient will not be 
stopped. The two-stage design is planned to stop further 
recruitment of patient if the defined efficacy boundary 
(see Table 7.7.2: 1) is not met at the first stage. 
The interim analyses for part III will be conducted when:
•
After the 17th patients has completed the 
third on-treatment imaging assessment (i.e. 
end of cycle 6).
•
If the 17th patient discontinues earlier than 
the third on-treatment imaging, the 
interim futility analysis will be triggered at 
approximately 4 months after the first 
administration of the 17th patient.
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 change
It was considered beneficial to discontinue the recruitment if 
the observed response rate is lower than the expected 
response rate at a prespecified interim time point. 
Section to be changed
7.7.2 Determination of sample size for Part III
Description of change
Futility boundaries for each cohort was added. The reference 
historical data was updated. Table 7.7.2: 1 to summarise the 
futility boundary and probability to observe the specified ORs 
by assumed underlying ORRs.

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Rationale for change
It was considered beneficial to discontinue the recruitment if 
the observed response rate is lower than the expected 
response rate at a prespecified interim time point. 
Section to be changed
9.1
Published references
Description of change
Added:
R19-0167
Efficacy and Safety of 
Pembrolizumab for Heavily Pretreated Patients With 
Advanced, Metastatic Adenocarcinoma or Squamous Cell 
Carcinoma of the Esophagus The Phase 2 KEYNOTE-180 
Study
R19-0168
Pembrolizumab in patients with 
advanced hepatocellular carcinoma previously treated 
with sorafenib (KEYNOTE-224): a non-randomised, 
open-label phase 2 trial
Rationale for change
For further reference of assumed ORs

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11.4
GLOBAL AMENDMENT 4
Date of amendment
23 Mar 2020
EudraCT number
EU number
Not applicable
BI Trial number
1381-0004
BI Investigational 
Medicinal Product(s)
BI 754091 and BI 754111
Title of protocol
An open label, Phase I study of BI 754091 monotherapy and 
combination therapy of BI 754091 and BI 754111 in Asian 
patients with advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Cover page and Synopsis – Coordinating investigator
Description of change
Updated:
Telephone: 
Telephone: 
Rationale for change
Affiliation of the coordinating investigator was changed.
Section to be changed
Synopsis and 2.1.1 Main objectives
Description of change
Main objectives of Part III were updated as follows:
•
To further investigate the safety, tolerability, and PK of the RD of BI 
754091 and BI 754111 combination in patients with 
gastric/esophagogastric junction cancer, esophageal cancer, or 
hepatocellular cancer, or non-small cell lung cancer (NSCLC)
To explore the efficacy of the RD of the combination of BI 754091 and BI 
754111 in patients with gastric/esophagogastric junction cancer, 
esophageal cancer, or hepatocellular cancer, or NSCLC
Rationale for change
Updated as the objectives apply to the new cohort for NSCLC.
Section to be changed
Synopsis, 3.1 Overall trial design and plan, and 7.1.3 Statistical design –
Part III (expansion)
Description of change
The planned number of patients were updated as follows:
Total: approximately 179 patients
Part III: approximately 155 patients
Rationale for change
The numbers were adjusted for the following updates:
-
Part III Cohort C was discontinued with 20 patients
Part III Cohort E was added with the planned number of patients of up to 
30
Section to be changed
Synopsis and section 3.3.1 Main diagnosis for trial entry

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Description of change
Added:
Cohort E: First line NSCLC patients with wildtype (wt) epidermal 
growth factor receptor [EGFR] and anaplastic lymphoma kinase 
[ALK] tumours of squamous or non-squamous origin.
Rationale for change
BI decided to explore the efficacy of study treatment in first line NSCLC 
patients
Section to be changed
Synopsis and section 3.3.2 Inclusion criteria
Description of change
Added:
Cohort E: First line squamous or non-squamous NSCLC patients:
•
Without EGFR mutations or ALK rearrangements
•
PD-L1 expression level <50%
Rationale for change
BI decided to explore the efficacy of study treatment in first line NSCLC 
patients
Section to be changed
Flow chart table
Description of change
The allowance window for 30-day safety follow-up was updated from +2 
to +7.
Rationale for change
To allow more flexibility.
Section to be changed
Flow Chart table and footnote h
Description of change
The column "follow-up visit for progression" was updated to "follow-up 
visit for PFS/OS"
Footnote h was updated as follows:
Patients enrolled in Part III Cohort E: 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 (in person or by telephone) until death, loss to follow-up, 
withdrawal of consent, or end of the whole trial. 
All other patients: Additional follow-up visits for progression PFS after 
the 30-day safety follow-up visit will only be performed in Part III for 
patients who did not progress on treatment. The follow-up visits for 
progression PFS will be performed once every 12 weeks at least (in person 
or 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
Follow-up visits for OS will be performed in Cohort E to collect OS data.
Section to be changed
Flow Chart table
Description of change
A new row for the blood sampling for biomarkers (PBMC [blood]) was 
added. The name of another blood sampling for PBMC biomarkers was 
renamed as "PBMC (extract)" so that it will not be confused with the new 
"PBMC (blood)" sampling.
Rationale for change
In cohort E, another PBMC flow cytometry analysis with the same panels 
as in preceding trial 1381-0002 will be implemented, in order to have a 
comparable set of data for the NSCLC cohort in these two trials.
Section to be changed
Flow Chart table and footnote m, and 5.1.1 Tumour assessments
Description of change
The imaging interval in the flow chart table was updated from 6 weeks to 2 
cycles, from 9 weeks to 3 cycles. The allowance windows for tumour 
assessments were updated from +/- 3 days to +/- 5 days
Rationale for change
Clarification and to allow more flexibility.

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Section to be changed
Flow Chart footnote k
Description of change
PBMC related part was updated as follows:
-
PBMC (extract): Blood samples will be taken and peripheral 
blood mononuclear cells (PBMC) will be extracted during Part II 
and Part III only at study sites in which the sample preparation is 
possible, on Day 1 (pre-treatment), 2, 8 of Cycle 1, on Day 1 
(pre-treatment) of Cycle 2, 3 and 5, and at the 30-day safety 
follow-up visit.
-
PBMC (blood): Blood samples for biomarker PBMC (blood) will 
be taken only in Part III cohort E 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-treatment visit. Kits will be 
provided from a designated laboratory logistics vendor. If the kits 
are not ready at study sites at the time of patient recruitment, this 
blood sampling will not be performed.
Rationale for change
In cohort E, another PBMC flow cytometry analysis with the same panels 
as in preceding trial 1381-0002 will be implemented, in order to have a 
comparable set of data for the NSCLC cohort in these two trials.
Section to be changed
Flow Chart footnote l
Description of change
Updated as follows:
[…]
-
If available and taken within 6 months of study start and no 
anti-tumour treatment has been given after the sample is taken, at 
least 20 (4-5 µm) sections from an archival FFPE block should be 
collected. If adequate archival tissue is not available, 2 fine
core-needle biopsies must be taken between screening and the day 
before the first study drug treatment.
-
Two fine core-needle biopsies on treatment at the end of Cycle 2 
(after 6 weeks of treatment), preferably from the same lesion.
[…]
Rationale for change
Clarification
Section to be changed
Flow Chart footnote n
Description of change
Following statement was added:
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.
Rationale for change
Clarification/reminder
Section to be changed
1.3
Rationale for performing the trial
Description of change
Following paragraphs were added:
Multiple immune checkpoint inhibitors […] 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 […], as a subsequent line 
of treatment for patients whose disease progresses.
Rationale for change
To provide the rationale to investigate the combination therapy of BI 
754091 and BI 754111 in the first line NSCLC.
Section to be changed
Description of change

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Rationale for change
Section to be changed
3.1
Overall trial design and plan
Description of change
Following paragraph was added:
In December 2019, BI decided to close the recruitment of new patients 
into Cohort C, based on an analysis of the available data from patients 
enrolled in this cohort. The data showed less than expected clinical 
efficacy for the patient population studied in this indication, and the 
likelihood that the cohort will meet the protocol defined criteria to 
continue at the planned futility analysis was considered very low. This 
decision did not affect the recruitment of other cohorts, the treatment 
of patients who were already receiving study treatment in Cohort C, 
or the overall benefit risk assessment of the combination therapy of BI 
754091 and BI 754111.
Rationale for change
To clarify that Cohort C was closed, its reason, and that this did not affect 
the recruitment other cohorts, treatment of existing patients, or benefit risk 
assessment of the combination therapy.
Section to be changed
3.3.3
Exclusion criteria
Description of change
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 
resected/ablated appropriately treated basal cell carcinoma of the 
skin or in situ carcinoma in situ of the uterine cervix, or other local 
tumours considered cured by local treatment
11. Any of the following cardiac criteria
[…]
o
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
o
Patients with an ejection 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 [ECHO], 
multi-gated acquisition scan [MUGA]). 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.
16. Active autoimmune disease or a documented history of autoimmune 
disease, except vitiligo or resolved childhood asthma/atopy, or 
asthma well controlled with steroids
Rationale for change
#8: To clarify exclusion of other active cancers and to align language 
across current studies with BI 754091.
#11: To clarify exclusion due to cardiac criteria and to align language 
across current studies with BI 754091.
#16: To clarify that patients with asthma will not be excluded if it is well 
controlled with steroids
Section to be changed
3.3.4.3
Discontinuation of the trial by the sponsor

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Description of change
Following condition was added:
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
4.1.4
Dose modifications and premedications
Description of change
Updated as follows:
[…]
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 or 
baseline – exceptions should be discussed and agreed with the sponsor) 
of the AE, 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 AEs
irAEs, 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 (unless unequivocally attributed to another 
cause) 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.
Rationale for change
Clarification
Section to be changed
4.2.2.1
Permitted concomitant medications
Description of change
Following bullet point was updated:
•
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
Clarification
Section to be changed
5.2.4.2
Biochemistry
Description of change
The standard biochemistry panel will consist of glucose, sodium, 
potassium, chloride, calcium, phosphate, venous bicarbonate HCO3 (if the 
local lab test is available at the study site), urea (or blood urea nitrogen 
[BUN]), creatinine, CPK, AST, ALT, alkaline phosphatase,
lactate dehydrogenase (LDH), bilirubin (total and direct), total protein, 
albumin, and uric acid. In addition, serum cholesterol, serum 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 Chart. The 
troponin measurement should be quantitative analysis and can be either 
Troponin I or T, according to the institutional standard as long as the 
testing method is consistent. In case of pathological CPK, then CPK-MB, 
additional tropoinin (either I or T), and myoglobin should be reactively 
tested and the findings documented.

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Rationale for change
It has been determined that these tests are not needed.
Section to be changed
5.2.7.5.2 Immune-related adverse events (irAEs)
Description of change
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. The sponsor has defined a list of irAEs in Appendix 10.1 Table 
10.1: 1 that must be reported as AESIs. If an Investigator determines 
another irAE (not on the list) should be an AESI, the Investigator may also 
report that event as an AESI. 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.
Rationale for change
To clarify the reporting of irAEs as AESI.
Section to be changed
5.4
Assessment of biomarkers
Description of change
[…]
•
Peripheral blood mononuclear cells (PBMC) will be characterized for 
the presence of individual cell lineages, and subsets of T cells will be 
further analysed for the expression of activation and checkpoint 
marker expression (PBMC [extract]).
•
In a complementary analysis to the above, PBMC (blood), 
myeloid-derived suppressor cells (MDSC), PD1+ and LAG3+ 
T-cells, PD-L1+ monocytes, as well as regulatory T-cells and 
activated T-effector memory cells and activated dendritic cells 
will be measured (see Section 5.4.2.1)
Rationale for change
An explanation regarding the complementary PBMC flow cytometry 
analysis was added.
Section to be changed
Description of change
Rationale for change
Section to be changed
Follow up visits for progression PFS (extended follow-up period)
Description of change
The name of the visits "follow-up visit for progression" was updated to 
"follow-up visit for PFS".
Rationale for change
Clarification
Section to be changed
6.2.3.4
Follow up visits for overall survival (OS)
Description of change
The section was added with the following contents:
Additional follow-up visits after the 30-day safety follow-up visit will 

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be performed for patients in Part III Cohort E. These will be 
performed once every 12 weeks at least (by telephone or in person) on 
the same schedule as PFS follow-up visits until death, loss to follow-up, 
or end of the whole trial as specified in Section 3.3.4.3. 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
Follow-up visits for OS will be performed in Cohort E to collect OS data.
Section to be changed
7.3.2.1
Secondary endpoint analyses for Part I and Part II
Description of change
Added:
Analyses of PK parameters, i.e., Cmax and AUC0-504 will be described in 
Section 7.3.5. More detail will be provided in TSAP.
Rationale for change
This statement was moved from 7.3.2.2 as these PK related parameters 
were secondary endpoints for Part I/II.
Section to be changed
7.3.2.2
Secondary endpoint analyses for Part III
Description of change
Following content was removed:
Progression-free survival (PFS) is defined as time from first drug intake 
until PD or death from any cause, whichever occurs earlier. The date of PD 
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
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 detail will be provided in TSAP.
Rationale for change
 
 A statement about the analysis for PK 
parameters for Part I and II was moved to section 7.3.2.1.
Section to be changed
7.4
Interim Analysis
Description of change
[…]
If deemed appropriate, aAn interim futility analysis will be performed for 
each cohort in part III. Until any decision from the futility analysis is done, 
the enrolment of next patient will not be stopped. The two-stage design is 
planned to stop further recruitment of patient if the defined efficacy 
boundary (see Table 7.7.2: 1) is not met at the first stage.
[…]
For cohort E, data from 1381-0002 will 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 change
The plan for the interim analysis for cohort E was added.
Section to be changed
7.7.2
Determination of sample size for Part III
Description of change
[…]

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Cohort E:
Patients with first-line squamous or non-squamous 
NSCLC patients without EGFR mutations or ALK rearrangements 
and PD-L1 expression level < 50%
[…]
For cohort E, around 20% ORR with antibody monotherapy is 
assumed. In Keynote-042 (R20-0754) which is randomised, open-label 
phase 3 trial of Pembrolizumab in patients with previously untreated 
locally advanced or metastatic non-small cell lung cancer without a 
sensitising EGFR mutation or ALK translocation, the ORR in the 
Pembrolizumab group was 118 pts, 39%[95%CI, 34-45](N=299) in the 
PD-L1 tumour proportion score of 50% or greater and 174 pts, 
27%[95%CI, 24-31](N=637) in the PD-L1 tumour proportion score of 
1% or greater. Based on the results, the ORR in the pembrolizumab 
group in the PD-L1 tumour proportion score of 1% to 50% was 17% 
(56 pts/338 pts).
In part III, a total of 140 155 patients will be enrolled and allocated to 4 5
cohorts. The sample size of each cohort is planned around 35 patients for 
cohort A to D. For cohort E, 30 patients is the maximum target sample 
size.
[…]
Table 7.7.2: 1 Early stopping criteria and probabilities for the two-stage 
approach for part III – The information about cohort E was added.
Rationale for change
Information regarding the sample size for Cohort E was added.
Section to be changed
8.7
Administrative structure of the trial
Description of change
The name of a role "Trial Clinical Monitor (TCM)" was updated to 
"Clinical Trial Leader (CTL)". 
Rationale for change
Based on an update in the sponsor's SOP.

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11.5
GLOBAL AMENDMENT 5
Date of amendment
21 Apr 2021
EudraCT number
EU number
Not applicable
BI Trial number
1381-0004
BI Investigational Medicinal 
Product(s)
BI 754091 and BI 754111
Title of protocol
An open label, Phase I study of BI 754091 
monotherapy and combination therapy of BI 
754091 and BI 754111 in Asian patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flowchart footnote and sections 5.2.5, 6.2.3.5, and 10.4
Description of change
Descriptions were added to remove some items from the 
required study procedures after an interim database lock.
Rationale for change
ECG is considered not required based on the safety data 
obtained so far. PK and biomarker sampling are not required 
after the interim database lock as sufficient samples/data 
have been collected.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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c16323837
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clinical-trial-protocol-version-06
An open label, Phase I study of BI 754091 monotherapy and combination therapy of
BI 754091 and BI 754111 in Asian patients with advanced solid tumours
Author-Clinical Trial Leader
23 Apr 2021 02:40 CEST
Author-Trial Clinical
Pharmacokineticist
23 Apr 2021 03:02 CEST
Author-Trial Statistician
23 Apr 2021 03:32 CEST
Approval-Therapeutic Area 
27 Apr 2021 19:53 CEST
Approval-Team Member Medicine
27 Apr 2021 20:36 CEST
Verification-Paper Signature
Completion
28 Apr 2021 02:42 CEST

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(Continued) Signatures (obtained electronically) 
 
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