An Open-label, Phase I Trial to Determine the Maximum-tolerated Dose and Investigate Safety, Pharmacokinetics, and Efficacy of BI 754091 in Patients With Advanced Solid Tumours
Phase: PHASE1
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-03 (13.0) / SAVED ON: 05 AUG 2015
 
Clinical Trial Protocol
Document Number:
c09063095-08
EudraCT No.:
2017-005043-33
BI Trial No.:
1381.1
BI Investigational 
Product:
BI 754091 (ezabenlimab)
Title:
An open-label, Phase I trial to determine the maximum-tolerated 
dose and investigate safety, pharmacokinetics, and efficacy of 
BI 754091 in patients with advanced solid tumours
Lay Title:
A trial to find and investigate a safe dose of a new substance 
(BI 754091) for patients with solid tumours
Clinical Phase:
Phase I
Physician
Trial Clinical 
Monitor:
Phone: 
Fax:
Coordinating
Investigator
Status:
Final protocol (revised protocol [based on global amendment 7])
Version and Date:
Version: 8.0
Date: 07 Mar 2023
Page 1 of 144
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PERMISSION.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754091
Protocol date:
22 Sep 2016
Trial number:
1381.1
Revision date:
07 March 2023
Title of trial:
An open-label, Phase I trial to determine the maximum-tolerated dose and 
investigate safety, pharmacokinetics, and efficacy of BI 754091 in patients with
advanced solid tumours
Investigator
Clinical phase:
I
Objectives:
Phase Ia Dose Escalation: To determine the maximum-tolerated dose (MTD) and 
the recommended Phase 2 dose (RP2D) and investigate the safety, 
pharmacokinetics (PK), biomarkers, and efficacy of BI 754091 in patients with 
advanced and/or metastatic solid tumours
Phase Ib Dose Expansion: To further evaluate the safety, the PK profile, 
biomarkers, and efficacy of the RP2D in 4 cohorts of patients with selected 
advanced and/or metastatic cancers 
Methodology:
Phase Ia Dose Escalation: Open-label, single arm, dose escalation (consecutive 
cohorts of escalating doses of BI 754091), Bayesian Logistic Regression Model 
(BLRM) with overdose control
Phase Ib Dose Expansion: Open-label, 4 dose-expansion cohorts
No. of patients: 
Approximately 145 patients, depending on dose-escalation results
Total entered:
Phase Ia Dose Escalation: approximately 15 patients
Phase Ib Dose Expansion at the RP2D: 4 cohorts of approximately 30-40
patients each
Each treatment:
All patients participating in any part of this trial will receive BI 754091.

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754091
Protocol date:
22 Sep 2016
Trial number:
1381.1
Revision date:
07 March 2023
Diagnosis:
Phase Ia Dose Escalation: Patients with a confirmed diagnosis of advanced, 
unresectable, and/or metastatic solid tumours.
Phase Ib Dose Expansion: advanced and/or metastatic cancers including 
tumours with specific histology/tumour types and/or specific genetic profiles as 
specified in the following cohorts :
-
Cohort 4: solid tumours including non-small-cell lung cancer (NSCLC), 
bladder cancer, melanoma, gastric cancer, ovarian cancer, triple-negative 
breast cancer (TNBC), and renal-cell cancer (RCC)
-
Cohort 5: Tumours with high tumour-mutational burden (TMB), excluding 
those with high microsatellite instability (MSI-high)
-
Cohort 6: Refractory squamous cell cervical, anal, and skin tumours.
-
Cohort 7: Recurrent human papillomavirus (HPV)-positive, or HPV-negative 
(per local testing), vaginal or vulvar squamous cell carcinoma (VSCC), not 
amenable to surgery.
Main criteria
for inclusion:
Phase Ia Dose Escalation – adult patients with a confirmed diagnosis of advanced, 
unresectable, and/or metastatic solid tumours (any type) who have received all 
therapy known to confer clinical benefit (including anti-PD-1 therapies, if relevant 
and if the last dose of the prior anti-PD-1 was received more than 60 days prior to 
starting study drug), or for whom no therapy of proven efficacy exists, or who are 
not amenable to standard therapies
Phase Ib Dose Expansion – adult patients with a confirmed diagnosis of select 
advanced, unresectable, and/or metastatic solid tumours who are anti-PD-1/PD-L1 
naïve but have failed conventional treatment (excluding anti-PD-1/PD-L1 
treatment), or for whom no therapy of proven efficacy exists, or who are not 
amenable to standard therapies.
All patients must have measurable lesions according to Response Evaluation 
Criteria in Solid Tumours (RECIST) v1.1 and/or Immune-Related Response 
Evaluation Criteria in Solid Tumours (iRECIST).
Additional specific criteria for the individual expansion cohorts include:
-
Cohort 4: Advanced and/or metastatic solid tumours including NSCLC, 
bladder cancer, melanoma, gastric cancer, ovarian cancer, TNBC, and RCC
-
Cohort 5: Patients with tumours that are TMB-high:  any tumour with TMB-
high status (>10 mutations/Mb), excluding those that are MSI-high (TMB and 
MSI status based on any validated test)
-
Cohort 6: Patients with squamous cell cervical, anal, and skin tumours that are
refractory to standard therapies.
-
Cohort 7: Patients with recurrent HPV-positive, or HPV-negative, vaginal or 
VSCC

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754091
Protocol date:
22 Sep 2016
Trial number:
1381.1
Revision date:
07 March 2023
Test product:
BI 754091
Dose:
Phase Ia Dose Escalation: starting dose is 80 mg (1 mg/kg for a 80-kg person) 
once every 3 weeks (q3w)
Phase Ib Dose Expansion: the RP2D established in Phase Ia
Mode of 
administration:
Intravenous infusion
Duration of treatment:
BI 754091 will be given on Day 1 of 21-day cycles for up to 1 year, or until 
progressive disease (PD) or unacceptable toxicity in the absence of other 
withdrawal criteria. If the patient is benefiting clinically at 1 year, he/she may 
continue after a case by case review with the sponsor, but no longer than 31 
August 2023.
Endpoints
Endpoints for the Phase Ia Dose Escalation:
Primary:
-
Number of patients experiencing dose-limiting toxicities (DLTs) graded 
according to the Common Terminology Criteria for Adverse Events (CTCAE 
Version 4.03/5.0), observed in the first cycle (3 weeks) in order to meet the 
objective of assessment of the MTD of BI 754091.
Secondary:
-
The following PK parameters will be calculated: Cmax and AUC0-504, after 
single and multiple dose of BI 754091, as measured during the first and 
subsequent cycles (administration q3w) (if data permits)
-
Number of patients experiencing DLTs from start of treatment until end of 
treatment (in all cycles)
-
Confirmed Objective Response (OR) according to RECIST v1.1 assessed by 
the Investigator.
Endpoints for the Phase Ib Dose Expansion:
Primary:
-
Number of patients with DLTs observed during the entire treatment period
-
Confirmed OR according to RECIST v1.1 as assessed by the Investigator
Secondary:
-
Progression-free survival (PFS) according to RECIST 1.1 as assessed by the 
Investigator
Safety will continue to be assessed by the recording of AEs, SAEs (including 
DLTs), physical examinations, laboratory evaluations, vital signs, and ECGs as:
-
Percentage of subjects with AEs 
-
Percentage of subject with SAEs

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Name of company:
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 754091
Protocol date:
22 Sep 2016
Trial number:
1381.1
Revision date:
07 March 2023
-
Percentage of subjects with clinical relevant abnormalities in vital signs,
laboratory evaluations or ECG parameters (note that clinically relevant 
abnormalities are those which have to be reported by the investigator as AEs).
Safety criteria:
Adverse events (AEs) according to CTCAE v. 4.03 / 5.0, incidence of DLTs for
determination of the MTD (Phase Ia dose escalation only), results of physical 
examinations, laboratory evaluations, vital signs, and electrocardiograms (ECGs).
Statistical methods:
Phase Ia: Dose escalation is guided by a BLRM with overdose control that will be 
fitted to binary toxicity outcomes. The estimate of parameters will be updated as 
data are accumulated using the BLRM. At the end of dose escalation, the toxicity 
probability at each dose level will be calculated to determine an estimate of the 
MTD. If there are too few or no DLTs for BLRM guided dose selection, PK 
and/or biomarker data will be taken into consideration for RPIID determination.
Phase Ib: data collected during this phase will be recorded and presented in a 
descriptive fashion.
No hypothesis testing is planned in either phase.

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FLOW CHART 1: BI 1381.1 (REFMAL 473) PHASE IA (DOSE ESCALATION) TRIAL ASSESSMENTS
Flow Chart 1
Trial Treatment Daysa,b
Cycle = 21 Days
Post-Treatment Daysb
Screening
Cycles 1, 2, and 4
Cycles 3, 5, and 
6+
End-of-
Treatmento
(EOT) Visit
30-Dayb
Safety 
Follow-up
PFS 
Follow-
upq
Assessments
-28 to -1
1
(±2 C3+)
2
(±2 C3+)
4
(±2 C3+)
8 (±1 C1)
(±2 C3+)
15 (±1 C1)
(±2 C3+)
1 (±2)
(within 7 days 
of EOT)
(+2)
Informed Consentc
X
Inclusion/Exclusion Criteria
X
Medical History and Demographicsd
X
Physical Examinationd, e
X
X
Xe,m
X
X
X
X
ECOG Performance Statusd, e
X
X
X (C3,5,7,9,etc)
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
12-Lead Digital Electrocardiogramd, f
X
X
Xf
X
(X)
Hematology and Clinical Chemistry Labsd
X
X
Xm
Xm
X
X
Urinalysisd
X
X
Pregnancy Test for Women of Child-
Bearing Potentiald, g
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Survivalq
Xq
Blood Samples for Biomarkers 
 
h
X
X
X
X
X
Blood Samples for 
i, p
X
Xq
X
X
Blood Samples for Pharmacokineticsj, p
X
X
X
X
X
X
Xj, p
Xj
Biopsyk
(X)
(X) (end C2)
(X)
Tumour Assessmentsd, l
X
Every 6 weeks (then every 9 weeks after 6 months of treatment)
BI 754091 infusion
X
X
DLT Assessment (report required at 
Phase Ia Cycle 1)n
X
X
X
Xm
Xm
X
X

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Flow Chart 1 Footnotes (Dose-Escalation)
a
All cycles are 3 weeks (21 days) in duration. Patients will continue treatment with BI 754091 until disease progression (PD) by RECIST and/or 
iRECIST, withdrawal of patient consent, an unacceptable toxicity occurs, or 1 year of treatment is completed, whichever occurs first. Patients will be 
allowed to stay on treatment in the case of initial radiological PD, if the Investigator feels that it is in the patient’s best interest and the patient signs an 
informed consent describing this circumstance. In addition, patients without PD may stay on trial after 1 year on a case-by-case basis after discussion 
with the Medical Monitor and the sponsor but no longer than 31 August 2023. Day 1 of Cycle 1 is defined as the day when BI 754091 is first 
administered. During Phase Ia (dose escalation), Cycle 2 cannot begin without Safety Review Committee approval.
b
Days are calculated as calendar days.
c
Informed consent must be obtained ≤28 days prior to the initiation of treatment.
d
Safety laboratory assessments including haematology, serum biochemistry, and urinalysis will be performed locally. The screening medical history and 
demographics, physical examination and Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), 
haematology, clinical chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, AST, 
ALT, alkaline phosphatase, bilirubin, lactate dehydrogenase, serum glucose, c-peptide, serum cholesterol [baseline only], serum triglycerides [baseline 
only], serum creatinine, serum urea nitrogen [or urea], serum uric acid, and TSH, free T4, and free T3), urinalysis, and screening pregnancy test should 
be done ≤14 days prior to initiation of treatment. Additionally, amylase and lipase should be analysed in case of symptoms of pancreatitis. If these 
assessments are performed within 72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 Day 1 with the exception of the ECOG 
performance status, an abbreviated physical examination, vital signs (pre- and post-infusion), and a single ECG required prior to first trial dose. Tumour 
assessments (scans) should be performed ≤28 days prior to initiation of treatment and copies may be collected by the sponsor or designee. Refer to 
Section 5.3 for additional details.
e
Physical examinations will be done at screening, on Day 1 of each treatment cycle, at the end-of-treatment (EOT) visit, and at the 30-day safety follow-
up visit. However, patients will have an additional abbreviated physical examination (focused on the specific disease, at the Investigator’s discretion) 
on Cycle 1 Day 15. ECOG performance status will be done at screening, on Day 1 of Cycles 1 and 2, on Day 1 of every other cycle beginning with 
Cycle 3, at the EOT visit, and at the 30-day follow-up visit.
f
Single digitalised ECGs must be done before blood work or other procedures after 5 minutes of rest at screening, Cycle 1 Day 1, Cycle 3 Day 1, Day 1 
of every third cycle thereafter (Cycles 6, 9, 12, etc), at the EOT visit, and whenever the Investigator deems it necessary. An ECG is optional at the 
30-day safety follow-up visit if the EOT visit ECG was normal and no drug-related abnormalities were detected in on-trial ECGs (see Section 5.3.3).
g
Women of child-bearing potential must have a serum βHCG pregnancy test at screening, on Day 1 of each cycle, and at the EOT visit. Beginning with 
Cycle 3, urine dipstick tests can be done on Day 1 of odd-numbered cycles (Cycles 3, 5, 7, etc).

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Flow Chart 2
Post-Treatment Daysb
Screening
Cycles 1, 4, and 8
Cycles 2, 
3, 5-7, & 9
Cycles 10, 
11, 13, 14, 
16, 17, etc
Cycles 12, 
15, 18, etc
End-of-
Treatmentn
(EOT) Visit
30-Dayb
Safety 
Follow-up
PFS, OS 
Follow-
upo,q
Assessments
-28 to -1
1
(±2 C4+)
2p
(±2 C4+)
8 (±1 
C1)
15p (±1 C1)
(±2 C4+)
1 (±2)
1 (±2)
1 (±2)
(within 7 
days of 
(+2)
BI 754091 infusion
X
X
X
X
Flow Chart 2 Footnotes (Dose Expansion)
a
All cycles are 3 weeks (21 days) in duration. Patients will continue treatment with BI 754091 until disease progression (PD) by RECIST and/or iRECIST, withdrawal 
of patient consent, an unacceptable toxicity occurs, or 1 year of treatment is completed, whichever occurs first. Patients will be allowed to stay on treatment in the case 
of initial radiological PD, if the Investigator feels that it is in the patient’s best interest and the patient signs an informed consent describing this circumstance. In 
addition, patients without PD may stay on trial after 1 year on a case-by-case basis after discussion with the Medical Monitor and the sponsor, but no longer than 31 
August 2023. Day 1 of Cycle 1 is defined as the day when BI 754091 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, serum biochemistry, and urinalysis will be performed locally. The screening medical history and demographics, 
physical examination and Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), haematology, clinical chemistry 
(sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, AST, ALT, alkaline phosphatase, bilirubin, lactate 
dehydrogenase, serum glucose, c-peptide, serum cholesterol [baseline only], serum triglycerides [baseline only], serum creatinine, serum urea nitrogen [or urea], serum 
uric acid, and TSH, free T4, and free T3), urinalysis, and screening pregnancy test should be done ≤14 days prior to initiation of treatment. Additionally, amylase and 
lipase should be analysed in case of symptoms of pancreatitis. If these assessments are performed within 72 hours of initiation of treatment, they do not need to be 
repeated on Cycle 1 Day 1 with the exception of the ECOG performance status, an abbreviated physical examination, vital signs (pre- and post-infusion), and a single 
ECG required prior to first trial dose. Tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment and copies may be collected by the 
sponsor or designee. Refer to Section 5.3 for additional details.
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. ECOG 
performance status will be done at screening, on Day 1 of Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, and at the 30-day 
follow-up visit.
f
Single digitalised ECGs must be done before blood work or other procedures after 5 minutes of rest at screening, Cycle 1 Day 1, Cycle 3 Day 1, Day 1 of every third 
cycle thereafter (Cycles 6, 9, 12, etc), at the EOT visit, and whenever the Investigator deems it necessary. An ECG is optional at the 30-day safety follow-up visit if the 
EOT visit ECG was normal and no drug-related abnormalities were detected in on-trial ECGs (see Section 5.3.3).

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g
Women of child-bearing potential must have a serum βHCG pregnancy test at screening, on Day 1 of each cycle, and at the EOT visit. Beginning with Cycle 3, urine 
dipstick tests can be done on Day 1 of odd-numbered cycles (Cycles 3, 5, 7, etc).
h
Blood samples for 
 for flow analysis will be collected (if feasible) during Cycle 1 on Day 1 (pre-treatment), Day 8, and 
Day 15, on Cycle 2 Day 1 (pre-treatment), and at EOT (see Section 5.5.2.1 and Table 10.4.2: 1).
i
Blood samples for cytokines will be collected (if feasible) during Cycle 1 on Day 1 (pre-treatment), Day 2, Day 8, and Day 15, on Cycle 2 Day 1 (pre-treatment), and 
at EOT (see Section 5.5.2.1 and Table 10.4.2: 1).
j
Blood samples for 
 will be collected from all patients as presented in Table 10.4.2: 1.
k
Pharmacokinetic (PK) blood sampling will be collected from all patients as presented in Table 10.4.2: 1.
l
The following fresh tumour biopsies will be mandatory for all patients in the Phase Ib dose-expansion cohorts of the trial (refer to Section 6.2.1.1):
-
2 core needle biopsies or 1 punch biopsy (refer to lab manual for specifications) from the most recent relapse (if within 6 months of trial start with no 
subsequent therapy); otherwise, a minimum of 2 core needle biopsies or 1 punch biopsy must be taken between the start of screening and the day before first 
treatment with BI 754091.
-
2 core needle biopsies or 1 punch biopsy on treatment at the end of Cycle 2 (6 weeks), preferably from the same lesion.
-
Another biopsy (optional) should be taken upon PD (according to RECIST v1.1 and iRECIST), if possible. An optional biopsy should also be taken if a patient 
has stable disease over 3 subsequent disease assessment periods.
m
Tumour assessments should be done according to RECIST v1.1 and iRECIST and should include 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 MRI). The same radiographic procedure 
must be used throughout the trial. In case of suspected (but not confirmed) bone metastasis at screening, tumour assessment at screening should include a bone scan. If 
bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT scan) should be performed. Correlative imaging should then be repeated 
at each tumour assessment (see Section 5.2.1 for more detail). Assessments will be performed by the Investigator at screening and every 2 cycles (6 weeks) for the first 
6 months of treatment and once every 3 cycles (9 weeks) thereafter until PD or start of further treatment for disease, and at the discretion of the Investigator.
n
If the decision is made to permanently discontinue BI 754091 during a scheduled visit, the EOT visit assessments should be performed instead of the scheduled visit.
o
Patients enrolled in Protocol Version 4.0 (expansion Cohort 4 and higher): Additional overall survival (OS) and progression-free survival (PFS) follow-up visits 
after the 30-day safety follow-up visit will be performed once every 12 weeks at least (by telephone) until death, loss to follow-up, withdrawal of consent, or end of the 
whole trial. Patients enrolled in Protocol Version 3.0 and earlier (expansion Cohort 1,2,3): Additional PFS follow-up visits after the 30-day safety follow-up visit 
will only be performed for patients who did not progress on treatment. These will be performed once every 12 weeks at least (by telephone) until PD, introduction of a 
new anti-cancer treatment, death, loss to follow-up, withdrawal of consent, or end of the whole trial.
p
The patients will not be required to go to the clinic on Cycle 4 Days 2 and 15 and Cycle 8 Days 2 and 15.  
q
Only patients completed the activity up to until the cut of date for the primary report. All remaining patients will undergo EOT and 30 days visits safety procedures 
only.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................... 1
CLINICAL TRIAL PROTOCOL SYNOPSIS........................................................................ 2
FLOW CHART 1: BI 1381.1 (REFMAL 473) PHASE IA (DOSE ESCALATION) 
TRIAL ASSESSMENTS ........................................................................................ 6
FLOW CHART 2: BI 1381.1 (REFMAL 473) PHASE IB (DOSE EXPANSION) 
TRIAL ASSESSMENTS ........................................................................................ 9
TABLE OF CONTENTS....................................................................................................... 12
ABBREVIATIONS ............................................................................................................... 17
1.
INTRODUCTION................................................................................................. 19
1.1
MEDICAL BACKGROUND ............................................................................... 19
1.2
DRUG PROFILE .................................................................................................. 20
2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT ............. 20
2.1
RATIONALE FOR PERFORMING THE TRIAL............................................... 20
2.2
TRIAL OBJECTIVES........................................................................................... 21
2.3
BENEFIT - RISK ASSESSMENT ....................................................................... 21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION............................... 23
3.1
OVERALL TRIAL DESIGN AND PLAN........................................................... 23
3.1.1
Administrative structure of the trial ...................................................................... 25
3.1.2
Safety Review Committee..................................................................................... 25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS ........................................................................................... 26
3.3
SELECTION OF TRIAL POPULATION ............................................................ 26
3.3.1
Main diagnosis for trial entry................................................................................ 26
3.3.2
Inclusion criteria.................................................................................................... 27
3.3.3
Exclusion criteria................................................................................................... 28
3.3.4
Removal of patients from therapy or assessments ................................................ 30
3.3.4.1
Removal of individual patients.............................................................................. 30
3.3.4.2
Discontinuation of the trial by the sponsor ........................................................... 30
4.
TREATMENTS..................................................................................................... 31
4.1
Investigational TREATMENTS............................................................................ 31
4.1.1
Identity of the Investigational Medicinal Product................................................. 31
4.1.2
Selection of doses in the trial ................................................................................ 31
4.1.3
Dose-escalation scheme ........................................................................................ 32
4.1.4
Dose modifications................................................................................................ 32

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4.1.5
Definition of dose-limiting toxicity....................................................................... 33
4.1.6
Definition of maximum-tolerated dose ................................................................. 34
4.1.7
Definition of evaluable patient.............................................................................. 34
4.1.8
Method of assigning patients to treatment groups................................................. 35
4.1.9
Administration of doses for each patient............................................................... 35
4.1.10
Blinding and procedures for unblinding................................................................ 35
4.1.11
Packaging, labelling, and re-supply ...................................................................... 35
4.1.12
Storage conditions................................................................................................. 36
4.1.13
Drug accountability............................................................................................... 36
4.2
Other treatments, Emergency Procedures, Concomitant medications, and 
RESTRICTIONS................................................................................................... 36
4.2.1
Other treatments and emergency procedures ........................................................ 36
4.2.2
Concomitant medications...................................................................................... 36
4.2.2.1
Permitted concomitant medications ...................................................................... 37
4.2.2.2
Prohibited concomitant medications ..................................................................... 37
4.2.3
Restrictions............................................................................................................ 38
4.2.3.1
Restrictions on diet and life style .......................................................................... 38
4.2.3.2
Restrictions regarding women of childbearing potential ...................................... 38
4.3
Treatment Compliance .......................................................................................... 39
5.
VARIABLES AND THEIR ASSESSMENT........................................................ 39
5.1
Trial Endpoints...................................................................................................... 39
5.1.1
Primary endpoints.................................................................................................. 39
5.1.2
Secondary endpoints.............................................................................................. 39
5.1.2.1
Secondary endpoints of the Phase Ia (dose escalation) portion of the trial........... 39
5.1.2.2
Secondary endpoints of the Phase Ib (dose expansion) portion of the trial .......... 40
5.2
Assessment of Efficacy ......................................................................................... 41
5.2.1
Tumour assessments.............................................................................................. 41
5.3
Assessment of Safety............................................................................................. 42
5.3.1
Physical examinations and ECOG performance status......................................... 42
5.3.2
Vital signs.............................................................................................................. 43
5.3.3
Electrocardiogram ................................................................................................. 43
5.3.4
Safety laboratory parameters................................................................................. 43
5.3.4.1
Haematology ......................................................................................................... 43
5.3.4.2
Biochemistry ......................................................................................................... 43
5.3.4.3
Urinalysis............................................................................................................... 44
5.3.4.4
Pregnancy test........................................................................................................ 44
5.3.5
Other safety parameters......................................................................................... 44
5.3.6
Assessment of adverse events ............................................................................... 44
5.3.6.1
Definition of adverse event ................................................................................... 44
5.3.6.2
Definition of adverse reaction............................................................................... 45
5.3.6.3
Definition of serious adverse events ..................................................................... 45
5.3.6.4
Adverse events considered ‘Always Serious’ ....................................................... 45
5.3.6.5
Adverse events of special interest (AESIs)........................................................... 46
5.3.6.6
Severity of adverse events..................................................................................... 48

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5.3.6.7
Causal relationship of adverse events ................................................................... 48
5.3.6.8
Adverse event collection and reporting................................................................. 49
5.3.6.9
Pregnancy.............................................................................................................. 50
5.3.6.10
Exemptions to SAE Reporting .............................................................................. 51
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................... 51
5.4.1
Assessment of pharmacokinetics........................................................................... 51
5.4.2
Methods of sample collection for pharmacokinetic analyses................................ 51
5.4.4
Pharmacokinetic/pharmacodynamic (PK/PDc) relationship................................. 52
5.5
.................................................................................... 52
5.5.1
Methods of sample collection................................................................................ 53
5.5.3
Biobanking ............................................................................................................ 54
5.6
Other assessments.................................................................................................. 54
5.6.1
Plasma sampling for 
............................................... 54
5.7
APPROPRIATENESS OF MEASUREMENTS................................................... 55
6.
INVESTIGATIONAL PLAN ............................................................................... 55
6.1
VISIT SCHEDULE............................................................................................... 55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS........................ 56
6.2.1
Screening period.................................................................................................... 56
6.2.1.1
Screening for tumour mutational burden (TMB) and MSI-high cohort................ 56
6.2.1.2
Baseline conditions................................................................................................ 56
6.2.1.3
Medical history...................................................................................................... 56
6.2.1.4
Concomitant therapies........................................................................................... 57
6.2.2
Treatment period ................................................................................................... 57
6.2.3
Follow-up period and trial completion.................................................................. 57
6.2.3.1
End-of-treatment visit............................................................................................ 57
6.2.3.2
30-day post-treatment safety visit ......................................................................... 58
6.2.3.3
Progression-free survival visits ............................................................................. 58
6.2.3.4
Overall survival visits............................................................................................ 58
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE....................................................................................................................... 58
7.1
STATISTICAL DESIGN - MODEL .................................................................... 58
7.1.1
Statistical design – Phase Ia (dose escalation) ...................................................... 58
7.1.1.1
Prior derivation...................................................................................................... 60
7.1.1.2
Statistical model assessment ................................................................................. 62
7.1.2
Statistical design – Phase Ib (dose expansion)...................................................... 62
7.2
NULL AND ALTERNATIVE HYPOTHESES ................................................... 62

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7.3
PLANNED ANALYSES ...................................................................................... 62
7.3.1
Primary endpoint analyses..................................................................................... 62
7.3.2
Secondary endpoint analyses................................................................................. 63
7.3.4
Safety analyses ...................................................................................................... 63
7.3.5
Pharmacokinetic and pharmacodynamic analyses ................................................ 64
7.4
Interim analyses..................................................................................................... 64
7.5
HANDLING OF MISSING DATA ...................................................................... 67
7.6
RANDOMISATION ............................................................................................. 67
7.7
DETERMINATION OF SAMPLE SIZE ............................................................. 67
7.7.1
Determination of sample size for Phase Ia............................................................ 67
7.7.2
Determination of sample size for Phase Ib............................................................ 67
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................... 68
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT............................................................................................................. 69
8.2
DATA QUALITY ASSURANCE ........................................................................ 69
8.3
RECORDS............................................................................................................. 69
8.3.1
Source documents.................................................................................................. 69
8.3.2
Direct access to source data and documents ......................................................... 71
8.3.3
Storage period of records ...................................................................................... 71
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS........................................ 71
8.5
STATEMENT OF CONFIDENTIALITY AND patient privacy.......................... 71
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ................................................................................................ 72
8.6
TRIAL MILESTONES ......................................................................................... 72
9.
REFERENCES...................................................................................................... 73
9.1
PUBLISHED REFERENCES............................................................................... 73
9.2
UNPUBLISHED REFERENCES......................................................................... 76
10.
APPENDICES....................................................................................................... 77
10.1
Immune-related adverse events of special interest................................................ 77
10.2
Management of immune-related adverse events................................................... 80
10.3
HANDLING PROCEDUREs for BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS ................................................ 82
10.4
Time schedules for Pharmacokinetic, Biomarker, and immunogenicity 
blood sampling ...................................................................................................... 83
10.4.1
Schedules for PK, biomarker, and immunogenicity blood sampling –
Phase Ia (dose escalation) cohorts......................................................................... 83

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10.4.2
Schedules for PK, biomarker, and immunogenicity blood sampling –
Phase Ib (dose expansion) - All Cohorts............................................................... 85
10.5
Statistical APPENDIX INCLUDING MODEL PERFORMANCE AND 
DATA SCENARIOS............................................................................................. 86
10.5.1
Hypothetical data scenarios................................................................................... 86
10.5.2
Operating Characteristics ...................................................................................... 87
11.
DESCRIPTION OF GLOBAL AMENDMENTS ................................................ 90

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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology
CL
Drug clearance
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DILI
Drug-Induced Liver Injury
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EF
Ejection fraction
EMA
European Medicines Agency
EOT
End-of-treatment visit
EWOC
Escalation with overdose control
FFPE
Formalin fixed and paraffin embedded
FM
Foundation Medicine
GCP
Good Clinical Practice
GEP
Gene-expression profile
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Committee on Harmonisation
irAE
Immune-related adverse events
IRB
Institutional review board
iRECIST
Immune Response Evaluation Criteria in Solid Tumours
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
mAB
Monoclonal antibody
MDSC
Myeloid-deprived suppressor cell
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
MSS
Microsatellite stability
MTD
Maximum-tolerated dose

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NSCLC
Non-small cell lung cancer
OR
Objective response
ORR
Objective response rate
PBMC
Peripheral blood mononuclear cell
PD
Progression of disease
PD-1
Programmed cell death 1 (receptor)
PDc
Pharmacodynamics
PD-L1
Programmed cell death ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
POLE
Polymerase epsilon (ε) catalytic subunit
PR
Partial response
q3w
Once every 3 weeks
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual-effect period
RO
Receptor occupancy (assay)
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SOP
Standard operating procedure
SRC
Safety Review Committee
TMB
Tumour mutational burden
TNBC
Triple negative breast cancer
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal

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1.
INTRODUCTION
This trial is sponsored by Boehringer Ingelheim (BI).
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). The American Cancer Society estimated that 
there will be approximately 595,000 deaths due to cancer in the United States during 2016. 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 minimise collateral immune-mediated damage to healthy tissue. The 
programmed-cell-death 1 (PD-1; CD279) receptor and its ligands, programmed-cell-death 
ligand 1 (PD-L1; B7-H1; CD274) and programmed-cell-death ligand 2 (PD-L2; B7-DC; 
CD273) are the major immune checkpoint master switches. The expression of PD-1 on 
immune cells, including T and B lymphocytes, natural killer (NK) cells and antigen 
presenting cells is upregulated in response to inflammation in peripheral tissue (R16-2360). 
While PD-L2 expression is limited, PD-L1 is expressed broadly and constitutively on many 
immune cells including T lymphocytes (T-cells), B lymphocytes, dendritic cells (DCs) and 
macrophages. As with PD-1 levels, the expression of PD-L1 is also induced as a result of 
peripheral tissue inflammation. The interaction between PD1 and PD-L1 results in an 
inhibitory signal that interferes with antigen receptor signaling, marked changes in the 
cytokine profile, decreased T-cell activation, increased activation of regulatory T-cells, and 
an increase in cytotoxic T-cell apoptosis. Collectively, these events lead to an immune 
suppressive environment and a dampening of the immune response. Many tumours usurp 
immune checkpoint pathways to evade immune response mediated destruction. PD-L1 
expression is induced on tumour cells, tumour stromal cells, and antigen-presenting cells in 
response to IFN-gamma produced by activated T-helper cells, cytotoxic T-cells and natural 
killer cells initially responding to tumour neoantigens in many cancer types. Tumour immune 
evasion is achieved when PD-L1 within the tumour microenvironment engages PD-1 
expressed on activated tumour infiltration T-cells and initiates the immune suppressive 
tumour microenvironment in which activated cytotoxic T-cells are inactivated and, some are 
sent down an apoptotic pathway (R16-2371).
Therefore, it stands to reason that blocking of immune checkpoint pathways may result in the 
reactivation of the suppressed tumour-specific cytotoxic T-cells capable of killing tumour 
cells leading to tumour elimination. To this end, preclinical data have clearly demonstrated 
that blockade of the PD-1/PD-L1 checkpoint pathway results in restoration of anti-tumour 
immune response. More importantly, clinical data have clearly demonstrated remarkable 

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survival benefits for treatment with anti-PD-1 monoclonal antibodies (mAb) (nivolumab and 
pembrolizumab) compared to standard of care in many tumour types including non-small cell 
lung cancer (NSCLC) (R15-3588; R16-0876; R15-3715; R15-6023), melanoma (R16-0864; 
R15-3780; R15-3778; R15-3777), renal cell carcinoma (RCC) (R16-2809), gastric cancer and 
squamous cell carcinoma of head and neck among others. Nivolumab is currently FDA-
approved for the treatment of NSCLC, melanoma, Hodgkin’s lymphoma, and RCC. 
Pembrolizumab is currently approved for the treatment of NSCLC, head and neck 
carcinomas, and melanoma. Results from anti-PD-1 studies in cervical carcinoma, an HPV-
linked gynecological cancer, provide rationale for studying immunotherapy in vulvar 
squamous cell carcinoma (VSCC). Preliminary data from the phase I/II CheckMate358 study 
(NCT 02488759), which evaluates nivolumab in virus-associated, recurrent or metastatic 
cervical, vaginal and vulvar carcinoma, showed that in the nivolumab-treated cohort, the
ORR and the disease control rate (ORR + SD) were 20.8% and 70.8%, respectively. 
Despite these encouraging clinical results with nivolumab and pembrolizumab, up to 80% of 
treated patients do not respond to current checkpoint inhibitors (R15-3588; R15-3778). The 
limited success achieved by checkpoint inhibitor monotherapy is likely due to multiple 
factors including the inherent complexity of the immune response, possible redundancy of 
checkpoint inhibitor pathways, the complexity of mechanisms of tumour immune evasion and 
the exclusion of effector T-cell from some tumours. These findings demonstrate the need for 
the development of new checkpoint inhibitors and checkpoint inhibitor combinations to 
improve response rates and outcomes for cancer patients.
1.2
DRUG PROFILE
BI 754091 is a humanized IgG4Pro isotype mAb 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 dosing frequency is expected to be once every 3 weeks 
(q3w) based on the pharmacokinetic (PK) properties of BI 754091 and similarities to the 
pharmacology, chemical and pharmaceutical properties, and PK of nivolumab and 
pembrolizumab.
For a more detailed description of the BI 754091 profile please refer to the current 
Investigator’s Brochure (IB).
2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT
2.1
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.
Immune checkpoint inhibition has been shown to be a promising therapeutic strategy. 
Programmed death receptor 1 (PD-1) represents one of the immune checkpoints used by 
tumours to suppress antitumour immunity. The safety and durable efficacy of anti-PD-1 
mAbs has been clearly established in multiple tumour types as indicated previously. 

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BI 754091 is an anti-PD-1 mAb that has been shown to have anti-tumour activity in several 
preclinical in vitro and in vivo studies (n00250946; n00250933; n00252624; n00252631).
This trial is the first study with BI 754091 in humans and will be conducted in 2 parts. The 
first part will include dose-escalation cohorts to determine the maximum-tolerated dose 
(MTD) and/or the recommended Phase 2 dose (RP2D). The second part consists of 4
expansion cohorts at the RP2D that will also further evaluate the safety, tolerability, efficacy, 
PK, and biomarkers of BI 754091. The dose-escalation portion of the trial will enrol patients 
with advanced and/or metastatic solid tumours, while the dose-expansion portion will enrol 
patients with advanced and/or metastatic solid tumours with select types of cancer and/or 
specific genetic mutations. Recent evidence has shown that several tumour types with high 
TMB have better response rates with immune checkpoint inhibitors (R17-0923; R16-1497). 
Therefore, patients with tumours with high mutation rates will be included in the expansion 
phase of this trial.  More recent data have demonstrated that the combination of nivolumab 
and ipilimumab had better efficacy in NSCLC patients with a tumour mutational burden of at 
least 10 mutations per megabase than those with <10 mutations per megabase (R18-1492). As 
such, a ≥10 mutation per megabase threshold was selected to define patients with high TMB
for this trial. 
Please see Section 3.3.2 for a list of target tumour types for the dose-expansion portion.
2.2
TRIAL OBJECTIVES
The main objective of the dose-escalation part of the trial is to determine the safety and 
tolerability, and to determine the MTD and/or the RP2D of BI 754091 on the basis of patients 
with dose-limiting toxicities (DLTs) in patients with selected advanced solid malignancies. 
Safety and tolerability will be evaluated by monitoring the occurrence of adverse events
(AEs), serious AEs (SAE), and laboratory parameter abnormalities, as well as changes to 
vital signs (see Section 5.3).
Secondary objectives are the determination of the PK profile of BI 754091 after single and 
multiple doses of BI 754091 (see Section 5.4.1), and the preliminary assessment of anti-
tumour activity (see Section 5.2).
In the dose-expansion part of the trial, the main objectives are to further assess the safety, 
efficacy, PK profile, and biomarkers of BI 754091 in tumours with specific tumour types 
and/or genetic mutations at the RP2D.
2.3
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 minimising 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 
event (irAEs). Indeed, mice deficient in PD-1 or its ligands (PD-L1 and PD-L2) were found 

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to be highly prone to development of autoimmune diseases (R16-2968; R16-2362; R16-2364; 
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-L1 (70%) mAbs. However, the 
majority of these AEs are mild in severity (R12-5176; R15-3588; R15-3715) and occur 
within the first 4 months of initiating therapy (R16-0899; R15-3780; R16-0864). 
Immune-related AEs affect mainly the gastrointestinal tract (including diarrhoea and, less 
frequently colitis), skin (including rash/erythema and, less frequently vitiligo), endocrine 
glands (including hypothyroidism, hyperthyroidism, and hypophysitis), liver (frequently 
asymptomatic elevated transaminases), and lung (pneumonitis) but could also potentially 
affect other tissues. Rare fatal cases of colitis and pneumonitis have been reported with use of 
immune checkpoint inhibitors. The main treatment of irAEs is the administration of steroids 
for 2 to 4 weeks; other immunosuppressive agents (such as infliximab, mycophenylate 
mofetil and cyclosporine) can be used in case of steroid-refractory irAE (R16-0899; R16-
0870; R16-0763). Treatment with BI 754091 is anticipated to be associated with a similar 
pattern of AEs. Immune-related AE management guidance will be provided in the trial 
documentation. Infusion-related reactions have been reported with checkpoint inhibitor 
treatment. These reactions occur infrequently and are typically managed based on symptoms 
using treatments ranging from treatment with histamine antagonists in mild cases to 
administration of epinephrine when symptoms of anaphylaxis are detected.
BI 754091 has not been tested in humans thus far, however, it is expected that BI 754091 will 
have a comparable safety profile to marketed anti-PD-1 mAbs. Repeat-dose administrations 
of BI 754091 at 0, 3, 30 or 100 mg/kg/dose of BI 754091 (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. Administration of BI 754091 had no adverse effects on clinical pathology 
parameters including haematology, immunophenotyping, and clinical chemistry. No 
BI 754091-related neurologic or ophthalmic physical examination findings, or changes in any 
haematology, coagulation, clinical chemistry, or urinalysis parameters were observed. 
BI 754091 was not associated with any gross or organ weight findings.
Based on these pre-clinical data, as well as clinical data obtained with other anti-PD-1 
inhibitor mAbs, the inhibitory effects of BI 754091 on PD-1 may translate into a clinical 
benefit in cancer patients. All doses planned to be tested are expected to have some level of 
efficacy. Efficacy is expected for patients with tumours that have a high rate of mutations, 
such as high levels of TMB and squamous cell skin cancers, which have about the highest 
mutation rate among cancers.
The dose-escalation scheme is guided by a Bayesian 2-parameter Logistic Regression Model 
(BLRM) (de-escalation of dose is possible in case of insufficient tolerability of a dose level) 
and is designed to escalate the dose quickly and minimise the risk of undue tolerability issues.
Therefore, treatment with BI 754091 is expected to provide patients with clinical benefit at an
acceptable risk.

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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 Section 5.3.6.5.4).
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I, open-label, multi-centre trial of BI 754091 administered as a single agent.
The trial design allows an escalation of dose with intensive safety monitoring to ensure the 
safety of the patients.
It is planned that approximately 15 patients with advanced solid malignancies will be 
enrolled in the Phase Ia portion of the trial, which will include dose-escalation of BI 754091
administered as monotherapy. The total number of patients will depend on the number of 
dose escalations necessary. Dose escalation will be guided by a BLRM with overdose control
(EWOC). The BLRM estimates the MTD by updating estimates of the probability of 
observing a DLT in the MTD evaluation period (first 3 weeks) for each dose level in the trial 
as patient information becomes available. At no time in the trial, will it be permitted to 
escalate to a dose which does not fulfil the EWOC principle (refer to Section 7).
Successive cohorts of patients will receive doses of BI 754091 until the MTD is reached. A 
cohort size of 3 patients will be treated at each dose level. Additional patients (up to 6 more) 
could be added to some previously evaluated cohorts to expand the safety and PK evaluation.
After all patients in a cohort have either experienced a DLT or have been observed for at least 
the MTD evaluation period (first 3 weeks) 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 which fulfil the EWOC criterion. 
Hypothetical data scenarios (see example in Section 10.5.1) will be calculated with potential 
cohort sizes and presented at the meetings with the Safety Review Committee (SRC, see 
Section 3.1.2). Based on the model and on additional information (PK, pharmacodynamics 
[PDc], patient profiles), the members of the SRC will reach a joint recommendation on the 
next dose level to be investigated and the size for the next dose-escalation cohort. However, 
the final decision on the next dose level and cohort size will be made mutually between the 
BI Clinical Program Leader and the SRC.
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 SRC will 
evaluate whether the next patients will be enrolled at the same dose level, or if they will be 
enrolled at a lower dose level.

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The SRC may recommend stopping the dose-finding phase after the criterion for MTD 
(Section 7.1) is fulfilled. Further patients may be included to confirm this MTD estimate, i.e., 
to confirm that the EWOC criterion is still fulfilled. If no DLT is observed at a dose at which 
the efficacy is considered sufficient, the SRC may decide to include an additional number of 
patients at the same dose level and to declare this dose as the recommended dose for further 
development (RP2D). The SRC can declare any dose that fulfils the EWOC criterion as 
RP2D, independent of the MTD estimate.
Following determination of the MTD and/or RP2D from the Phase Ia portion, separate 
cohorts of approximately 30-40 patients each will be conducted in patients with select 
advanced solid malignancies including tumours with specific histology/tumour types and/or 
specific genetic profiles as specified in the following cohorts:
∀
Cohort 4: Solid tumours including NSCLC, bladder cancer, melanoma, gastric cancer, 
ovarian cancer, triple-negative breast cancer, and renal-cell cancer
∀
Cohort 5: Tumours with high TMB excluding those with high microsatellite instability 
(MSI-high)
∀
Cohort 6: Refractory squamous cell cervical, anal, and skin tumours
∀
Cohort 7: Recurrent human papillomavirus (HPV)-positive, or HPV-negative, vaginal or 
vulvar squamous cell carcinoma (VSCC)
The Phase Ib portion of the trial will further evaluate the safety, tolerability, efficacy, PK
profile, and biomarkers of BI 754091.
The analysis of the squamous cell tumour cohort (Cohort 6) and the VSCC cohort (Cohort 7) 
will follow a two-stage approach. 
The interim analysis for Cohort 6:
∀
Squamous cervical and/or anal cancer, Stage 1 will include 10 treated patients.
∀
Squamous skin tumours, Stage 1 will include 10 treated patients.
The interim analysis for Cohort 7:
∀
Vaginal or VSCC, Stage 1 will include 20 treated patients.
Based on the interim analyses results, the sponsor will determine if recruitment into these 
tumour groups will continue or be terminated (recruitment does not have to pause while 
interim analysis is conducted). More details on the interim analyses are specified in Section
7.4. The sponsor reserves the right to terminate recruitment in any of the tumour groups if the 
recruitment target is not met. Patients who are already enrolled may continue in the trial 
regardless of recruitment termination of their cohort.
Patients will continue treatment with BI 754091 until disease progression (PD) according to 
the Response Evaluation Criteria in Solid Tumours (RECIST) and the Guidelines for 
Response criteria for use in trials testing immunotherapeutics (iRECIST) (R17-0923, 
withdrawal of patient consent, an unacceptable toxicity occurs, or 1 year of treatment is 
completed, whichever occurs first but no longer than 31 August 2023. Patients will be 
allowed to stay on treatment in the case of initial radiological PD, if the Investigator feels that 

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it is in the patient’s best interest. In addition, patients without PD may stay on trial after 1
year on a case-by-case basis after discussion with the Medical Monitor and the sponsor, but 
no longer than 31 August 2023. After this date treatment with the ezabenlimab will no longer 
be available.
3.1.1
Administrative structure of the trial
A contract research organisation,
, is 
responsible for project management, medical management, site management, data 
management, site regulatory document management, some aspects of safety management and 
reporting, medical writing, and medical monitoring.
The Global Study 
from
 and the Coordinating 
Investigator,
, are
responsible for coordinating Investigators at different centres participating in this multicentre 
trial. Tasks and responsibilities are defined in contracts.
An SRC (see Section 3.1.2) including representatives from clinical sites, sponsor
representatives, and
members, will be established to assess the progress of the 
clinical trial, including making safety and efficacy assessments at specified intervals, making 
dose-escalation decisions, and recommending to the sponsor whether to continue, modify, or 
stop the trial. The tasks and responsibilities of the SRC will be documented. The SRC will 
maintain written records of all its meetings.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in Investigator Site File (ISF).
The Statistical analysis will be done by BI according to BI Standard Operating Procedures 
(SOPs).
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs and
SOPs as agreed upon and documented. A list of 
responsible persons and relevant local information can be found in the ISF.
An Interactive Response Technology (IRT) vendor will be used in this trial. Details will be 
provided in an IRT Manual available in the ISF.
3.1.2
Safety Review Committee
Members of the SRC will include:
∀
Medical Monitor for the trial
∀
Principal Investigators, or delegates, from each investigational site.
In addition, one other physician from the following will be invited:
∀
BI Safety Physician, or delegate
∀
BI Clinical Program Leader responsible for the project.

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The BI Safety Physician, BI Clinical Program Leader, or delegate, should always attend the 
SRC, if there are safety issues for discussion.
The
Medical Monitor, or delegate, should always be present at the SRC.
Other BI and non-BI technical experts may also be invited, as appropriate. The SRC
documentation for this trial will define the exact membership and who should be present for 
decisions to be made.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
Dose escalation and cohort size will be determined based on the recommendation of the SRC, 
guided by a Bayesian model with overdose control. An EWOC design will increase the 
chance of treating patients at efficacious doses while reducing the risk of overdosing. This 
design is based on practical experience and is an efficient method due to its ability to identify 
the dose with a desired toxicity rate and its allocation of a greater proportion of patients to 
doses at or close to that desired dose (R13-4802; R13-4804; R13-4805). The use of Bayesian 
models for Phase I studies has also been advocated by the European Medicines Agency 
(EMA) guideline on small populations (R07-4856) and by the FDA (R13-4881).
The results from this trial will form the basis for decisions for future studies.
3.3
SELECTION OF TRIAL POPULATION
A log of all patients enrolled into the trial (i.e., who have signed an informed consent form 
[ICF]) will be maintained in the ISF at the investigational site irrespective of whether or not 
they have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients with selected advanced, unresectable, and/or metastatic solid tumours, who are anti-
PD-1 naïve but have failed conventional treatment or for whom no therapy of proven efficacy 
exists, or who are not amenable to standard therapies are eligible for either portion of this 
trial.
Patients included in the dose-escalation phase are not eligible to enter the dose-expansion
phase.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.

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3.3.2
Inclusion criteria
For inclusion in the trial, patients must fulfil all of the following criteria:
1. Provision of signed and dated, written ICF prior to any trial-specific procedures, 
sampling, or analyses. If a patient declines to participate in the voluntary 
pharmacogenetics component of the trial, he/she will not be excluded from other 
aspects of the trial.
2. Patients ≥18 years of age at the time of signature of the ICF
3. Phase Ia (dose escalation):
∀
Patients with a histologically confirmed diagnosis of advanced, unresectable, 
and/or metastatic solid tumours (any type)
∀
Patients who have received all therapy known to confer clinical benefit (including 
anti-PD-1 or anti-PD-L1 therapies, if relevant), or for whom no therapy of proven 
efficacy exists, or who are not amenable to standard therapies. Patients with anti-
PD-1 or anti-PD-L1 experience must have a minimum of 60 days between the last 
dose of the previous anti-PD-1/PD-L1 and Cycle 1 Day 1 of BI 754091 treatment.
∀
Patients may agree to provide optional paired biopsies.
4. Phase Ib (dose expansion):
∀
Patients with a histologically confirmed diagnosis of select advanced, 
unresectable, and/or metastatic solid tumours with specific histology/tumour types 
and/or specific genetic profiles as specified in the following cohorts:
-
Cohort 4: solid tumours including NSCLC, bladder cancer, melanoma, 
gastric cancer, ovarian cancer, triple-negative breast cancer, and renal-cell 
cancer
-
Cohort 5: Tumours with high TMB (showing ≥10 mutations/mega base) 
excluding those with high microsatellite instability (MSI-high) (TMB and 
MS status based on any validated test). Refer to Section 6.2.1.1 for details.
-
Cohort 6: Refractory squamous cell cervical, anal, and skin tumours.
-
Cohort 7: Recurrent HPV-positive, or HPV-negative (per local testing), 
vaginal or VSCC, not amenable to surgery. 
∀
All patients must have measurable lesions according to RECIST v1.1 criteria, 
must have at least 1 tumour lesion amenable to biopsy, and must be medically fit 
and willing to undergo a biopsy before first treatment and, unless clinically 
contraindicated, after 6 weeks on therapy.
∀
Patients who are anti-PD-1 and anti-PD-L1 naïve but have failed conventional 
treatment (excluding anti-PD-1 treatment), or for whom no therapy of proven 
efficacy exists, or who are not amenable to standard therapies.
5. Eastern Cooperative Oncology Group (ECOG, R01-0787) score: 0 to 1
6. Life expectancy of at least 12 weeks after the start of the treatment according to the
Investigator’s judgement
7. Females of child-bearing potential willing to use adequate contraceptive measures
from the time of screening until 6 months after trial discontinuation, who are not or 
will not be breast feeding, and agree to have pregnancy tests prior to the start of 
dosing and at regular visits during the trial. Females not of childbearing potential
must have evidence of such by fulfilling one of the following criteria at screening:

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-
Post-menopausal: defined as more than 50 years-of-age and amenorrhoeic 
for at least 12 months following cessation of all exogenous hormonal 
treatments
-
Documentation of irreversible surgical sterilization by hysterectomy, 
bilateral oophorectomy, or bilateral salpingectomy
-
Women under 50 years-of-age would be considered postmenopausal if they 
have been amenorrhoeic for at least 12 months following the cessation of
exogenous hormonal treatments, and have serum follicle-stimulating 
hormone and luteinizing hormone levels in the postmenopausal range for the 
institution.
-
For women of childbearing potential using a contraceptive pill, an additional 
barrier method is necessary.. Acceptable highly effective methods of 
contraception include total sexual abstinence when this is in line with the 
preferred and usual lifestyle of the study participant (periodic abstinence 
such as calendar, ovulation, symptothermal, post-ovulation methods and 
withdrawal are not acceptable methods of contraception), an intrauterine 
device or intrauterine hormone-releasing system, bilateral tubal ligation, and 
vasectomised partner (with post-vasectomy proof of absence of sperm)
8. Male patients must be willing to use barrier contraception (i.e., condoms) for the 
duration of the trial and for 6 months after trial treatment discontinuation.
3.3.3
Exclusion criteria
Patients must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Major surgery (major according to the Investigator’s assessment) performed within 
12 weeks prior to first trial treatment or planned within 12 months after screening, e.g.,
hip replacement
2. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.2) or any drug considered likely to interfere with the safe conduct of the 
trial
3. Previous enrolment in this trial
4. Any investigational or antitumour treatment within 4 weeks or 5 half-life period 
(whichever is shorter) prior to the initial administration of BI 754091.
5. Presence of other active invasive cancers other than the one treated in this trial within 5 
years prior to screening, with the exception of appropriately treated basal-cell 
carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumours 
considered cured by local treatment.
6. Untreated brain metastasis(es) that may be considered active. Patients with previously 
treated brain metastases may participate provided they are stable (i.e., without evidence 
of PD by imaging for at least 4 weeks prior to the first dose of trial treatment, and any 
neurologic symptoms have returned to baseline), and there is no evidence of new or 
enlarging brain metastases
7. Inadequate organ function or bone marrow reserve as demonstrated by the following 
laboratory values:
-
Absolute neutrophil count <1.5 x 109/L (<1500/mm3)
-
Platelet count <100 x 109/L

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-
Haemoglobin <90 g/L (<9 g/dL)
-
Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no 
demonstrable liver metastases or >5 times ULN in the presence of liver metastases
-
Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver 
metastases or >5 times ULN in the presence of liver metastases
-
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
-
Creatinine >1.5 times ULN or creatinine clearance <50 mL/min (measured or 
calculated by Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration
equation); confirmation of creatinine clearance is only required when creatinine is 
>1.5 times ULN.
8. Any of the following cardiac criteria:
-
Mean resting corrected QT interval (QTc) >470 msec
-
Any clinically important abnormalities (as assessed by the Investigator) in rhythm, 
conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, 
third degree heart block
-
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years-of-age, or any 
concomitant medication known to prolong the QT interval
-
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.
9. History of pneumonitis within the last 5 years
10. History of severe hypersensitivity reactions to other mAbs
11. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 
4 weeks prior to the first dose of BI 754091
12. Active autoimmune disease or a documented history of autoimmune disease, except 
vitiligo or resolved childhood asthma/atopy
13. Known history of human immunodeficiency virus infection or an active hepatitis B or C 
virus infection. HIV infection is allowed for patients in cohort 6 (cervical/anal squamous) 
and cohort 7 (vulvar).
14. Interstitial lung disease
15. Chronic alcohol or drug abuse or any condition that, in the Investigator’s opinion, makes 
him/her an unreliable trial subject, unlikely to complete the trial, or unable to comply with 
the protocol procedures.

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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:
∀
The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
∀
The patient needs to take concomitant drugs that interfere with the investigational product 
other than those listed under ‘Permitted concomitant medications’ (see Section 4.2.2.1).
∀
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy)
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the Investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
Given the patient’s agreement, the patient will undergo the procedures for the end-of-
treatment (EOT) visit and follow up as outlined in the Flow Chart 1, Flow Chart 2, and 
Section 6.2.3.
For all patients the reason for withdrawal (e.g., AEs) must be recorded in the electronic case 
report form (eCRF). These data will be included in the trial database and reported.
During their first treatment cycle, patients withdrawn for a reason other than having a DLT or 
patients who miss more than one visit will be replaced after discussion between the sponsor 
and the Investigator if the information that needed to be collected during that visit is not 
available and makes the patient non-evaluable for the PK analyses or safety parameters 
(including evaluation for DLTs).
Patients who come off trial due to a DLT will not be replaced.
If a patient should become pregnant during the trial, the treatment with BI 754091 must 
immediately be stopped. The patient will be followed up until delivery or termination of 
pregnancy (see Section 5.3.6.9 for information on pregnancy forms). The data of the patient 
will be collected and reported in the eCRF until the last patient’s last visit and any events 
occurring thereafter will be reported in the BI drug safety database.
3.3.4.2
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

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2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the clinical trial protocol (CTP), or the 
contract disturbing the appropriate conduct of the trial.
4. Completion of treatment by all patients and the sponsor determines that sufficient survival 
data has been collected.
5. Termination of the development program by the sponsor .
In case the trial is ended by the sponsor, the available clinical trial data will be analyzed and 
reported approximately one year after the last patient has been enrolled. Patients who are still 
being treated with BI 754091 when the primary report of the trial is being prepared, will be 
kept on treatment in this trial and finalize the clinical observation period by 31 August 2023 
at the latest. Data of those patients will then be reported in a revised report and it will be 
noted in the primary report that such a revised report will be written.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Product
Details of the drug product, BI 754091, are presented in Table 4.1.1: 1.  Additional details are 
presented in the BI 754091 IB and Pharmacy Manual.
Table 4.1.1: 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.
4.1.2
Selection of doses in the trial
Given that the patients to be enrolled in this trial will have advanced/metastatic cancer, it is 
preferable to set the starting dose at a level that is anticipated to bring them clinical benefit. 
Research by Bai et al (R13-4749) found that the fixed-dosing approach (flat dosing) is the 
recommended first option for administration of mAbs in first-in-human studies. Hence, we 

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plan to test BI 754091 at a flat starting dose of 80 mg (equivalent to 1 mg/kg for an 80-kg 
person) to be administered via infusion q3w. A sample dose-escalation scheme is shown in 
Section 4.1.3. The actual dose escalation will be guided by the BLRM, and the final decision 
will be made by the SRC (see Section 3.1.2).
The starting dose was selected based on the well-established positive safety profile of 
approved anti-PD-1 mAbs and the observation that maximum serum target engagement is 
reached with doses of 1 mg/kg administered q3w. Therefore, the selected starting dose is 
expected to be in the therapeutic range providing participating patients with a reasonable 
chance of clinical benefit while reducing the risk of toxicities. The estimated exposures for 
the planned starting dose are 94 x AUC and 173 x Cmax lower than the exposures at the no-
observable-adverse-effect level of 100 mg/kg/dose in the 13-week toxicity study in 
cynomolgus monkeys. The predicted efficacious human dose is 2 mg/kg (160 mg for an 
80-kg person) q3w.
4.1.3
Dose-escalation scheme
The dose is planned to be escalated in cohorts. The sample dose levels to be assigned to 
separate cohorts of patients are listed in Table 4.1.3: 1. Intermediate or lower dose levels, 
depending on the number of DLTs observed in the trial, and dose levels higher than 400 mg 
(as long as they fulfil the EWOC criterion) may be investigated if agreed upon between 
Investigator and sponsor.
Table 4.1.3: 1 Example of dose escalation*
Dose Escalation Rules
Example Dose Levels
Dose level
Increment from previous 
dose
Proposed dose
first
Starting dose
80 mg
second
200%
240 mg*
third
67%
400 mg*
*Actual dose assignments for individual patients will be communicated separately as 
determined by the SRC.
At the end of each treatment cohort, BI will convene a meeting with the SRC members. At 
the dose-escalation meeting the clinical course (safety information including but not limited 
to both DLTs and all Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 
toxicity data during Cycle 1) for each patient in the current dose cohort will be described in 
detail. Updated safety data on other ongoing patients, including data in later cycles, 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
There will be no dose reductions or escalations of BI 754091. The dose may be delayed for 
up to 6 weeks because of AEs, following discussion with the Medical Monitor.

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4.1.5
Definition of dose-limiting toxicity
Dose-limiting toxicities (DLTs) will be recorded throughout the trial. The BI DLT 
Assessment report is required to be completed and submitted by the Investigator after Phase I 
Cycle 1 only. This report should be submitted to the Medical Monitor and a copy kept in the 
ISF. Only DLTs occurring during Phase I Cycle 1 will be used for dose-escalation decisions. 
All relevant safety information (including DLTs) will be considered when selecting the 
RP2D.
Previous anti-PD-1 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 / 5.0. For the purpose of a 
dose-finding decision, any of the following AEs occurring during the first cycle of treatment 
(21 days) will be classified as DLTs following review by the Investigators and the sponsor.
Haematologic toxicities:
∀
Neutropenia ≥ Grade 4 present for >7 days
∀
Febrile neutropenia
∀
Neutropenia Grade 3 with documented infection
∀
Any Grade 3 thrombocytopenia with bleeding or a requirement for platelet transfusions
∀
≥ Grade 4 thrombocytopenia (platelets <25,000/μL).
Non-haematological toxicities:
∀
AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without initial 
findings of cholestasis (e.g., findings consistent with Hy's law or the FDA definition of 
potential DILI)
∀
≥Grade 4 AST or ALT of any duration
∀
Any ≥Grade 3 non-haematologic toxicity with the following exceptions:
-
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with immunosuppressive 
therapy within 2 weeks
-
Grade 3 fatigue that persists <7 days
-
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
-
Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated with 
clinical or radiographic evidence of pancreatitis
-
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical intervention
-
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention
-
Alopecia
-
Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that 
are managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy, and the patient is asymptomatic.
-
Grade 3 tumour flare.
∀
Any Grade 4 or 5 AE

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∀
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 2 weeks or requires 
systemic treatment
∀
Any treatment-related ≥ Grade 2 toxicity that persists and results in an inability to 
administer BI 754091 on Cycle 2 Day 1.
The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays, will be analysed to determine if a 
given toxicity should be considered a DLT for dose escalation purposes.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria but 
occur after the initial 21-day DLT period and during the first 90-day assessment period.
These, as well as all toxicities, will be monitored throughout the trial. If any late immune-
related DLT is reported during dose-escalation, the BLRM will be rerun including the late 
immune-related DLT, and updated results will be reviewed in the SRC meeting to 
recommend the next dose level and cohort size.
4.1.6
Definition of maximum-tolerated dose
The MTD may be considered reached if at least one DLT is observed in the trial and one of
the following criteria is fulfilled:
∀
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.50
OR
∀
At least 15 patients have been treated in the trial, of which at least 6 have been treated at 
the MTD.
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 and either:
∀
has completed the minimum safety evaluation requirements during the first cycle (first 
3 weeks)
OR
∀
has experienced a DLT during the first cycle (first 3 weeks).

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4.1.8
Method of assigning patients to treatment groups
After assessment of all inclusion and exclusion criteria, each eligible patient in the Phase Ia 
(dose escalation) portion of the trial will be assigned the lowest medication dose available at 
the time of enrolment.
To determine the dose regimen for the next cohort, the available toxicity information 
(including DLTs, AEs that are not DLTs, and AE information post-Cycle 1), PK, and PDc 
information, as well as the recommendations from the BLRM will be evaluated by the SRC 
members at the dose decision meeting. The parties must reach a consensus on whether to 
declare MTD, escalate the dose any further, or whether to de-escalate and/or expand 
recruitment into particular cohorts. Minutes from these meetings will be prepared and 
circulated to the trial team and each Investigator for comment prior to finalization. Dose 
escalation will continue until identification of the MTD estimate is encountered or until the 
trial is terminated for other reasons.
To further characterise the safety (e.g. specific suspected treatment-related AEs) or PK/PDc 
of BI 754091, one or several doses that are considered acceptably safe (i.e., shown to be 
lower than or equal to any potential MTD) may be expanded. Dose escalation may be 
terminated at any time based on emerging safety concerns without establishing the MTD.
In the second part (Phase Ib Dose Expansion), all patients will be treated with the schedule 
and dose determined by the assessment of DLTs and PK and biomarker results from the
Phase Ia portion of the trial. Patient numbers will be assigned as enrolment (screening) 
occurs.
4.1.9
Administration of doses for each patient
Vials of BI 754091 will be diluted and administered via infusion according to the details in 
the Pharmacy Manual.  Sites will provide normal saline (sodium chloride 0.9%) for the 
dilution of study drug.  For sites in the UK, the saline must be an EU licensed product.
4.1.10
Blinding and procedures for unblinding
Not applicable in this open-label trial.
4.1.11
Packaging, labelling, and re-supply
The investigational product will be provided by BI. It will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice. Each site will be provided 
with an initial shipment of trial drug supply. It will be the responsibility of the Investigator or 
designee to monitor that supply to ensure the site has enough for current and potential 
patients.
will monitor expiry dates of trial drug to trigger replacement supplies as 
needed. As needed, sites will request additional re-supply from
by using the 
Drug Request and Shipment form, which is available in the ISF. Upon receipt of the request, 
will trigger drug supply for the site using an IRT ‘light’ system. No re-supply 
will be possible after 31 August 2023.

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For details of packaging and the description of the label, refer to the ISF.
4.1.12
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
4.1.13
Drug accountability
The Investigator, or designee, will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled:
∀
Approval of the trial protocol and Informed Consent Form (ICF) by the Institutional 
Review Board (IRB)
∀
Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the Principal Investigator
∀
Availability of a signed and dated CTP
∀
Availability of the proof of a medical license for the Principal Investigator
∀
Availability of Form 1572.
The Investigator, or designee, must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or alternative 
disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator, or designee, will maintain records that document adequately that the patients 
were provided the specified doses and reconcile all investigational products received from the 
sponsor. Unused and partially used trial drug will be destroyed on site at the end of the trial
(after relevant reconciliations have been completed and records reviewed by the clinical 
monitor).
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
CONCOMITANT MEDICATIONS, AND RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used in this trial or special emergency 
procedures to be followed.
4.2.2
Concomitant medications
Rescue medication to reverse the action of BI 754091 is not available. Therefore, potential 
side effects of BI 754091 have to be treated symptomatically.

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Concomitant therapy, with reasons for the treatment, must be recorded in the eCRF during 
the screening and treatment periods, starting at the date of signature of the ICF and ending at 
the 30-day follow-up visit. After the 30-day follow up, only concomitant therapy indicated 
for treatment of a related AE has to be reported. If a new anti-cancer treatment is started, it 
will be documented in the eCRF, on a separate page of follow-up therapy, different from the 
concomitant therapies pages.
4.2.2.1
Permitted concomitant medications
∀
If medically feasible, patients taking regular medication should be maintained on it 
throughout the trial.
∀
Pre-medication will not be required, but may be utilised following the first dose of 
BI 754091. This includes medications for the management of nausea, diarrhoea, and 
vomiting for which the patient must be treated according to institutional standards.
∀
Supportive care and other medications that are considered necessary for the patient’s 
well-being may be given at the discretion of the Investigator.
∀
Blood transfusions are allowed at any time during the trial, except to meet inclusion 
criteria. There must be at least 4 weeks between a patient’s last transfusion and the 
screening laboratory assessment. Exceptions to this will be considered by the sponsor on 
a case by case basis.
∀
Patients already receiving erythropoietin at the time of screening for the trial may 
continue it, provided they have been receiving it for more than one month at the time trial 
treatment is started. Prophylactic erythropoietin should not be started during the first 
3 weeks of any cohort, but may be started thereafter.
∀
Granulocyte colony stimulating factors should not be used prophylactically during the 
first 3 weeks of any cohort. Thereafter, prophylactic colony stimulating factors may be 
used according to institutional standards.
∀
For symptom control, palliative radiotherapy is permitted for any lesion in the dose-
escalation part of the trial, except during the first cycle as it could interfere with the DLT 
evaluation for MTD determination. Following the first cycle of the dose-expansion phase 
(Phase Ib), palliative radiotherapy is allowed only for non-target lesions, following 
discussion with the Medical Monitor, provided that the reason for radiotherapy does not 
reflect PD and does not interfere with response assessment. Palliative radiotherapy is not 
allowed during the first cycle. Lesions that have been exposed to radiotherapy are no 
longer evaluable, and may not be included in the assessment of the non-target lesions and 
the overall assessment. These lesions may also not be used anymore for a trial biopsy. 
Unless in emergency situations, the Medical Monitor should be contacted prior to the 
administration of palliative radiotherapy in the expansion phase.
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.
∀
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 

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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, CT scan contrast 
hypersensitivity) are acceptable upon discussion with the Medical Monitor.
∀
Live attenuated vaccines during the trial through 30 days after the last dose of 
investigational product are prohibited.
∀
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 BI 754091.
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, females of childbearing potential can be included into this trial provided that they agree 
to use a highly-effective contraception method. These are 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.
Highly-effective methods of contraception include:
∀
Total sexual abstinence when this is in line with the preferred and usual lifestyle of the 
study participant, OR
∀
Bilateral tubal ligation, OR 
∀
Vasectomised partner (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate and provided that partner is the sole sexual partner of the woman of 
childbearing potential study participant), OR 
∀
Intrauterine device or intrauterine hormone-releasing system.
Details of these contraception methods are also described in the patient information in the 
ICF.
Women of childbearing potential must follow these methods during the trial and for at least 
6 months after the end of the trial treatment. Although use of a contraceptive pill is 
considered a highly-effective method of birth control, women of childbearing potential taking 
a contraceptive pill must use an additional barrier method for the entire duration of the trial 
treatment intake and for 6 months after the end of the trial treatment intake.

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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 will be administered intravenously 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.
5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary endpoints
The primary endpoint of the Phase Ia dose-escalation portion of the trial is:
∀
Number of patients experiencing DLTs graded according to CTCAE Version 4.03 / 5.0
observed in the first cycle (3 weeks) in order to meet the objective of assessment of the 
MTD of BI 754091.
The MTD is defined as the highest dose with less than 25% risk of the true DLT rate being 
above 33%. For definition of DLTs, refer to Section 4.1.5.
A BLRM employing the EWOC principle will be used during the escalation phase for 
selection of doses to investigate and for estimation of the MTD. Cohorts of patients will 
receive escalating doses of BI 754091 until the MTD is reached. Each cohort will consist of 
newly enrolled patients. Estimation of the MTD during the escalation phase of the trial will 
be based upon the estimation of the probability of a DLT in Cycle 1 in the set of evaluable 
patients for MTD. The corresponding methodology is described in Section 7 and 
Appendix 10.5. The MTD estimate established during the dose escalation phase will be re-
investigated after the expansion phase by re-running the BLRM including all data from 
escalation and expansion phase, in particular also considering the DLT information from all 
treatment cycles.
The primary endpoints of the Phase Ib dose-expansion portion of the trial are:
∀
Number of patients with DLTs observed during the entire treatment period.
∀
Confirmed Objective Response (OR), defined as the best overall response of confirmed 
complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed 
by the Investigator
5.1.2
Secondary endpoints
5.1.2.1
Secondary endpoints of the Phase Ia (dose escalation) portion of the trial
The secondary endpoints of the Phase Ia dose-escalation portion of the trial are:

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∀
The following PK parameters of BI 754091 (if feasible) will be evaluated after the first 
and after multiple administrations of BI 754091:
-
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
∀
Confirmed OR according to RECIST v1.1 as assessed by the Investigator
∀
Number of patients experiencing DLTs from the start of treatment until end of treatment
(in all cycles) as assessed approximately every 3 weeks.
5.1.2.2
Secondary endpoints of the Phase Ib (dose expansion) portion of the trial
The secondary endpoints of the Phase Ib dose-expansion portion of the trial are:
∀
Progression-free survival (PFS) defined from date of start of BI 754091 to the date of 
disease progression or death, whichever is earlier, according to RECIST v1.1 as assessed 
by the Investigator
∀
Safety will continue to be assessed by the recording of AEs, SAEs (including DLTs), 
laboratory evaluations, vital signs, and ECGs as:
-
Percentage of subjects with AEs 
-
Percentage of subject with SAEs
-
Percentage of subjects with clinical relevant abnormalities in vital signs, laboratory 
evaluations or ECG parameters (note that clinically relevant abnormalities are 
those which have to be reported by the investigator as AEs).

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5.2
ASSESSMENT OF EFFICACY
5.2.1
Tumour assessments
The tumour response will be evaluated according to RECIST Version 1.1 (R09-0262) and 
iRECIST (R17-0923). 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 considered measurable at baseline unless the lesions occurred 
after irradiation. Tumour assessment will be performed at screening (as close as possible to 
the treatment start and no more than 28 days before the start of BI 754091), every 2 cycles
during the first 6 months, and at the EOT visit (if not performed within the last 4 weeks).
Following 6 months of treatment, tumour assessments can be done once every 3 cycles, and 
at the discretion of the Investigator.

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If the patient stops with the trial medication intake for a reason other than PD, the tumour 
assessment according to RECIST will be performed according to standard of care until the 
last follow-up needed according to protocol (PD, death, lost to follow-up, end of the trial).
Following PD, a patient may continue to receive treatment for a year if the Investigator, 
Medical Monitor, and sponsor agree that the patient is deriving clinical benefit.
Copies of scans are to be collected by the sponsor upon request 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.
5.3
ASSESSMENT OF SAFETY
The safety of BI 754091 will be assessed by a descriptive analysis of incidence and severity 
of AEs graded according to CTCAE (Version 4.03/5.0), the incidence of DLTs, laboratory 
data, and results of physical examination. Safety will be assessed in a descriptive way without 
confirmatory analysis.
Dose-limiting toxicities observed during the MTD evaluation period (first 3 weeks) will be 
considered for MTD determination. However, all DLTs observed in all treatment cycles will 
be considered for determining a RP2D. The BLRM model will be re-run including the DLT 
information from all cycles. Based on both estimates, the recommended dose for further 
development will be selected. At regular intervals, all available safety data including AEs 
qualifying as DLTs will be submitted to the SRC. The SRC will independently assess this 
information and provide recommendations for trial conduct and dose escalation. If there are 
too few or no DLTs for BLRM guided dose selection, PK and/or biomarker data will be taken 
into consideration for RPIID determination.
5.3.1
Physical examinations and ECOG performance status
Physical examinations will be performed at screening, prior to trial medication administration 
on Day 1 of each cycle, at the EOT visit, and at the 30-day safety follow-up visit. However, 
patients will have an additional abbreviated physical examination (focused on the specific 
disease, at the Investigator’s discretion) on Cycle 1 Day 15.
The physical examination will include measurement of height (screening only) and of body 
weight, and the evaluation of the ECOG performance score. Weight will be measured during 
screening and at each full physical examination (not during abbreviated physical 
examinations).
The ECOG score will be assessed at screening, on Day 1 of Cycles 1 and 2, on Day 1 of 
every other cycle beginning with Cycle 3 prior to trial medication intake, at the EOT visit, 
and at the 30-day safety follow-up visit.

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5.3.2
Vital signs
Vital signs (blood pressure, body temperature, and pulse rate after 2 minutes 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.
5.3.3
Electrocardiogram
Local ECGs will be done throughout the trial. There will not be a centralised analysis. Single 
digitalized ECGs must be done at screening, Cycle 1 Day 1, Cycle 3 Day 1, Day 1 of every 
third cycle thereafter (Cycles 6, 9, 12, etc.), at the EOT visit, and whenever the Investigator 
deems it necessary. An ECG is optional at the 30-day safety follow-up visit if the EOT visit 
ECG was normal and no drug-related abnormalities were detected in on-trial ECGs.
When the ECG time point is concomitant with a blood sampling (or any other procedure), the 
ECG must always be performed prior to the blood sampling (or other procedure) to allow the 
recording in reproducible resting conditions. Detailed instructions for correct ECG recording 
are provided in the ISF. In case of drug-related ECG changes, additional ECG monitoring 
will be performed in the respective and later cycles of treatment, as deemed necessary by the 
Investigator.
The recordings will be checked for pathological results (to be recorded as AEs) by the 
Investigator.
5.3.4
Safety laboratory parameters
Blood (venous) samples will be collected at the times indicated in Flow Chart 1 and Flow 
Chart 2 and will be analysed by the sites’ local safety laboratories. Screening laboratory 
assessments performed within 72 hours of the first trial treatment administration are not 
required to be repeated on Cycle 1 Day 1. In cases where screening laboratory investigations 
have been performed >72 hours prior to the first trial treatment intake, the results of the new 
laboratory investigations performed within 72 hours of the first trial treatment administration 
must be available to confirm eligibility.
5.3.4.1
Haematology
Red blood cell count, haemoglobin, haematocrit, mean corpuscular volume, white blood cell 
count, and differential blood count will be expressed in absolute values, and platelets will be 
measured.
5.3.4.2
Biochemistry
The standard biochemistry panel will consist of glucose, sodium, potassium, chloride, 
calcium, phosphate, venous bicarbonate HCO3, creatinine, AST, ALT, alkaline phosphatase, 
lactate dehydrogenase (LDH), bilirubin, total protein, albumin, urea nitrogen (or urea), and 
uric acid. In addition, cholesterol, triglycerides, c-peptide, and creatine phosphokinase will be 
done at baseline and when clinically indicated. In case of pathological creatine 

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phosphokinase, further evaluation (e.g., by troponin assays) must be performed and the 
findings documented.
A thyroid panel (TSH, free T4, and free T3) will be done at the time of each standard 
biochemistry panel.
Additionally, amylase and lipase should be analysed in case of symptoms of pancreatitis.
5.3.4.3
Urinalysis
Urine (pH, glucose, erythrocytes, leukocytes, protein, and nitrite) will be analysed by dipstick
(semi-quantitative measurements) during the screening visit, at the EOT visit, and as 
clinically indicated. In case of pathological findings, further evaluation must be performed 
and the findings documented.
5.3.4.4
Pregnancy test
Beta human chorionic gonadotropin (β-HCG) pregnancy test in urine or serum will be
performed for women of childbearing potential at screening, within 14 days prior to first trial 
treatment, on Day 1 of each cycle prior to administration of BI 754091, before the start of 
each repeated cycle, and at the EOT visit.
5.3.5
Other safety parameters
None
5.3.6
Assessment of adverse events
5.3.6.1
Definition of adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.

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5.3.6.2
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 
exposure. Conditions of use outside the marketing authorisation include off-label use, 
overdose, misuse, abuse and medication errors.
5.3.6.3
Definition of serious adverse events
An SAE is defined as any AE that:
∀
results in death,
∀
is life-threatening. This refers to an AE in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
∀
requires inpatient hospitalisation or
∀
prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity, or
∀
is a congenital anomaly / birth defect, or
∀
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalisation or development of dependency or abuse.
∀
Any suspected transmission via a medicinal product of an infectious agent is also 
considered an SAE.
Patients may be hospitalised for administrative reasons during the trial, including 
hospitalisation for respite care. These as well as hospitalisations/surgical procedures which 
were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalisation/surgical procedure has not 
changed/worsened after signing the informed consent).
5.3.6.4
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 Section 5.3.6.8, subsections “AE Collection” and AE reporting to 
sponsor and timelines”.
In accordance with the EMA initiative on Important Medical Events, BI has 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 given above. The latest list of ‘Always 

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Serious AEs’ can be found in the electronic document system. These events should always be 
reported as SAEs as described above.
5.3.6.5
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. 
AESI need to be reported within the same timeframe that applies to SAEs and according to 
the information in Section 5.3.6.8.
For this trial, DLTs, infusion-related AEs, DILI events, hepatic injury and qualifying irAEs, 
as defined in Appendix 10.1, are AESIs (see Section 5.3.6.5.2 and Section 5.3.6.5.3, 
respectively).
5.3.6.5.1
Dose-limiting toxicities (DLTs)
All DLTs are considered to be AESIs, and must be reported as such. The definition of DLT is 
presented in Section 4.1.5.
5.3.6.5.2
Immune-related adverse events (irAE)
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. All immune-related events are to be reported as AEs. Some irAEs also 
need to be reported as AESIs as defined in Table 10.1: 1. If an Investigator determines a 
Grade 3 event (not on the list) to be immune related, the Investigator should also report that 
event as an AESI.
Recommendations for the management of irAEs are presented in Appendix 10.2.
5.3.6.5.3
Infusion-related reactions
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of BI 754091 may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate.
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional 
standard may be administered prior to subsequent infusions at the discretion of the 
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the study, treatment with 
BI 754091 will be permanently discontinued.
As with any mAb, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 

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and trial personnel must be trained to recognize 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 
within 24 hours of the event:
∀
Allergic reaction
∀
Anaphylaxis
∀
Cytokine-release syndrome
∀
Serum sickness
∀
Infusion reactions
∀
Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential infusion-
related AE, the Investigator may also report that event as an AESI.
5.3.6.5.4
Hepatic injury and drug-induced liver injury (DILI)
During the course of the trial the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets the 
hepatic injury definition or potential Hy’s Law criteria at any point during the trial.
The Investigator participates, together with the Medical Monitor and BI clinical project 
representatives, in review and assessment of cases meeting potential hepatic injury and Hy’s 
Law criteria. Hy’s Law criteria are met if there is no alternative explanation for the elevations 
in liver biochemistry other than a DILI caused by the investigational product.
The Investigator is responsible for recording data pertaining to these cases and for reporting 
them as AEs and/or SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Hepatic injury definition:
In patient with normal baseline hepatic function, hepatic injury is defined by the following 
alterations in hepatic laboratory parameters:
∀
An elevation of AST and/or ALT ≥3 times the ULN combined with an elevation of total 
bilirubin ≥2 times the ULN measured in the same blood draw sample. And/or
∀
Marked peak AST and/or ALT elevation ≥10 times the ULN.
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)

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∀
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.
5.3.6.6
Severity of adverse events
The severity of AEs should be classified and recorded in the eCRF according to the CTCAE 
Version 4.03/5.0.
5.3.6.7
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 was evident.
∀
There is evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g., pre-existing 
or concomitant diseases, or co-medications) exist.
∀
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g., Stevens-Johnson syndrome).
∀
There was an indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
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).
∀
The event continued despite the withdrawal of the medication, taking into account the 
pharmacological properties of the compound (e.g., after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
There may be additional arguments amongst those stated before, like alternative 
explanation (e.g., situations where other drugs or underlying diseases appear to provide a 
more likely explanation for the observed event than the drug concerned).

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For sites outside of the US, country-specific fax numbers will be provided in the ISF/Study 
reference manual.
The same timeline applies if follow-up information becomes available. On specific occasions, 
the Investigator could inform the
upfront via telephone by 
calling the 
SAE reporting phone number (
). This does 
not replace the requirement to complete and fax the BI SAE form.
With receipt of any further information 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 on the BI SAE Report form. The Investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as (S)AEs in the eCRF and SAE form (if applicable):
∀
Worsening of pre-existing conditions
∀
Changes in vital signs, ECGs, physical examinations, and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after an individual patient’s end of trial must be 
followed up until they have resolved, they have been sufficiently characterised, or no further 
information can be obtained.
5.3.6.9
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy to the
The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure must be followed up and 
reported to the sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical 
Trials (Part B).
The ISF will contain the Pregnancy Monitoring Forms for Clinical Trials (Parts A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.

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5.3.6.10
Exemptions to SAE Reporting
Disease progression is a trial endpoint for analysis of efficacy and as such is exempted from 
reporting as an AE or an SAE.  Progression of the subject's underlying malignancy will be 
recorded on the appropriate pages of the eCRF as part of efficacy data collection only and 
will not be reported on the SAE Form. It will therefore not be entered in the safety database 
(ARISg) and hence not get expeditiously reported. Death due to disease progression is also to 
be recorded on the appropriate eCRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy, the event must be reported as an SAE on 
the SAE Form and on the eCRF.
Examples of exempted events of PD may be:
∀
Progression of underlying malignancy (progressive disease [PD]): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 
∀
Hospitalisation/procedures due solely to the progression of underlying malignancy (PD)
∀
Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g., imaging, clinical measurement): if the symptom can exclusively be determined to be 
due to the progression/relapse of the underlying malignancy and does meet the expected 
pattern of progression for the disease under study.
Exempted events are collected and tracked following a protocol specified monitoring plan. 
Exempted events are monitored at appropriate intervals throughout the study at quarterly 
Program Safety Management Team Meetings.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of pharmacokinetics
If data allow, the PK parameters of BI 754091 mentioned as secondary and further endpoints 
(see Section 5.1.2 and Section 5.1.3, respectively) will be evaluated using non-compartmental 
analysis methods according to BI internal SOP.
.
5.4.2
Methods of sample collection for pharmacokinetic analyses
For quantification of analyte plasma concentrations, samples will be drawn at the time points 
listed in Flow Chart 1 and Flow Chart 2 under PK sampling and specified in PK time 
schedules in Appendix 10.4 (Phase Ia dose escalation: Table 10.4.1: 1 and Table 10.4.1: 2, 
and all cohorts in Phase Ib dose expansion: Table 10.4.2: 1).
If collected from an arm, it is essential to collect blood from the arm that is opposite to the 
arm used for infusion in order to avoid artificially high or low drug concentration 
determinations. Further details on sample characteristics, processing, handling, and shipment 

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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.
5.4.4
Pharmacokinetic/pharmacodynamic (PK/PDc) relationship
No formal analysis of a PK/PDc relationship is planned.
If data suggest a PK/PDc relationship of special parameters 
 
 an analysis may be performed. Further assessments might be 
done, if feasible.
, but if 
BI 754091 behaves similarly to pembrolizumab, a maximum RO of 80% will be measured 
already at the starting dose of 80 mg (1 mg/kg for an 80-kg person) (R16-2024). Most other 
potential PDc markers (e.g., CD8 infiltration) occur at the tumour site and are dependent on 
efficacy, and are therefore not suited to establish a PK/PDc relationship.
Data may also 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.
5.5

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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.
5.5.1
Methods of sample collection
Pre- and on-treatment tumour biopsy collections for biomarker and PDc analyses will be 
mandatory from all patients in the Phase Ib dose-expansion portion of the trial. In addition, 
biopsies should be taken according to the flowchart and Section 5.5.2.3. Patients in the dose-
escalation cohorts may consent to optional paired biopsies. All samples must be adequately 
labelled by the trial site personnel. Details about tumour tissue and blood sample collection, 
plasma/serum preparation, required tubes, labelling of tubes, storage and shipment (frequency 
and addresses) will be provided in the ISF.

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Details on sample collection, characteristics, processing, handling, and shipment are provided 
in the Laboratory Manual. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the final trial report has been signed.
Note that for some disease indications, it may be necessary to use plasma samples collected 
prior to administration of test article in order to assess the performance of the ADA assay. 
Such use of pre-dose samples will not compromise the collection of valid ADA data for those 
pre-dose samples.
5.7
APPROPRIATENESS OF MEASUREMENTS
All assessments have been planned in accordance with traditional oncology Phase I trial
methodology.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of 2 parts. The first part is a dose-escalation phase (Phase Ia) to determine 
the MTD and the recommended dose for the Phase Ib dose expansion. The schedule shown to 
have a more favourable safety, PK, and biomarker profile will be chosen to be further 
investigated in the expansion phase. The second part (Phase Ib) is an expansion phase to 
further evaluate safety, efficacy and PK profile of BI 754091, as well as biomarker values as 
a result of treatment.
Patients meeting the inclusion and exclusion criteria for the part they are participating in and 
who have given their written ICF, are eligible for participation in the trial. Patients will visit 
the clinical site at the time points specified in Flow Chart 1 (dose escalation) and Flow Chart
2 (dose expansion). If a patient misses a scheduled visit, and reports to the Investigator
between the missed visit and the next scheduled visit, the assessments for the missed visit 
must be done with the actual date and the reason must be given for the delayed visit. For the 
biopsies and PK sampling procedures of Cycle 1, the patient must however still be under 
treatment and not in a treatment break period in order to perform the evaluations planned for
the missed visit. The next visit must then take place at the scheduled time after the first 
administration of the trial drug in the respective treatment cycle.
Once the decision for any reason is made for a patient to stop the treatment with BI 754091, 
an EOT visit must occur as soon as possible (preferably within 7 days). After the EOT visit, 
the patient must undergo a follow-up evaluation 30 (+2) days after the last BI 754091 
administration. 
The trial will be conducted according to the principles of Good Clinical Practice (GCP).

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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The procedures required at each trial visit in both portions of the trial are presented in Flow 
Chart 1 (dose escalation) and Flow Chart 2 (dose expansion) of this protocol. The key 
procedures required include:
∀
PK samples throughout the trial
∀
Reporting of all AEs occurring after the ICF has been signed
∀
Baseline and on-treatment blood biomarker and immunogenicity assessments
∀
Tumour biopsy biomarker assessments
∀
Tumour assessments (based on CT/PET and/or MRI scan) according to RECIST 
Version 1.1 and iRECIST must be performed once every 2 cycles (meaning every 
6 weeks if there are no delays in cycles but as close as possible to the end of the second of 
the 2 cycles of treatment if there was a delay) after the start of BI 754091.
6.2.1
Screening period
The screening period may run over a period of 28 days (period within the trial and before the 
first intake of BI 754091). For the detailed description of the tests to be performed during this 
period and their timing, please refer to Flow Chart 1 (dose escalation) and Flow Chart 2 (dose 
expansion).
6.2.1.1
Screening for tumour mutational burden (TMB) and MSI-high cohort
For Cohort 5, the TMB, as well as the microsatellite stability (MS) status have to be assessed. 
Patients that have high TMB (defined as ≥10 mutations/Mb) and are MS stable (MSS) will be 
included. Any validated assay may be used to determine the MS status and TMB.
If polymerase epsilon (ε) catalytic subunit (POLE) mutation status is known for any patient in 
the TMB-high cohort, this information should be collected.
6.2.1.2
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.
6.2.1.3
Medical history
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, 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 

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neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
line 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.
Exclusion Criterion #13 (see Section 3.3.3) does not apply to the patients with cervical/anal 
and vulvovaginal cancer enrolling into Cohorts 6 and 7. However, virology testing should 
still be done and the status of HIV and hepatitis B or C virus should be collected on the 
eCRF.
6.2.1.4
Concomitant therapies
Relevant concomitant diagnoses and/or therapies present at trial entry and/or during 
screening and relevant to the patient’s safety during the trial as judged by the Investigator 
will be recorded in the eCRF (see Section 4.2.2 for details on concomitant medications). 
Post-trial therapy for advanced or metastatic disease will also be documented.
6.2.2
Treatment period
Please refer to Flow Chart 1 (dose escalation) and Flow Chart 2 (dose expansion) for a 
detailed presentation of each visit during the treatment period.
6.2.3
Follow-up period and trial completion
6.2.3.1
End-of-treatment visit
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason, as soon as possible, but no later than 7 days after permanent discontinuation of the 
trial medication or when the Investigator decided with the patient to permanently discontinue 
the trial medication or became aware that the trial medication had been terminated.
The assessments of the EOT visit will then be performed instead of at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of treatment discontinuation, unless it has been done within the past 
4 weeks.
For patients still on treatment with ezabenlimab at the time point of this protocol amendment, 
the investigators are asked to prepare for discontinuation of patients from the current 
investigational treatment with ezabenlimab and to switch them to alternative available 
treatment options outside of the current protocol no later than by the final availability of 
ezabenlimab in August 2023 the latest. After this date treatment with the ezabenlimab will no 
longer be available.
For these patients only EOT visit will be performed. 30-day post-treatment safety visit as 
well as Progression-free survival visits are not applicable.

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6.2.3.2
30-day post-treatment safety visit
The safety follow-up visit is performed 30 (+2) days after permanent discontinuation of the 
trial medication. The information collected at this visit must include all new AEs that 
occurred after the EOT visit, and a follow-up of AEs ongoing at EOT.
A patient will be considered as having completed the trial if he/she discontinues because of
PD and has performed the safety follow-up visit 30 days after EOT, or was lost to follow up,
or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for any 
other reason, he/she will be considered as withdrawn.
6.2.3.3
Progression-free survival visits
Additional follow-up visits after the 30-day safety follow-up visit will only be performed for 
patients who did not progress on treatment. These will be performed once every 12 weeks at 
least (by telephone) until PD, introduction of a new anti-cancer treatment, death, loss to 
follow-up, or end of the whole trial as specified in Section 3.3.4.2.
6.2.3.4
Overall survival visits
Additional follow-up visits after the 30-day safety follow-up visit will be performed for 
patients that enrolled in Protocol Version 4.0 and beyond. These will be performed once 
every 12 weeks at least (by telephone) on the same schedule as PFS survival visits until 
death, loss to follow-up, or end of the whole trial as specified in Section 3.3.4.2. If the 
sponsor determines that enough OS data has been collected from select cohorts, sites could be 
instructed to discontinue OS visits for those cohorts.
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a Phase I, open-label, dose-escalating trial to determine the MTD and the RP2D for 
BI 754091 in patients with solid tumours. In addition, the safety and PK profiles, biomarkers, 
and efficacy of BI 754091 will also be assessed.
7.1.1
Statistical design – Phase Ia (dose escalation)
The objective of the Phase Ia portion of the trial is to determine the MTD and the RP2D. The 
MTD is defined as the highest dose with less than 25% risk of the true DLT rate being above 
0.33 (EWOC criterion) under the condition of at least one DLT observed in this trial. The 
Phase Ia dose-finding will be guided by a BLRM with overdose control (R13-4803).
The model is given as follows:
logit(p(d)) = log(α) + β*log(d/d*),
where logit(p) = log(p/(1-p)). 

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p(d) represents the probability of having a DLT in the first cycle at dose d, d* = 800 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:
Under dosing:
[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:
∀
At least one DLT observed in the trial, and either 
∀
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.50, OR
∀
At least 15 patients have been treated in the trial, of which at least 6 at the MTD.
The SRC may recommend stopping the dose-finding phase after the criteria for MTD are
fulfilled. If no DLTs are observed during the Phase Ia dose-escalation phase, the SRC may 
conclude that the MTD was not found and decide to include an additional number of patients 
at a dose of which the efficacy is considered sufficient as the dose recommended for further 
testing. This dose level may be equal or below the highest tested dose level. 
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of two
multivariate normal distributions, i.e.
π(θ) = φ1π1(θ) + φ2π2(θ) 
with 
φi, i = 1, 2 the prior mixture weights (φ1+ φ2 = 1)
and 
πi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where

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##
∃
%
&&
∋
(
)
∗
2
22
,
22
,
11
,
22
,
11
,
2
11
,
i
i
i
i
i
i
i
i
i
+
,
+
+
,
+
+
+
Mixtures of prior distributions have the advantage of allowing for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
7.1.1.1
Prior derivation
For the current trial, limited information about PD-1 from human data was available (Phase I 
Study of Pembrolizumab [MK-3475; Anti–PD-1 Monoclonal Antibody] in Patients with 
Advanced Solid Tumours [R16-2024]). PD-1 is considered as a well-tolerated treatment with 
low DLT rate. Therefore, the 2 mixture components were established as follows:
1. A weakly informative prior was derived to reflect a priori assumption that the median 
DLT rate at the starting dose of 80 mg would equal 0.001%, and the median DLT rate at 
3200 mg would equal 30%. This yields μ1 = (-4.855, 1.062). The standard deviations 
were set such that large uncertainty about the parameter means is reflected, and the 
correlation was set to 0, thus yielding σ1,11 = 2, σ1,22  = 1 and ρ1 = 0, respectively. The 
prior weight φ1 for the first component was chosen as 0.9.
2. A high-toxicity weakly informative prior was derived to reflect the case that the 
compound would be much more toxic than expected. For this prior component, it was 
assumed that the median DLT rate at 80 mg would equal 5%, and the median DLT at 
3200 mg would equal 70%. These assumptions yield μ2 = (-0.578, 0.028). The standard 
deviations and correlations were set identical to the weakly informative prior, i.e. σ2,11 = 
2, σ2,22  = 1 and ρ2 = 0, respectively. The prior weight φ2 for the second component was 
chosen as 0.1.
A summary of the prior distribution is provided in Table 7.1.1.1: 1. Additionally, the prior 
probabilities of DLT at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1.1.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1.1.1: 1. As can be seen from 
both the table and the figure, the prior medians of the DLT probabilities are all quite low for
the selected doses in the range of 80 mg to 800 mg which is in-line with the prior medians 
derived from the weakly informative prior, and the uncertainty around the medians is large, 
showing the low amount of information this prior provides. This is also supported by the 
prior sample size, i.e., the information contained in the prior. This is approximately equal to 
1.35 patients. A detailed evaluation of the model using hypothetical data scenarios and 
operating characteristics is provided in the statistical appendix (see Appendix 10.5).

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Table 7.1.1.1: 1 Summary of prior distribution
Prior 
Component
Mixture
Weight
Mean 
vector
Std Dev 
vector
Correlation
1: Weakly 
Informative 
Prior
0.9
(-4.855, 
1.062)
(2.000, 
1.000)
0.000
2: High Tox
0.1
(-0.578, 
0.028)
(2.000, 
1.000)
0.000
Table 7.1.1.1: 2
Prior probabilities of DLTs at selected doses
Dose
Probability of true DLT rate in
Quantiles
Mg
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
Std Dev
2.5%
50%
97.5%
80
0.970
0.012
0.019
0.018
0.090
0
0
0.218
160
0.961
0.015
0.024
0.023
0.103
0
0
0.319
240
0.953
0.017
0.029
0.028
0.113
0
0
0.398
320
0.946
0.020
0.034
0.033
0.122
0
0.001
0.456
480
0.930
0.026
0.044
0.043
0.139
0
0.002
0.56
640
0.912
0.034
0.054
0.055
0.154
0
0.004
0.645
800
0.881
0.049
0.070
0.075
0.172
0
0.01
0.727
Figure 7.1.1.1: 1
Prior medians and 95% credible intervals

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7.1.1.2
Statistical model assessment
The model was assessed using 2 different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could occur 
in the actual trial, the maximal doses allowed in the next cohort by the model are
investigated. Data scenarios thus provide a way to assess the ‘on-study’ behaviour of the 
model.
2. Simulated operating characteristics: these illustrate for different assumed true dose-
toxicity relationships, how often a correct dose would be declared as MTD by the model. 
They are a way to assess the ‘long-run’ behaviour of the model.
In summary, the model showed very good behaviour as assessed by these metrics. More 
details can be found in Appendix 10.5. The simulations for scenarios and operating 
characteristics were produced using RStudio version 0.98.507.
7.1.2
Statistical design – Phase Ib (dose expansion)
The Phase Ib (dose-expansion) portion of the trial will recruit approximately 130 patients 
with selected locally advanced or metastatic cancers at the dose and schedule recommended 
by the SRC.
The analyses of the safety and efficacy for this portion of the trial will be descriptive and 
exploratory in nature.  Additional analysis may be applied to evaluate the robustness of the 
efficacy results. More details will be specified in the TSAP.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. 
7.3
PLANNED ANALYSES
For the determination of the MTD, only MTD-evaluable patients will be considered. For 
other analysis of efficacy and safety 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 Trial Statistical Analysis Plan (TSAP).
No per protocol set will be used in the analysis. However, important protocol violations will 
be summarised with details specified in the TSAP.
7.3.1
Primary endpoint analyses
In order to identify the MTD of the trial, the number of patients with DLTs at each dose level
during the Phase Ia MTD evaluation period (first three weeks) must be presented. Patients 
who discontinue during the first treatment course for reasons other than a DLT will be 
excluded from the determination of the MTD.

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In addition, the number of patients with DLTs that occurred during the entire treatment 
period, including Phase Ia and Phase Ib, will be summarised at each dose level. The BLRM 
will be rerun to re-evaluate the MTD and RP2D together with all relevant data collected 
during Phase Ib.
For the primary efficacy endpoint of Phase Ib, objective response rate (ORR) will be 
summarised and presented with 95% two-sided confidence intervals using the Clopper-
Pearson method.
7.3.2
Secondary endpoint analyses
For PFS, the Kaplan-Meier curve and estimates will be displayed with 95% confidence
intervals, using Greenwood’s variance formula. The detailed censoring rules are specified in 
the TSAP.
Details on statistical inference for PK parameters, e.g. dose proportionality using Cmax and 
AUC etc., and all other secondary endpoints analysis will be specified in the TSAP.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. 
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. All 
AEs with an onset between start of treatment and end of the REP, a period of 30 days after 
the last dose of trial medication, will be considered ‘treatment-emergent’ and assigned to the 
treatment period for evaluation. Adverse events that start before first drug intake and 
deteriorate under treatment will also be considered as ‘treatment-emergent’.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of MedDRA.
Laboratory data will be analysed quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 

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Treatment groups will be compared descriptively with regard to distribution parameters as 
well as frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Pharmacokinetic parameters as described in Section 5.4.1 will be calculated by means of non-
compartmental analysis. The derivation of PK parameters is described in BI internal SOP.
Further details on analysis will be described in the TSAP.
7.4
INTERIM ANALYSES
The sponsor will continuously monitor the safety. The dose-escalation design dictates that the 
sponsor and the SRC perform regular safety evaluations. These evaluations will be unblinded 
to dose.
If considered necessary, as soon as the MTD is determined, an evaluation of the safety 
aspects will be performed. Results of this evaluation will be documented and archived. If 
applicable, such an analysis will be defined in more detail in the TSAP.
No formal interim analysis of PK data is planned. However, an exploratory analysis of PK 
will be done after patients in Cohort 1 complete Cycle 1 and once patients in Cohort 2 
complete Cycle 1. Further exploratory analyses of PK might be performed if considered 
reasonable.
Exploratory PK analyses will be based on planned sampling times, if information on actual 
times should not be available. The results of these evaluations will be preliminary and may be 
subject to change, as these do not involve a formal database lock. No interim report will be 
written for exploratory PK analyses. If medically justified, further or fewer exploratory PK 
analyses may be performed.
Interim efficacy analyses are planned for selected groups of patients (defined in Section 3.1) 
in the Phase Ib portion of the trial. Because of the expected challenge in recruiting these 
patients, the two-stage design is planned to stop further recruitment of the specific patient 
group if the defined efficacy boundary (see Table 7.4: 1) is not met at the first stage. Interim 
efficacy analyses were not deemed necessary for the TMB high cohort 5 as recent literature 
already demonstrates an association between high TMB and better response rates for patients 
taking immune checkpoint inhibitors (R18-1492).
The interim analyses for Cohort 6 will be conducted when:
∀
10 patients with squamous cervical and/or anal cancer have been treated, and the 10th
patient has been on treatment for ~3 months.
∀
10 patients with squamous skin tumours have been treated, and the 10th patient has 
been on treatment for ~3 months.

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The interim analysis for Cohort 7 will be conducted when 20 patients with vaginal or VSCC 
have been treated, and the 20th patient has been on treatment for ~3 months. 
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.
∀
Literature on preliminary data of nivolumab and pembrolizumab (R17-3902; R17-
3903; R17-3822) showed ORR ranges from 13% to 24% in patients with squamous 
cervical and anal tumours. Therefore, an underlying ORR of 25% is assumed. The 
probability of observing zero responders out of 10 and stopping at interim is 6%, and 
the probability of observing ≥20% ORR at final analysis is 77%. If the underlying 
ORR is 5%, the probability of stopping early is 61%, and the false positive probability 
of observing ≥20% ORR at final analysis is almost 0.
∀
It was shown in Chalmers ZR et al, 2017 (R17-3824) that the population with 
squamous skin cancer had very high proportion of patients with high TMB (~70%). 
Therefore, the clinical benefit is expected to be similar to patients with high TMB 
(R17-3768). Assume the underlying ORR is 50%, the probability of observing 
<3 responders out of 10 and stopping at interim is 5%, and the probability of 
observing ≥40% ORR at final analysis is 87%. If the underlying ORR is 20%, the
probability of stopping early is 67%, and the false positive probability of observing 
≥40% ORR at final analysis is 1%.
∀
Literature on preliminary data from older chemotherapy/targeted agent trials (R18-
2645; R18-2646; R18-2647) and early phase immunotherapy trials (R18-2650; R18-
2651) showed ORR ranges from 13% to 29% in patients with recurrent, inoperable 
VSCC. Therefore, an underlying ORR of 25% is assumed. The probability of 
observing 0 or 1 responder out of 20 and stopping at interim is 2%, and the 
probability of observing ≥20% ORR at final analysis is 82%. If the underlying ORR is 
5%, the probability of stopping early is 74%, and the false positive probability of 
observing ≥20% ORR at final analysis is almost 0.

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Table 7.7.2: 1 Probabilities of observing certain objective response rates
Assumed 
underlying ORR
Sample 
size
Probability to observe at least
ORR >= 25% (>=8 
responders)
ORR >= 30% (>=9 
responders)
ORR >= 35% (>= 
11 responders)
15%
30
7%
3%
0%
20%
30
24%
13%
3%
25%
30
49%
33%
11%
30%
30
72%
57%
27%
35%
30
88%
78%
49%
40%
30
96%
91%
71%
45%
30
99%
97%
86%
For the selected squamous tumours cohort (Cohort 6), probability calculations are provided in 
Table 7.4: 1 using the two-stage approach. Depending on the Stage 1 result for the squamous 
cohort, sample size may vary between 20 and 60 patients.
For the vaginal or VSCC cohort (Cohort 7), probability calculations are provided in Table 
7.4: 1 using the two-stage approach. If the stage 1 result is positive (i.e., at least 2 responders 
out of 20 patients), sample size for this cohort will be increased to 40 patients; otherwise, 
recruitment will be stopped in case of negative interim analysis. 
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline 
for GCP, relevant BI SOPs, and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor with regard 
to publication of the results of this trial are described in the Investigator contract. As a rule, 
no trial results should be published prior to finalization of the Clinical Trial Report.

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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 IRB and competent authority according to national and 
international regulations. The same applies for the implementation of changes introduced by 
amendments.
Prior to patient participation in the trial, written signed ICF must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the ICF and any additional patient-information form 
retained by the Investigator as part of the trial records. A signed copy of the ICF and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The Investigator must give a full explanation to trial patients based on the ICF information. A 
language understandable to the patient should be chosen, technical terms and expressions 
avoided, if possible. The patient must be given sufficient time to consider participation in the 
trial. The Investigator obtains written consent of the patient’s own free will with the ICF after 
confirming that the patient understands the contents. The Investigator must sign (or place a 
seal on) and date the ICF. If a trial collaborator has given a supplementary explanation, the 
trial collaborator also signs (or places a seal on) and dates the ICF.
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 the IRB or regulatory authorities. The quality assurance auditor will have access 
to all medical records, the Investigator’s trial-related files and correspondence, and the ICF
documentation of this clinical trial.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by 
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible,
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail). 

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Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make 3 documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in the
medical records, will be acceptable.
Before providing any copy of patients’ source documents to the sponsor, the Investigator 
must ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted to ensure patient 
confidentiality.
Copies of tumour assessments scans may be collected by the sponsor upon request. This 
could include CT/PET scans of the chest and abdomen and/or imaging of any other known or 
suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT/PET scan or 
MRI).
If the patient is not compliant with the protocol, any corrective action (e.g., re-training) must 
be documented in the patient file.
For the eCRF, data must be derived from source documents, for example:
∀
Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases [if applicable])
∀
Medication history
∀
Adverse events and outcome events (onset date [mandatory], and end date [if available])
∀
Serious AEs (onset date [mandatory], and end date [if available])
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with 
properly documented medical evaluation (in validated electronic format [if available])
∀
Completion of 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 makes the 
patient ineligible for the clinical trial.
∀
Technical information collected on PK sampling days (e.g., PK sampling times, repeated 
vital signs linked with PK) may be collected on specific paper PK logs, which will be 
considered as source data for related entries in eCRF and are considered part of the ISF.

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8.3.2
Direct access to source data and documents
will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality reviews. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the monitor, auditor, and regulatory inspector 
(e.g., FDA). The monitor and auditor may review all CRFs and ICFs. The accuracy of the 
data will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to the 
national or local requirements (whichever are is longer) valid at the time of the end of the 
trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
will retain trial documents according to contractual agreements with the sponsor.
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 5.3.6.10, 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 World Health 
Organization GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, the IRB, and the regulatory authorities.

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8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular
∀
A Quality Management System has been implemented to ensure the adherence with the 
principles of GCP as outlined in 'Note For Guidance On Good Clinical Practice' 
(CPMP/ICH/13 5/95)
∀
The BI-internal facilities storing and analysing biological samples and data from clinical 
trial participants as well as the laboratories' activities for clinical trials sponsored by BI
are regularly audited. The analytical groups and the banking facilityare therefore assessed 
to be qualified for the storage and use of biological samples and data collected in clinical 
trials.
∀
Samples and data are used only if an appropriate ICF is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the trial. 
The end of the trial is defined as the date of the last visit of the last patient in the trial (‘Last 
Patient Out’).
The ‘Last Patient Drug Discontinuation’ (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of suspected unexpected serious 
adverse reactions occurring with the trial medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.

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9.
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 
Human Use (CHMP): guideline on clinical trials in small populations. 
London, 27 July 2006: doc. ref. CHMP/EWP/83561/2005.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009;45:228-47.
R12-5176
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et 
al. Improved survival with ipilimumab in patients with metastatic melanoma. 
N Engl J Med. 2010;363(8):711-23.
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A Guide to 
Rational Dosing of Monoclonal Antibodies. Clin Pharmacokinet. 
2012;51(2):119-35.
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol. 2013;71:1107-14.
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2008;27:2420-39.
R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A.
Translation of innovative designs into phase I trials. J Clin Oncol. 
2007;25(31):4982-6.
R13-4805
Le Tourneau C, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted agents. 
Plos One. 2012; 7(12):e51039.
R13-4881
FDA's critical path initiative. U.S. Food and Drug Administration; 2012 
[webpage updated 28 December 2012; accessed 8 November 2013]. 
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm
07668 9.htm.
R15-3504
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence 
worldwide in 2012 [homepage]. World Health Organization International 
Agency on Cancer; 2012. http://globocan.iarc.fr/Default.aspx.
R15-3588
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, 
et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. 
N Engl J Med. 2012;366(26):2443-54.
R15-3715
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et 
al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell 
lung cancer. N Engl J Med. 2015;373(2):123-35.
R15-3777
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. 
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-
refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 
trial. Lancet Oncol. 2015;18(8):908-18.

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R15-3778
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-
programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-
refractory advanced melanoma: a randomised dose-comparison cohort of a 
phase 1 trial. Lancet 2014;384:1109-17.
R15-3780
Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD et al. 
Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-
refractory or -naive melanoma. J Clin Oncol. 2013;31(34):4311-8.
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Garon EB, Rizvi NA, Hui, R, Leighl N, Balmanoukian AS, Eder JP, et al. 
KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-
cell lung cancer. N Engl J Med. 2015;372(21):2018-28.
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Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et 
al. Management of immune checkpoint blockade dysimmune toxicities: a 
collaborative position paper. Ann Oncol. 2016; February 11: 
doi:10.1093/annonc/mdv623.
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Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman 
WH, et al. Survival, durable tumor remission, and long-term safety in patients 
with advanced melanoma receiving nivolumab. J Clin Oncol. 
2014;32(10):1020-30.
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Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay 
S, et al. Immune-related adverse events with immune checkpoint blockade: a 
comprehensive review. Eur J Cancer 2016;54:139-48.
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Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, 
advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet 2016;387(10027):1540-50.
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Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint 
inhibitors. Cancer Treat Rev. 2016;44:51-60.
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Le DT, Uram JN,Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 
blockade in tumors with mismatch-repair deficiency. N Engl J Med. 
2015;372:2509–20.
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Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram 
M, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal 
antibody) in patients with advanced solid tumors. Clin Cancer Res. 
2015;21(19):4286-93.
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Francisco LM, Sage PT, Sharpe AH. The PD-I Pathway in Tolerance and 
Autoimmunity. Immunol Rev. 2010;236:219-42.
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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 motif-
carrying immunoreceptor. Immunity 1999;11:141-51.
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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.

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Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et 
al. CheckMate 025 Investigators. Nivolumab versus everolimus in advanced 
renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-13.
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Dong H, Zhu G, Tamada K, Flies DB, van Deursen JMA, 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):265-8.
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Okazaki T, Okazaki I, Wang J, Sugiura D, Nakaki F, Yoshida T, et al. PD-1 
and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity 
in mice. J Exp Med. 2011;208(2):395-407.
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Seymour L, Bogaerts J, Perone A, Ford R, Schwartz LH, Mandrekar S, et al. 
RECIST Working Group iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152.
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Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al.  
Tumor mutational burden as an independent predictor of response to 
immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598-608. 
doi: 10.1158/1535-7163.MCT-17-0386. Epub 2017 Aug 23.
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Pakish JB, Jazaeri AA. Immunotherapy in gynecologic cancers: Are we there 
yet? Curr Treat Options Oncol. 2017;18:59. doi: 10.1007/s11864-017-0504-y.
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Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. 
Analysis of 100,000 human cancer genomes reveals the landscape of tumor 
mutational burden. Genome Med. 2017;9:34. doi: 10.1186/s13073-017-0424-2
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Ott PA, Piha-Paul SA, Munster P, Pishvaian MJ, van Brummelen EMJ, Cohen 
RB, et al. Safety and antitumor activity of the anti-PD-1 antibody 
pembrolizumab in patients with recurrent carcinoma of the anal canal. ESMO.
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Morris VK, Salem ME, Nimeiri H, Iqbal S, Singh P, Ciombor K, et al. 
Nivolumab for previously treated unresectable metastatic anal cancer 
(NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol 
2017;18:446–53.
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Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-
Valette C, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor 
mutational burden.  N Engl J Med. 2018 Apr 16. doi: 
10.1056/NEJMoa1801946. [Epub ahead of print]
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Horowitz NS, Olawaiye AB, Borger DR, Growdon WB, Krasner CN, 
Matulonis UA, Liu JF, Lee J, Brard L, Dizon DS. Phase II trial of erlotinib in 
women with squamous cell carcinoma of the vulva. Gynecol Oncol. 2012 
Oct;127(1):141-6. 
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Witteveen PO, van der Velden J, Vergote I, Guerra C, Scarabeli C, Coens C, 
Demonty G, Reed N. Phase II study on paclitaxel in patients with recurrent, 
metastatic or locally advanced vulvar cancer not amenable to surgery or 
radiotherapy: a study of the EORTC-GCG (European Organisation for 
Research and Treatment of Cancer--Gynaecological Cancer Group). Ann 
Oncol. 2009 Sep;20(9):1511-6.
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Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. Phase II 
trial of bevacizumab in the treatment of persistent or recurrent squamous cell 

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carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 
2009 Mar 1;27(7):1069-74.
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Schellens JHM, Marabelle A, Zeigenfuss S, Ding J, Pruitt SK, Chung HC. 
Pembrolizumab for previously treated advanced cervical squamous cell 
cancer: Preliminary results from the phase 2 KEYNOTE-158 study. J Clin 
Oncol 35, 2017 (suppl; abstr 5514)
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Hollebecque A, Meyer T, Moore KN, Machiels J-PH, De Greve J, López-
Picazo JM. An open-label, multicohort, phase I/II study of nivolumab in 
patients with virus-associated tumors (CheckMate 358): Efficacy and safety in 
recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers. J Clin 
Oncol 35, 2017 (suppl; abstr 5504)
9.2
UNPUBLISHED REFERENCES
n00250946
 Binding Kinetics of BI 754091 Binding to human PDl and cyno 
PD 1. 13 Sep 2016.
n00250933
 Ligand blocking of PD-1 antibody BI 754091. 27 Jul 2016.
n00252624
 BI 754091 ADCC Report. 14 Sep 2016.
n00252631
. BI 754091 CDC Report. 16 Sep 2016.
001-MCS-36-472_RD-01 Noncompartmental Pharmacokinetic/Pharmacodynamic Analyses 
of Clinical Studies

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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 (reported as an AESI if ≥Grade 2)
∀
Acute interstitial pneumonitis
∀
Interstitial lung disease
∀
Pneumonitis
Colitis (reported as an AESI if ≥Grade 2 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)
∀
Intestinal obstruction
∀
Colitis
∀
Colitis microscopic
∀
Enterocolitis
∀
Enterocolitis haemorrhagic
∀
Gastrointestinal perforation
∀
Necrotizing colitis
∀
Diarrhea
Endocrine (reported as an AESI if ≥Grade 3 or ≥Grade 2 and resulting in dose 
modification or use of systemic steroids to treat the AE)
∀
Adrenal insufficiency
∀
Hyperthyroidism
∀
Hypophysitis
∀
Hypopituitarism
∀
Hypothyroidism
∀
Thyroid disorder
∀
Thyroiditis
∀
Hyperglycaemia, if ≥ Grade 3 and associated with ketosis or metabolic acidosis
Endocrine (reported as an AESI)
∀
Type 1 diabetes mellitus (if new onset)

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

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Immune-related adverse events of special interest
Renal (reported as an AESI if ≥ Grade 2)
∀
Nephritis
∀
Nephritis autoimmune
∀
Renal failure
∀
Renal failure acute
∀
Creatinine elevations (report as an irAE if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)
Skin (reported as an AESI for any grade)
∀
Dermatitis exfoliative
∀
Erythema multiforme
∀
Stevens-Johnson syndrome
∀
Toxic epidermal necrolysis
Skin (reported as an AESI if ≥ Grade 3)
∀
Pruritus
∀
Rash
∀
Rash generalized
∀
Rash maculopapular
∀
Any rash considered clinically significant in the physician’s judgment
Other (reported as an AESI 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 event toxicities associated with anti-PD-1 mAbs are 
presented below. BI 754091 should be permanently discontinued for Grade 3-4 pneumonitis, 
Grade 3-4 adrenal insufficiency, Grade 4 diabetes mellitus, any grade encephalitis, Grade 4 
hypophysitis, Grade 4 rash, Grade 3-4 or recurrent colitis of any grade, any recurrent 
Grade 3-4 AE, transaminase >5 times ULN or total bilirubin >3 times ULN, 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:
-
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
28 days.
-
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
-
For Grade 3-4 events immediately treat with i.v. steroids. Administer additional 
anti-inflammatory measures, as needed.
-
BI 754091 should be permanently discontinued for Grade 3-4 pneumonitis, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2 AEs that do not recover to Grade 1 or less within 
12 weeks.
∀
Diarrhoea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).
-
All subjects who experience diarrhoea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via i.v. infusion.  For Grade 2 or higher 
diarrhoea, consider GI consultation and endoscopy to confirm or rule out colitis.
-
For Grade 2 diarrhoea/colitis that persists greater than 3 days, administer oral 
corticosteroids.
-
For Grade 3 or 4 diarrhoea that persists >1 week, treat with i.v. steroids followed 
by high-dose oral steroids.
-
For Grade 3 or 4 colitis, or recurrent colitis of any grade, permanently discontinue
BI 754091 and immediately treat with i.v. steroids followed by high-dose oral 
steroids.
-
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
-
BI 754091 should be permanently discontinued for Grade 3-4 or recurrent colitis of 
any grade, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.
∀
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis) Grade 3, or
≥Grade 3 hyperglycaemia, if associated with ketosis (ketonuria) or metabolic acidosis
-
For Type 1 diabetes mellitus Grade 3-4 or Grade 3-4 hyperglycaemia

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

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∀
Hepatic:
-
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with i.v. or oral corticosteroids
-
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.
-
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 28 days.
-
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
transaminase >5 times ULN or total bilirubin >3 times ULN, 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:
-
For Grade 2 events, treat with corticosteroids.
-
For Grade 3-4 events, treat with systemic corticosteroids.
-
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
-
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less within 
12 weeks.
∀
Adrenal insufficiency
-
BI 754091 should be permanently discontinued for Grade 3-4 adrenal insufficiency 
or persistent Grade 2 AEs that do not recover to Grade 1 or less within 12 weeks.
∀
Rash
-
BI 754091 should be permanently discontinued for Grade 4 rash, any recurrent 
Grade 3 AE or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.
∀
Encephalitis
-
BI 754091 should be permanently discontinued for any grade encephalitis.
∀
Infusion reactions:
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.
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 SCHEDULES FOR PHARMACOKINETIC, BIOMARKER, AND 
IMMUNOGENICITY BLOOD SAMPLING
10.4.1
Schedules for PK, biomarker, and immunogenicity blood sampling –
Phase Ia (dose escalation) cohorts
Table 10.4.1: 1
Time schedule for PK, biomarker 
 
blood sampling during Cycles 1, 2, and 4 - Phase Ia dose-escalation 
cohorts
Treatment
Cycles
Day
Time Point 
[hh:min]
CRF Time
Event
PK
1, 2, 4
1
Just before start of 
infusion
-0:05
Blood sampling
X
X
X
0:00
0:00
Start of BI 
754091 infusion
---
Sampling during 
infusion
0:30
Blood sampling
X
Immediately before 
end of infusion*
1:00
Blood sampling
X
1.5 hours post SOI
1:30
Blood sampling
X
2 hours post SOI
2:00
Blood sampling
X
4 hours post SOI
4:00
Blood sampling
X
7 hours post SOI
7:00
Blood sampling
X
2
24 hours post SOI
24:00
Blood sampling
X
X
4
72 hours post SOI
72:00
Blood sampling
X
8
168 hours post SOI
168:00
Blood sampling
X
X
15
336 hours post SOI
336:00
Blood sampling
X
EOT
Within 7 days of 
treatment
discontinuation
Blood sampling
X
X
30-Day FU
30 days after last 
drug administration
Blood sampling
X
X
X
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; EOT = end of treatment; FU = follow 
up; PK = pharmacokinetics; 
*In the event that infusion duration is >15 minutes longer than planned, the subsequent time points for PK blood collection 
on the day of drug infusion should be adjusted accordingly.

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Table 10.4.1: 2
Time schedule for PK, biomarker
 
blood sampling during Cycles 3, 5 through 12, 14, 17, EOT (end-of-
treatment visit) and 30-day FU (follow-up visit) - Phase Ia dose-
escalation cohorts
Treatment
Cycles
Day
Time Point 
[hh:min]
CRF Time
Event
PK
3, 5 to 12, 
14, and 17
1
Just before start of 
infusion
-0:05
Blood sampling
X
X
X
0:00
0:00
Start of BI 
754091 infusion
---
Immediately 
before end of 
infusion
1:00
Blood sampling
X
EOT
Blood sampling
X
X
30-day FU
Blood sampling
X
X
X
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; EOT = end of treatment; FU = follow 
up; PK = pharmacokinetics; 
; only done during dose escalation, if feasible)

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10.5
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS
A BLRM with overdose control will be used to guide dose escalation in this study. The 
BLRM is introduced in Section 7.1.1, 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 (first three weeks). 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 10.5.2: 1. In addition, recommendations for 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 EWOC facilitates on-trial dose-escalation decisions (see Table 
10.5.2: 2). For simplicity reasons, a cohort size of 3 patients who are all evaluable is 
assumed. The simulations for scenarios and operating characteristics were produced using 
RStudio version 0.98.507.
10.5.1
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5.1: 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model. It is assumed that 
each cohort has exactly 3 patients who are all evaluable. 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 80 mg. In this case, the next optimal dose, i.e., the dose with the highest 
probability of being in the target interval, is 800 mg. However, to have the next dose level at 
800 mg seems too aggressive and thus the recommended dose for next level should be 
provided by the SRC.
Scenario 2 represents the case that no DLTs are observed in both the 80 mg and the 240 mg 
cohorts with 3 patients in each cohort. The probabilities of each dose level under both target-
dose and over-dose range are lower than the probabilities in Scenario 1 as expected.
Scenario 3 represents the case that no DLTs are observed in the first 3 patients at the starting 
dose of 80 mg but there is one DLT in the next dose level, 240 mg. In this case, the next 
optimal dose is 320 mg which has the highest probability in the target dose level. However, it 
will be SRC’s decision whether to have another cohort tested at dose 240 mg or to increase 
the dose level to 320 mg, since one DLT was observed at the dose level of 240 mg.

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Table 10.5.1: 1
Hypothetical data scenarios
Scenario
Dose 
(mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
Recommended 
Dose (mg)
Next optimal dose
P(under 
dose)
P(target 
dose)
P(over 
dose)
1
80
0
3
0.001
800
0.898
0.054 
0.047
2
80
240
0
0
3
3
0
800
0.919
0.047
0.034
3
80
240
0
1
3
3
0.186
320
0.506
0.247
0.247
4
80
240
0
1
3
6
0.031
560
0.541
0.247
0.212
5
80
240
400
0
1
0
3
6
3
0.033
800
0.613
0.217
0.170
6
80
240
400
0
1
1
3
6
3
0.195
400
0.406
0.399
0.195
*non-DLT drug-related AE of CTCAE grade ≥2
**Overdose-probability of the next optimal dose is too high (violates EWOC criterion), therefore the maximal allowed dose 
would be chosen as next dose by the model.
10.5.2
Operating Characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulation. Table 10.5.2: 1
describes 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. Scenarios 
1 and 2 reflect the extremes of very low and very high toxicity probabilities, respectively. 
Scenario 3 covers a true dose-toxicity relationship that does not have a logistic form. Finally, 
Scenario 4 reflects the possibility of having very low DLT rates at the lower dose levels and 
high DLT rates at the upper dose levels. Scenario 1 is more similar to the prior distribution of 
this trial. The stopping rule is the same as the MTD criteria mentioned in Section 7.1.1.

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Table 10.5.2: 1 Assumed True Dose-Toxicity Scenarios
Scenario
Dose (mg)
80             160             240          320           400            480            3200
1: Low Tox
0.00001    0.0005         0.009      0.013        0.028         0.050         0.160
2: High Tox
0.050        0.097          0.140       0.180        0.249         0.309         0.359
3: Non-Logistic
0.001        0.0102        0.0397     0.1795      0.220         0.269         0.339
4: Low-High
0.001        0.040           0.180       0.280        0.360        0.380          0.500
Bold numbers indicate true DLT rates in the target interval [0.16, 0.33].
For each of these scenarios, 1000 trials were simulated. 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 10.5.2: 2.
Table 10.5.2: 2 Simulated Operating Characteristics
Scenario
% of Trials Declaring an 
MTD with True DLT Rate in
# Patients
# DLT
Und
erdo
se
Targe
t dose
Overd
ose
Stoppe
d
Before 
MTD
Mean
(Min-Max)
Mean
(Min-
Max)
1: Low Tox
94.0
0
0
6.0
25.36 (12-
60)
1.011 (0-
4)
2: High Tox
16.7
83.3
0
0
17.18 (3-
42)
3.152 (1-
11)
3: Non-
Logistic
4.5
95.5
0
0
16.03 (12-
39)
2.48 (1-9)
4: Low-High 
Tox
6.7
46.0
47.3
0
17.83 (6-
42)
3.78 (1-
11)
In Scenario 1 (low-toxicity scenario), since none of the assumed true dose-toxicity scenarios
were beyond 16%, 94% of the simulated trials declared a dose as MTD with true DLT rate in 
the under dose range. 6% of the trials stopped before MTD was reached and this is because 
the very low-toxicity level to allow a trial stop before reaching an MTD. For Scenario 2
(high-toxicity scenario), 83.3% of the simulated trials declared an MTD with true DLT rate in 
the target dose range. This is an expected situation as assumed dose-toxicity scenarios at 
320 mg, 400 mg, and 480 mg lie within the target dose level. Results of Scenario 3 (high-
toxicity scenario) are very close to the results of Scenario 2 as the setting for the high-dose 

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level is similar between these two scenarios. Results of Scenario 4 (Low-High scenario) show 
~50% of the simulated trials declared a dose as MTD with true DLT rate in both the targeted 
dose range and also overdose range. This is because in the setup, assumed true dose-toxicity 
rates at 400 mg, 480 mg, and 320 mg were above 33%.
The mean patient numbers range from 16.03 (Scenario 3) to 25.36 (Scenario 1) and only 
Scenario 1 had the maximum of 60 patients. The patient numbers are as expected and 
decrease when moving away from the low-toxicity scenario.  In summary, the considered 
data scenarios show a reasonable behaviour of the model and the operating characteristics 
demonstrate a good precision of MTD determination.

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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
01 November 2016
EudraCT number
Not applicable
BI Trial number
1381.1
BI Investigational Product
BI 754091
Title of protocol
An open-label, Phase I trial to determine the 
maximum-tolerated dose and investigate safety, 
pharmacokinetics, and efficacy of BI 754091 in 
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.  Please note 
that formatting changes and minor changes to punctuation or spelling that do not affect 
meaning are not noted in this summary.
Section to be changed
Synopsis: Main criteria for inclusion
Description of change
Phase Ia (dose escalation) – adult patients with a 
confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours (any type) who have received 
all therapy known to confer clinical benefit (including 
anti-PD-1 therapies, if relevant and if last dose of the 
prior anti-PD-1 received more than 60 days prior to 
starting study drug), or for whom no therapy of 
proven efficacy exists, or who are not amenable to 
standard therapies
Rationale for change
In response to the FDA review, the decision was made to 
allow patients who had received previous treatment with 
an anti-PD-1 therapy to enter the dose-escalation phase 
(Part 1a) of the trial.
Section to be changed
Synopsis: Main criteria for inclusion

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Description of change
Phase Ib (dose expansion) – adult patients with a 
confirmed diagnosis of select advanced, unresectable, 
and/or metastatic solid tumours (non-small cell lung 
cancer, bladder cancer, melanoma, gastric cancer, 
ovarian cancer, triple-negative breast cancer [TNBC], or 
renal cell carcinoma) Patients who are anti-PD-1 naïve, 
but have failed conventional treatment (excluding 
anti-PD-1 treatment), or for whom no therapy of proven 
efficacy exists, or who are not amenable to standard 
therapies
Rationale for change
Clarification that patients in the dose-expansion portion 
(Part 1b) of the trial still must be naïve to anti-PD-1 
therapy.
Section to be changed
Flow Chart Footnote d (third sentence)
Description of change
If these assessments are performed within 72 hours of 
initiation of treatment, they do not need to be repeated on 
Cycle 1 Day 1 with the exception of the ECOG 
performance status, an abbreviated physical examination, 
vital signs (pre- and post-infusion), and a single ECG 
required prior to first trial dose.
Rationale for change
To clarify this requirement for the sites.
Section to be changed
Flow Chart and Footnote k
Description of change
The collection of optional DNA banking samples was 
removed from the protocol.  All footnotes following 
Footnote k were reordered.
Rationale for change
Optional DNA banking has been removed as the number 
of samples is not anticipated to be enough to provide 
significant benefit to the patients or the sponsor.
Section to be changed
Flow Chart Footnote i, Section 5.5.2.1, and footnotes of
Tables 10.4.1: 1 and 10.4.1: 2
Description of change
Blood samples for biomarkers
 
 will be collected (if 
feasible)
Rationale for change
To clarify that this test may not be done.
Section to be changed
Flow Chart 1 Footnote k, Flow Chart 2 Footnote l, 
Section 5.5.2.3
Description of change
Stable disease over 3 subsequent measurements would 
also be qualified as a response, and a biopsy (optional) 
would be taken at that time point
An optional biopsy 
should also be taken if a patient has stable disease 
over 3 subsequent disease assessment periods.
Rationale for change
Clarification
Section to be changed
Section 3.1 Overall trial design and plan
Description of change
Successive cohorts of patients will receive doses of BI 
754091 until the MTD is reached. A cohort size of 3 
patients will be treated at each dose level. Additional 
patients (up to 6 more) could be added to some 
previously evaluated cohorts to expand the safety and 
PK evaluation. At least 3 patients will be required for 
any dose-escalation cohort (refer to Section 7).

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A Safety Review Committee (SRC, see Section 3.1.2) 
may also recommend the size for the next dose escalation 
cohort. However, the final decision on the next cohort 
size will be made mutually between the BI Clinical 
Program Leader and the SRC. After all patients in a 
cohort have either experienced a DLT or have been 
observed for at least the MTD evaluation period (first 
3 weeks) 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 which fulfil 
the EWOC criterion. Hypothetical data scenarios 
(example in Section 10.5.1) will be calculated with 
potential cohort sizes and presented at the meetings 
with the Safety Review Committee (SRC, see Section 
3.1.2). Based on the model and on additional information 
(PK, pharmacodynamics [PDc], patient profiles), the 
members of the SRC will reach a joint decision
recommendation on the next dose level to be 
investigated and the size for the next dose-escalation 
cohort. However, the final decision on the next dose 
level and cohort size will be made mutually between 
the BI Clinical Program Leader and the SRC.
Rationale for change
In response to the FDA review, clarification was added 
on how the number of patients per dose level will be 
determined during dose escalation.
Section to be changed
Section 3.3.2 Inclusion Criterion #4
Description of change
Phase 1a (dose escalation) – patients who have 
received all therapy known to confer clinical benefit 
(including PD-1 therapies, if relevant), or for whom 
no therapy of proven efficacy exists, or who are not 
amenable to standard therapies. Patients with PD-1 
experience must have a minimum of 60 days between 
the last dose of the previous PD-1 and Cycle 1 Day 1 
of BI 754091 treatment. Phase 1b (dose expansion) -
Ppatients who are anti-PD-1 naïve but have failed 
conventional treatment (excluding anti-PD-1 treatment), 
or for whom no therapy of proven efficacy exists, or who 
are not amenable to standard therapies.
Rationale for change
In response to the FDA review, the decision was made to 
allow patients who had received previous treatment with 
an anti-PD-1 therapy to enter the dose-escalation phase 
(Part 1a) of the trial. Patients must still be naïve to anti-
PD-1 therapies in order to enter the dose-expansion 
phase.
Section to be changed
Section 3.3.2 Inclusion Criterion #8
Description of change
Females of child-bearing potential willing to use 
adequate contraceptive measures from the time of 
screening until 6 months after trial discontinuation, who 
are not or will not be breast feeding, and agree to have 
pregnancy tests prior to the start of dosing and at regular 
visits during the trial. Females not of childbearing 
potential must have evidence of such by fulfilling one of 
the following criteria at screening:

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-
Post-menopausal: defined as more than 
50 years-of-age and amenorrhoeic for at least 12 months 
following cessation of all exogenous hormonal 
treatments
-
Documentation of irreversible surgical 
sterilization by hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy, but not tubal ligation.
Rationale for change
The sponsor considers tubal ligation as a highly effective 
form of birth control and the current ICF text reflects 
this.
Section to be changed
Section 4.1.5 Definition of dose-limiting toxicity
Description of change
•
Any ≥Grade 3 non-haematologic toxicity with 
the following exceptions:
-
Grade 3 irAE that resolves to ≤ Grade 1 or to 
baseline with immunosuppressive therapy within 23
weeks
-
Grade 3 rash that resolves to ≤ Grade 1 within 
23 weeks
-
Grade 3 infusion reaction that resolves within 6 
hours to ≤ Grade 1 with the appropriate clinical 
management
Rationale for change
Exceptions were updated to reflect FDA feedback.
Section to be changed
Section 4.1.5 Definition of dose-limiting toxicity
Description of change
Late immune-related DLTs are irAEs that meet the same 
grading criteria as DLT criteria but occur after the initial 
21-day DLT period and during the first 90-day 
assessment period. These, as well as all toxicities, will be 
monitored throughout the trial. If any late immune-
related DLT is reported during dose-escalation, the 
BLRM will be rerun including the late immune-
related DLT, and updated results will be reviewed in 
the SRC meeting to recommend the next dose level 
and cohort size.
Rationale for change
In response to the FDA review, text was added to clarify 
how information on late immune-related DLTs will be 
used in making dosing (or other) decisions during the 
trial.
Section to be changed
Section 5.3.1 Physical examinations and ECOG 
performance status
Description of change
The ECOG score will be assessed at screening, on Day 1 
of Cycles 1 and 2, on Day 1 of every other cycle 
beginning with Cycle 3treatment cycle prior to trial 
medication intake, at the EOT visit, and at the 30-day 
safety follow-up visit.
Rationale for change
To clarify this statement for the sites and to align with 
the Study Flow Footnote e.
Section to be changed
Section 5.3.6.3 Definition of serious adverse events
Description of change
is to be deemed serious for any other reason if it is an 
important medical event when based upon appropriate 
medical judgment which may jeopardise the patient and 
may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definitions. 

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Medical and scientific judgement should be exercised in 
deciding whether other situations should be considered 
serious reactions, such as important medical events that 
might not be immediately life threatening or result in 
death or hospitalisation, but might jeopardise the patient 
or might require intervention to prevent one of the other 
outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation or development of 
dependency or abuse. 
Any suspected transmission via a medicinal product of an 
infectious agent is also considered an SAE.
Rationale for change
Corrected to align with the sponsor’s accepted safety 
language.
Section to be changed
Section 5.3.6.5.3 Infusion-related reactions
Description of change
If anthe infusion-related reaction is Grade 3 or higher in 
severity at any point during the study, treatment with 
BI 754091 will be permanently discontinued.
Rationale for change
In response to the FDA review, this statement was 
clarified.
Section to be changed
Section 5.3.6.5.4 Hepatic injury and Ddrug-induced 
liver injury (DILI)
Description of change
During the course of the trial the Investigator will remain 
vigilant for increases in liver biochemistry. The 
Investigator is responsible for determining whether a 
patient meets the hepatic injury definition or potential 
Hy’s Law criteria at any point during the trial.
The Investigator participates, together with the Medical 
Monitor and BI clinical project representatives, in review 
and assessment of cases meeting potential hepatic injury 
and Hy’s Law criteria. Hy’s Law criteria are met if there 
is no alternative explanation for the elevations in liver 
biochemistry other than a DILI caused by the 
investigational product.
Hepatic injury definition:
In patients with normal baseline hepatic function, 
hepatic injury is defined by the following alterations 
in hepatic laboratory parameters:
•
An elevation of AST and/or ALT ≥3 times the 
ULN combined with an elevation of total bilirubin ≥2 
times the ULN measured in the same blood draw 
sample. And/or
•
Marked peak AST and/or ALT elevation ≥10 
times the ULN.
Rationale for change
To clarify potential liver injury by including hepatic 
injury definitions in addition to the definition of Hy’s 
Law criteria.
Section to be changed

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Description of change
Rationale for change
Section to be changed
Section 5.5.3 Biobanking
Description of change
At the Cycle 1 Day 1 visit, one 8.5 mL blood sample for 
DNA banking will be collected in a PAXgene Blood 
DNA tube for those patients in either portion of the trial 
who agree by checking the appropriate box in the ICF. 
The DNA Banking sample, derived from the original 
blood sample, will be stored at the sponsor. The stored 
DNA may retrospectively be analysed, e.g., to identify 
whether there are other genetic factors that could 
contribute to a better therapeutic outcome or a higher risk 
of developing treatment related adverse drug reactions.
Note: Participation in the DNA banking sampling and the
long-term storage and use of leftover samples is 
voluntary and not a prerequisite for participation in the 
trial. The biological samples to be banked will be stored 
after the appropriate separate boxes are checked on the 
ICF by consenting patients in accordance with local 
ethical and regulatory requirements.
Rationale for change
Optional DNA banking has been removed as the number 
of samples is not anticipated to be enough to provide 
significant benefit to the patients or the sponsor.
Section to be changed
Section 5.5.3 Biobanking
Description of change
Any leftover samples (including tissue, plasma, serum, 
ADA, DNA, RNA, etc.) from the trial may be stored at 
the sponsor or an external biobanking facility on behalf 
of the sponsor for up to 30 years.
Rationale for change
ADA samples will be stored as per Section 5.6.1
Section to be changed
Section 8.4 Expedited reporting of adverse events
Description of change
BI is responsible to fulfil their legal and regulatory 
reporting obligation in accordance with regulatory
requirements.
Rationale for change
For clarification purposes.

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Section to be changed
Section 10.2 Management of immune-related (only parts 
that changed are presented)
Description of change
Management of immune-related event toxicities 
associated with anti-PD-1 mAbs are presented below. 
BI 754091 should be permanently discontinued for 
Grade 3-4 pneumonitis, Grade 3-4 adrenal 
insufficiency, Grade 4 diabetes mellitus, any grade 
encephalitis, Grade 4 hypophysitis, Grade 4 rash, 
Grade 3-4 or recurrent colitis of any grade, any 
recurrent Grade 3-4 AE, transaminase >5 times ULN 
or total bilirubin >3 times ULN, 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.
Description of change
•
Pneumonitis:
-
BI 754091 should be permanently 
discontinued for Grade 3-4 pneumonitis, inability to 
taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2 AEs 
that does not recover to Grade 1 or less within 12 
weeks.
Description of change
•
Diarrhoea/Colitis:
-
For Grade 3 or 4 diarrhoea/colitis that persists 
>1 week, treat with i.v. steroids followed by high-dose 
oral steroids.
-
For Grade 3 or 4 colitis, or recurrent colitis 
of any grade, permanently discontinue BI 754091 and 
immediately treat with i.v. steroids followed by high-
dose oral steroids.
-
BI 754091 should be permanently 
discontinued for Grade 3-4 or recurrent colitis of any 
grade, inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.
Description of change
•
Type 1 diabetes mellitus (if new onset, 
including diabetic ketoacidosis) Grade 3-4, or ≥ Grade 3 
hyperglycaemia, if associated with ketosis (ketonuria) or 
metabolic acidosis
-
For Type 1 diabetes mellitus Grade 3-4 or 
Grade 3-4 hyperglycaemia
•
Insulin replacement therapy is recommended for 
Type I diabetes mellitus and for Grade 3-4 
hyperglycaemia associated with metabolic acidosis or 
ketonuria.
-
BI 754091 should be permanently 
discontinued for Grade 4 diabetes mellitus, any 
recurrent Grade 3 AE or persistent Grade 2-3 AE 
that does not recover to Grade 1 or less within 12 
weeks.
Description of change
•
Hypophysitis:
-
For Grade 3 4 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 

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days. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.
-
For Grade 4 events, permanently discontinue 
BI 754091, and treat with an initial dose of i.v. 
corticosteroids followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 28 
days. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.
-
BI 754091 should be permanently 
discontinued for Grade 4 hypophysitis, any recurrent 
Grade 3 AE, inability to taper steroids to 10 mg or 
less prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.
•
Hepatic:
-
BI 754091 should be permanently 
discontinued for any recurrent Grade 3-4 AE, 
transaminase >5 times ULN or total bilirubin >3 
times ULN, inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.
•
Renal failure or nephritis:
-
BI 754091 should be permanently 
discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone 
or equivalent within 12 weeks, or persistent Grade 2-3 
AEs that do not recover to Grade 1 or less within 12 
weeks.
Description of change
•
Adrenal insufficiency
-
BI 754091 should be permanently 
discontinued for Grade 3-4 adrenal insufficiency or 
persistent Grade 2 AEs that do not recover to Grade 1 
or less within 12 weeks.
Description of change
•
Rash
-
BI 754091 should be permanently 
discontinued for Grade 4 rash, any recurrent Grade 3 
AE or persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.
Description of change
•
Encephalitis
-
BI 754091 should be permanently 
discontinued for any grade encephalitis.
Rationale for change
In response to the FDA review, the information in 
Section 10.2 was updated to clarify that BI 754091 
should be permanently discontinued for the 
recommended irAEs.

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Day 1 (pre-treatment), and at the 30-day follow-up visit 
(see Section 5.5.2.1 and Appendix 10.4).
Rationale for change
A mechanism-of-action-related PD effect of anti-PD-1 
treatment may be detected in the periphery, and may also 
be independent of whether the tumour responds.
Section to be changed
Flow chart - Adverse event row
Description of change
The superscript ‘o’ (Phase Ia Cycle 1 only) was removed 
from Days 8 and 15 check boxes for Cycles 1, 2, and 4.
Rationale for change
These superscripts were in error, since adverse events will 
be collected at every visit.
Section to be changed
Abbreviations
Description of change
Added CKD-EPI: Chronic Kidney Disease Epidemiology
Rationale for change
New criterion added to the protocol
Section to be changed
Section 3.3.3 Exclusion Criterion #7
Description of change
Creatinine >1.5 times ULN or creatinine clearance <50 
mL/min (measured or calculated by Cockcroft Gault
Chronic Kidney Disease Epidemiology (CKD-EPI) 
Collaboration equation); confirmation of creatinine 
clearance is only required when creatinine is >1.5 times 
ULN.
Rationale for change
To comply with comment from regulatory authority and 
align with sponsor’s latest approach for estimating kidney 
function.
Section to be changed
Section 5.3.6.3
Description of change
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).
Rationale for change
Updated to align with the sponsor’s latest safety language.
Section to be changed
Section 5.3.6.4
Description of change
Cancers of new histology and exacerbations of existing 
cancer must be reported as serious events regardless of the 
amount of time between discontinuation of the drug and 
the occurrence of the cancer.
Every new occurrence of cancer of new histology must 
be classified as a serious event
regardless of the duration between discontinuation of 
the trial medication and must be reported as described 
in Section 5.3.6.8, subsections “ AE Collection” and 
AE reporting to sponsor and timelines”.
Rationale for change
This change will clarify the exempting of progressive 
disease from expedited SAE reporting.
Section to be changed
Section 5.3.6.8.1

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Description of change
The rules for Adverse Event Reporting exemptions 
still apply.
Rationale for change
This change will clarify the exempting of progressive 
disease from expedited SAE reporting.
Section to be changed
Section 5.3.6.8.1
Description of change
The following should also be recorded as SAEs/AEs in 
the eCRF and SAE form (if applicable):
•Worsening of the underlying disease or of other pre-
existing conditions 
•
Changes in vital signs, ECGs, physical 
examinations, and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already exist prior trial inclusion 
they will be considered as baseline conditions.
Rationale for change
This change will clarify the exempting of progressive 
disease from expedited SAE reporting.
Section to be changed
Section 5.3.6.10
Description of change
5.3.6.10 Exemptions to SAE Reporting
Disease Progression is a trial endpoint for analysis of 
efficacy and as such is exempted from reporting as an 
AE or an SAE.  Progression of the subject's underlying 
malignancy will be recorded on the appropriate pages 
of the eCRF as part of efficacy data collection only and 
will not be reported on the SAE Form. It will therefore 
not be entered in the safety database (ARISg) and 
hence not get expeditiously reported. Death due to 
disease progression is also to be recorded on the 
appropriate (e)CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal 
relationship between the study drug(s) and the 
progression of the underlying malignancy, the event 
must be reported as an SAE on the SAE Form and on 
the (e)CRF.
Examples of exempted events of PD may be:
•
Progression of underlying malignancy 
(Progressive disease [PD]):  if PD is clearly 
consistent with the suspected progression of 
the underlying malignancy as defined by the 
respective response criteria. 
•
Hospitalization/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. 

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Exempted events are collected and tracked following a 
protocol specified monitoring plan.  Exempted events 
are monitored at appropriate intervals throughout the 
study at quarterly Program Safety Management Team 
Meetings.
Rationale for change
This change will clarify the exempting of progressive 
disease from expedited SAE reporting
Section to be changed
Section 5.4.2 Methods of sample collection for 
pharmacokinetic analyses
Description of change
Rationale for change
These are unnecessary details that can be specified in the 
Laboratory Manual.
Section to be changed
Description of change

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Rationale for change
Section to be changed
Section 5.5 First 2 bullets
Description of change
Rationale for change
To clarify the types of assays that may be performed.
Section to be changed
Description of change

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done after 5 to 6 patients in Cohort 1 complete Cycle 1 
and once patients in Cohort 2 complete Cycle 1. 
Furthermore, exploratory analyses might be performed 
if considered reasonable, e.g., after the last patient of the 
dose-escalation Phase Ia portion completes Cycle 4, there 
willmight be an exploratory analysis to further 
characterise the PK and immunogenicity.
Rationale for change
These edits reflect the latest modifications to the statistical 
methods.
Section to be changed
Section 8.3.1 Source documentation - new paragraph 
added
Description of change
Copies of tumour assessments scans may be collected 
by the sponsor upon request.  This could include 
CT/PET scans of the chest and abdomen and/or 
imaging of any other known or suspected sites of 
disease (e.g., pelvis, brain) using an appropriate 
method (CT/PET scan or MRI).
Rationale for change
Clarification that the sponsor may collect tumour 
assessment scans.
Section to be changed 
Section 8.4
Description of change
Exemptions from expedited reporting are described in 
Section 5.3.6.10, if applicable.
Rationale for change
This change will clarify the exempting of progressive 
disease from expedited SAE reporting
Section to be changed 
Appendix 10.4 - Tables 10.4.1:1 and 10.4.2:1
Description of change
The Time Point column was filled for rows that were 
previously blank. For Table 10.4.2:1, 2 PK sampling time 
points were removed (1:30 and 2:00 hours post treatment), 
and updates in PDMC sampling were applied, as 
previously mentioned.
Rationale for change
To clarify the time point information, harmonise 
PK sampling with the sampling that will be done 
in the second protocol with BI 754091, and to 
clarify the PBMC samplings.

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Section to be changed
Flow chart 1 Footnote d and Section 5.3.4.2 Biochemistry
Description of change
The standard biochemistry panel will consist of glucose, 
sodium, potassium, chloride, calcium, phosphate, venous 
bicarbonate HCO3, urea, creatinine, creatine 
phosphokinase (CPK), AST, ALT, alkaline phosphatase, 
lactate dehydrogenase (LDH), bilirubin, total protein, 
albumin, urea nitrogen (or urea), and uric acid.
Additionally, amylase and lipase should be analysed in 
case of symptoms of pancreatitis.
Rationale for change
To clarify that within the biochemistry panel, either urea 
nitrogen or urea will be collected (instead of both) 
depending on local practice.
In addition, to clarify that additional safety testing should 
be added in case of pancreatitis.
Section to be changed
Flow chart 2 Footnote l 
Description of change
The following fresh tumour biopsies will be mandatory 
for all patients in the Phase Ib dose-expansion portion
cohorts of the trial (refer to Section 6.2.1.1):
- The equivalent of 2 fine core needle biopsies (archival)
or 1 punch biopsy (refer to lab manual for 
specifications) from the most recent relapse (if within 6 
months of trial start with no subsequent therapy); 
otherwise, a minimum of 2 fine core needle biopsies or 1 
punch biopsy must be freshly taken between screening 
and the day before first treatment with BI 754091.
- The equivalent of 2 fine core needle biopsies or 1 
punch biopsy on treatment at the end of Cycle 2 (6 
weeks), preferably from the same lesion.
- Another fresh biopsy (optional) should be taken upon 
PD (according to RECIST v1.1 and irRECIST), if 
possible. Stable disease over 3 subsequent measurements
would also be qualified as a response, and a biopsy 
(optional) would be taken at that time point.  An optional 
biopsy should also be taken if a patient has stable 
disease over 3 subsequent disease assessment periods.
Rationale for change
To clarify expectations for biopsy collection.
Section to be changed
Section 2.1 Rationale for performing the trial
Description of change
[…]
The second part is primarily a safety consists of 3
expansion cohorts at the RP2D that will also further 
evaluate the safety, tolerability, efficacy, PK, and
biomarkers and the preliminary efficacy of BI 754091. 
The dose-escalation portion of the trial will enrol patients 
with advanced and/or metastatic solid tumours, while the 
dose-expansion portion will enrol patients with advanced 
and/or metastatic solid tumours with select types of 
cancer and/or specific genetic mutations. Recent 
evidence has shown that several tumour types with 
high TMB have better response rates with immune 
checkpoint inhibitors (R17-3651; R16-1497). 
Therefore, patients with tumours with high mutation 

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rates will be included in the expansion phase of this 
trial.
[…]
Rationale for change
To describe the details and rationale of the additional 
expansion cohorts
Section to be changed
Section 2.2 Trial objectives
Description of change
The main objective of the dose-escalation part of the trial 
is to determine the safety and tolerability, PK, biomarkers, 
and efficacy, and to determine the MTD and/or the RP2D 
of BI 754091 on the basis of patients with dose-limiting 
toxicities (DLTs) in patients with selected advanced solid 
malignancies. Safety and tolerability will be evaluated by 
monitoring the occurrence of adverse events (AEs), 
serious AEs (SAE), and laboratory parameter 
abnormalities, as well as changes to vital signs (see 
Section 5.3).
[…]
In the dose-expansion part of the trial, the main objectives 
are to further assess the safety, efficacy, PK profile, and
biomarkers of BI 754091 in tumours with specific 
tumour types and/or genetic mutations at the RP2D.
Rationale for change
To clarify the objectives between the 2 parts of the study 
and to give additional details about the addition expansion 
cohorts.
Section to be changed
Section 2.3 Benefit – Risk Assessment
Description of change
[…]
Based on these pre-clinical data, as well as clinical data 
obtained with other anti-PD-1 inhibitor mAbs, the 
inhibitory effects of BI 754091 on PD-1 may translate 
into a clinical benefit in cancer patients. All doses planned 
to be tested are expected to have some level of efficacy. 
Efficacy is expected for patients with tumours that 
have a high rate of mutations, such as high levels of 
TMB and squamous cell skin cancers, which have 
about the highest mutation rate among cancers.
Rationale for change
To describe the benefit expected for patients enrolled into
the new expansion cohorts.
Section to be changed
Section 3.1 Overall trial design and plan and synopsis
Description of change
[…]
Following determination of the MTD and/or RP2D from 
the Phase Ia portion, a separate cohorts of approximately
30 patients each will be conducted in patients with 
selected advanced solid malignancies likely to benefit 
from treatment with an anti PD 1 mAbs including
NSCLC, bladder, melanoma, gastric cancer, ovarian 
cancer, triple negative breast cancer (TNBC), and RCC 
will be conducted tumours with specific 
histology/tumour types and/or specific genetic profiles 
as specified in the following cohorts:
∀
Cohort 4: Solid tumours including NSCLC, 
bladder cancer, melanoma, gastric cancer, ovarian 
cancer, triple-negative breast cancer, and renal-
cell cancer

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∀
Cohort 5: Tumours with high TMB excluding 
those with high microsatellite instability (MSI-
high)
∀
Cohort 6: Refractory squamous cell cervical, anal, 
and skin tumours
The Phase Ib portion of the trial will further evaluate the 
safety, tolerability, efficacy, PK profile, and biomarkers, 
and efficacy of BI 754091.
The analysis of the squamous cell tumour cohort 
(Cohort 6) will follow a two-stage approach. The 
interim analysis for:
∀
Squamous cervical and/or anal cancer, Stage 1 
will include 10 treated patients.
∀
Squamous skin tumours, Stage 1 will include 
10 treated patients.
Based on the interim analyses results, the sponsor will 
determine if recruitment into these tumour groups will 
continue or be terminated. More details on the interim 
analyses are specified in Section 7.4. The sponsor 
reserves the right to terminate recruitment in any of 
the tumour groups if the recruitment target is not met. 
Patients who are already enrolled may continue in the 
trial regardless of recruitment termination of their 
cohort.
[…]
Rationale for change
To describe the additional expansion cohorts in detail and 
to describe the 2-stage interim analysis of Cohort 6.
Section to be changed
Section 3.3.2 Inclusion Criteria and synopsis
Description of change
3.
Phase Ia (dose escalation):
∀
Patients with a histologically confirmed diagnosis of 
advanced, unresectable, and/or metastatic solid 
tumours (any type)
∀
Patients who have received all therapy known to 
confer clinical benefit (including anti-PD-1 or anti-
PD-L1 therapies, if relevant), or for whom no therapy 
of proven efficacy exists, or who are not amenable to 
standard therapies. Patients with anti-PD-1 or anti-
PD-L1 experience must have a minimum of 60 days 
between the last dose of the previous anti-PD-1/PD-
L1 and Cycle 1 Day 1 of BI 754091 treatment.
∀
[Moved here] Patients may agree to have provide
optional paired biopsies.
4.
Phase Ib (dose expansion):

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∀
[Moved here] Patients with a histologically 
confirmed diagnosis of select advanced, 
unresectable, and/or metastatic solid tumours
with specific histology/tumor types and/or specific 
genetic profiles as specified in the following 
cohorts:
-
Cohort 4: solid tumours including NSCLC, 
bladder cancer, melanoma, gastric cancer, 
ovarian cancer, triple-negative breast cancer, and 
renal-cell cancer
-
Cohort 5: Tumours with high TMB based on 
Foundation Medicine’s assay (showing 
≥20 mutations/mega base) excluding those with 
high microsatellite instability (MSI-high]) based 
on Foundation Medicine’s assay or another  
validated test. Refer to Section 6.2.1.1 for details.
-
Cohort 6: Refractory squamous cell cervical, 
anal, and skin tumours
∀
All patients must have measurable lesions 
according to RECIST v1.1 and irRECIST criteria,
must have at least 1 tumour lesion amenable to 
biopsy, and must be medically fit and willing to 
undergo a biopsy before first treatment and, unless 
clinically contraindicated, after 6 weeks on therapy.
∀
[Moved here] Patients who are anti-PD-1 and 
anti-PD-L1 naïve but have failed conventional 
treatment (excluding anti-PD-1 treatment), or for 
whom no therapy of proven efficacy exists, or 
who are not amenable to standard therapies.
[…]
Rationale for change
To clarify details of the inclusion criteria related to the 
additional expansion cohorts.
This section was rearranged to better organize and group 
together specific criteria for each of the different phases.
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
4.
Any investigational or anti-tumour treatment 
within 4 weeks or 5 half-life period (whichever is 
shorter)30 days prior to the initial administration of BI 
754091.
Rationale for change
To clarify that the wash-out period may be shorter for 
drugs with a short half-life.
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
5.
History within the last 5 yearsPresence of 
otheran active invasive malignancy cancers other than 
the one treated in this trial within 5 years prior to 
screening, with the exception of appropriately 
treatedresected/ablated basal or squamous-cell carcinoma 
of the skin, or carcinoma in situ carcinoma of the uterine
cervix, or other local tumours considered cured by local 
treatment.
Rationale for change
To clarify exclusion of other active cancers and to align 
language across current studies with BI 754091

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Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
9.
Any of the following cardiac criteria:
-
Mean resting corrected QT interval (QTc) >470 
msec
-
Any clinically important abnormalities (as 
assessed by the Investigator) in rhythm, conduction, or 
morphology of resting ECGs, e.g., complete left bundle 
branch block, third degree heart block
-
Any factors that increase the risk of QTc 
prolongation or risk of arrhythmic events such as heart 
failure, hypokalaemia, congenital long QT syndrome, 
family history of long QT syndrome or unexplained 
sudden death under 40 years-of-age, or any concomitant 
medication known to prolong the QT interval
-
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.
-
Ejection fraction <55% or the lower limit of 
normal of the institutional standard.
Rationale for change
To clarify exclusion of other active cancers and to align 
language across current studies with BI 754091
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
13
Known history of human immunodeficiency 
virus infection or an active hepatitis B or C virus infection
(exception: this criteria does not apply to patients with 
cervical/anal tumours enrolling in Cohort 6)
Rationale for change
Due to the high incidence of HIV in patients with cervical 
and anal cancers, and no anticipated safety concerns exist 
for including such patients in the trial, Exclusion Criterion 
#13 (see Section 3.3.3) does not apply to the patients with 
cervical/anal cancer enrolling into Cohort 6.
Section to be changed
Section 3.3.4.2 Discontinuation of the trial by the sponsor
Description of change
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 Good Clinical Practice (GCP), the 
clinical trial protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial.
4.
Completion of treatment by all patients and 
the sponsor determines that sufficient survival data 
has been collected.
Rationale for change
Clarification of the sponsor’s rights to discontinue the trial 
in case sufficient survival data has been collected.
Section to be changed
Section 4.2.2.1 Permitted concomitant medications
Description of change
•
Blood transfusions are allowed at any time 
during the trial, except to meet inclusion criteria. There 
must be at least 4 weeks between a patient’s last 
transfusion and the screening laboratory assessment. 
Exceptions to this will be considered by the sponsor on 
a case by case basis.
Rationale for change
This change clarifies the expectations for time since 
previous transfusions. This time line reflects the half-life 
of red blood cells.
Section to be changed
Section 4.2.2.2 Prohibited concomitant medications
Description of change
[…]
Herbal preparations/medications are not allowed 
throughout the trial unless agreed to by the Principal 
Investigator. These herbal medications include, but are 
not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. If instructed by the 
Principal Investigator, Ppatients should stop using these 
herbal medications 7 days prior to first dose of study 
treatment.
Rationale for change
To clarify that the Principal Investigator can make 
exceptions for prohibited herbal preparations/medications.
Section to be changed
Section 5.1.1 Primary endpoints and synopsis
Description of change
The primary endpoints of the Phase Ib dose-expansion 
portion of the trial isare:
∀
Number of patients with DLTs observed during the 
entire treatment period.
∀
Objective response (OR), defined as the best 
overall response of complete response (CR) or 
partial response (PR) according to RECIST v1.1 
as assessed by the Investigator
Rationale for change
Objective response has been added as a primary endpoint 
for the expansion cohorts.
Section to be changed
Section 5.1.2.1 Secondary endpoints of the Phase Ia (dose 
escalation) portion of the trial
And
Section 5.1.2.2 Secondary endpoints of the Phase Ib (dose 
expansion) portion of the trial
And
Section 5.1.3 Further endpoints

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∀
Depending on available data, the same PK 
parameters calculated during the Phase Ia portion of 
the trial will be calculated for the dose-expansion 
portion, if feasible.
Section to be changed
Description of change

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Rationale for change
Section to be changed
Section 5.3.6.5 Adverse events of special interest (AESIs)
Description of change
[…]
For this trial, DLTs, irAEs, infusion-related AEs, DILI 
events, and hepatic injury, and qualifying irAEs, as 
defined in Appendix 10.1, are AESIs (see Section 
5.3.6.5.2 and Section 5.3.6.5.3, respectively).
Rationale for change
To add a link to the appendix defining irAEs.
Section to be changed
Section 5.3.6.5.2 Immune-related adverse events (irAE)
Description of change
[…] All immune-related events are to be reported as 
AEs. Some irAEs also need to be reported as AESIs as 
defined by the sponsor has defined a list of potential 

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irAEs in Table 10.1: 1 in Appendix 10.1 These irAEs 
must be reported as AESIs. If an Investigator determines 
another irAEa Grade 3 event (not on the list) to be 
immune related, should be a potential irAESI, the 
Investigator may should also report that event as an 
AESI.
Rationale for change
Changes in this section are to clarify that all immune-
related AEs are reported as AEs. When they meet the 
criteria in Table 10.1:1, they also need to be reported as 
AESIs.
Section to be changed
Section 5.3.6.8.1 Adverse event collection
Description of change
[…]
For sites outside of the US, country-specific fax 
numbers will be provided in the ISF/Study reference 
manual.
[…]
The following should also be recorded as SAEs (S)AEs in 
the eCRF and SAE form (if applicable):
∀
Worsening of pre-existing conditions
∀
Changes in vital signs, ECGs, physical examinations, 
and laboratory test results, if they are judged 
clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion 
they will be considered as baseline conditions.
All SAEs (S)AEs, including those persisting after an 
individual patient’s end of trial must be followed up until 
they have resolved, they have been sufficiently 
characterised, or no further information can be obtained.
Rationale for change
To clarify country-specific fax numbers will be provided 
for the reporting of AEs and to clarify that the excerpt is 
referring to all AEs (serious and non-serious) and not just 
serious AEs.
Section to be changed
Section 5.4.1 Assessment of pharmacokinetics and 
Section 7.3.5 Pharmacokinetic and pharmacodynamics 
analyses
Description of change
If data allow, the PK parameters of BI 754091 mentioned 
as secondary and further endpoints (see Section 5.1.2 and 
Section 5.1.3, respectively) will be evaluated using non-
compartmental analysis methods according to BI internal 
SOP (001-MCS-36-472_RD-01 [2.0actual version] and 
Kinesis Venn Life Sciences SOP ‘SOP-1.PKA.03 Non-
compartmental PK/PD Analysis’).
The parameters are defined as:
•
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

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Rationale for change
Section to be changed
Section 6.2.1.1 Screening for tumour mutational burden 
(TMB) and MSI-high cohort
Description of change
For Cohort 5, the TMB, as well as the microsatellite 
stability (MS) status have to be assessed. Patients that 
have high TMB (defined as ≥20 mutations/Mb) and 
are MS stable (MSS) will be included. Whereas for MS 
status determination any validated assay may be used, 
the TMB has to be measured by 
 
(FM). Patients may be included that fulfil the criteria 
(1) having undergone testing by FM previously; (2) if 
evidence is available that the criteria may be fulfilled 
(or with sponsor approval) after providing archival 
tumour material (as specified in the lab manual) and 
testing by FM; or (3) if evidence is available that the 
criteria may be fulfilled, after providing an additional 
fresh tumour biopsy and testing by FM.  Options 2 
and/or 3 may be discontinued at the sponsor’s 
discretion.
If polymerase epsilon (ε) catalytic subunit (POLE) 
mutation status is known for any patient in the TMB-
high cohort, this information should be collected.
Rationale for change
Details for determining TMB are added and information 
about collecting available POLE information is added in 
this new section of the protocol
Subsequent sections are renumbered accordingly.
Section to be changed
Section 6.2.1.3 Medical history
Description of change
[…]
Exclusion Criterion #13 (see Section 3.3.3) does not 
apply to the patients with cervical/anal cancer 
enrolling into Cohort 6. However, virology testing 
should still be done and the status of HIV and hepatitis 
B or C virus should be collected on the eCRF.
Rationale for change
To clarify that although patients with HIV may be 
enrolled into Cohort 6, virology testing should still be 
performed with results recorded in the eCRF.
Section to be changed
Section 6.2.3.4 Overall survival visits (new section added)
Description of change
Additional follow-up visits after the 30-day safety 
follow-up visit will be performed for patients that 

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enrolled in Protocol Version 4.0 and beyond. These 
will be performed once every 12 weeks at least (by 
telephone) on the same schedule as PFS survival visits 
until death, loss to follow-up, or end of the whole trial 
as specified in Section 3.3.4.2. If the sponsor 
determines that enough OS data has been collected 
from select cohorts, sites could be instructed to 
discontinue OS visits for those cohorts.
Rationale for change
Overall survival is an objective of the dose-expansion part 
of the study, so this visit has been added to the study plan 
table for patients going forward.
Section to be changed
Section 7.1 Statistical design model
Description of change
This is a Phase I, open-label, dose-escalating trial to 
determine the MTD and the RP2D for BI 754091 in 
patients with solid tumours and to recommend a dose for 
Phase Ib dose expansion. In addition, the safety and PK 
profiles, biomarkers, and efficacy of BI 754091 will also 
be assessed.
Rationale for change
This is to improve consistency in terminology across the 
text.
Section to be changed
Section 7.1.1 Statistical design – Phase Ia (dose 
escalation)
Description of change
The objective of the Phase Ia portion of the trial is to 
determine the MTD and recommend a dose for Phase Ib 
dose expansion the RP2D.
Rationale for change
To present only the objectives of Phase Ia, because the 
Phase Ib objectives are expanded and in a separate section
Section to be changed
Section 7.1.2 Statistical design – Phase Ib (dose 
expansion)
Description of change
The Phase Ib (dose-expansion) portion of the trial will 
recruit approximately 30 90 patients with selected locally 
advanced or metastatic cancers that are likely to benefit 
from treatment with an anti PD 1 mAb at the dose and 
schedule recommended by the SRC.
The analyses of the safety and efficacy for this portion of 
the trial will be descriptive and exploratory in nature.
Additional analyses may be applied to evaluate the 
robustness of the efficacy results. More details will be 
specified in the TSAP.
Rationale for change
Additional cohorts have been added to the expansion 
phase increasing the total number of patients to be 
enrolled. New analyses of the additional cohorts are 
added.
Section to be changed
Section 7.2 Null and Alternative Hypotheses
Description of change
No formal hypothesis testing is planned in this trial. All 
analyses in this trial are descriptive and exploratory.
Rationale for change
To only present a statement about the hypotheses without 
including a description of analyses.

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Section to be changed
Section 7.3 Planned analyses
Description of change
The Trial Statistical Analysis Plan (TSAP) will specify 
the important protocol violations in detail.
For the determination of the MTD, only MTD-evaluable 
patients will be considered. For the other analysis of 
secondary and furtherefficacy and safety 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 
Trial Statistical Analysis Plan (TSAP).
[Moved here] No per protocol set will be used in the 
analysis. However, important protocol violations will 
be summarised. The Trial Statistical Analysis Plan ( with 
details specified in the TSAP) will specify the important 
protocol violations in detail.
Rationale for change
For clarification.
Section to be changed
Sections 7.3.1, 7.3.2, and 7.3.3
Description of change
Primary endpoint analyses
In order to identify the MTD and the recommended dose 
for the Phase Ib portion of the trial, the number of patients 
with DLTs at each dose level during the Phase Ia MTD 
evaluation period (first three weeks) must be presented. 
Patients who discontinue during the first treatment course 
for reasons other than a DLT will be excluded from the 
determination of the MTD.
[…]
For the primary efficacy endpoint of Phase Ib, 
objective response rate (ORR) will be summarised and 
presented with 95% two-sided confidence intervals 
using the Clopper-Pearson method.
Secondary endpoint analyses
Efficacy endpoints will be summarised descriptively.For 
PFS, the Kaplan-Meier curve and estimates will be 
displayed with 95% confidence intervals, using 
Greenwood’s variance formula. The detailed censoring 
rules are specified in the TSAP.
[…]
Further endpoint analyses
For further efficacy endpoints analyses, details will be 
provided in TSAPsimilar analysis as specified for OR 
will be performed for binary endpoints (e.g. disease 
control), and similar analysis as specified for PFS will 
be performed for time-to-event endpoints (e.g. 
duration of response and OS). For tumour shrinkage 
over time, spider plots will be presented for the 
percentage changes from baseline in the sum of (1) 
target lesions and (2) total measured tumour burdens, 
respectively. Further details and other analyses are 
specified in the TSAP.
Rationale for change
To clarify the planned analyses of the efficacy endpoints

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Section to be changed
Section 7.4 Interim analyses
Description of change
No formal interim analysis of efficacy data is foreseen, 
although efficacy data when available may be considered 
as part of the safety evaluations.The sponsor will 
continuously monitor the safety. The dose-escalation 
design dictates that the sponsor and the SRC perform 
regular safety evaluations. These evaluations will be 
unblinded to dose.
[…]
No formal interim analysis of PK data is planned. 
However, an exploratory analysis of PK will be done after 
patients in Cohort 1 complete Cycle 1 and once patients in 
Cohort 2 complete Cycle 1. Furthermore exploratory 
analyses of PK might be performed if considered 
reasonable., e.g. after the last patient of the dose
escalation Phase Ia portion completes Cycle 4, there 
might be an exploratory analysis to further characterise 
the PK and immunogenicity.
No pre specified interim or exploratory PK analysis is 
planned for the dose expansion Part II portion of the trial. 
Exploratory PK analyses will be based on planned 
sampling times, if information on actual times should 
not be available. The results of these evaluations will be 
preliminary and may be subject to change, as these do not 
involve a formal database lock. No interim report will be 
written for exploratory PK analyses.  If medically 
justified, further or fewer exploratory PK analyses 
may be performed.
[…]
Interim efficacy analyses are planned for selected 
groups of patients (defined in Section 3.1) in the Phase 
Ib portion of the trial. Because of the expected 
challenge in recruiting these patients, the two-stage 
design is planned to stop further recruitment of the 
specific patient group if the defined efficacy boundary 
(see Table 7.4: 1) is not met at the first stage.
The interim analyses will be conducted when:
•
10 patients with squamous cervical and/or 
anal cancer have been treated, and the 10th patient 
has been on treatment for ~3 months.
•
10 patients with squamous skin tumours have 
been treated, and the 10th patient has been on 
treatment for ~3 months.
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.
•
Literature on preliminary data of nivolumab 
and pembrolizumab (R17-3902; R17-3903; R17-3822) 

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showed ORR ranges from 13% to 24% in patients 
with squamous cervical and anal tumours. Therefore, 
an underlying ORR of 25% is assumed. The 
probability of observing zero responders out of 10 and 
stopping at interim is 6%, and the probability of 
observing ≥20% ORR at final analysis is 77%. If the 
underlying ORR is 5%, the probability of stopping 
early is 61%, and the false positive probability of 
observing ≥20% ORR at final analysis is almost 0.
•
It was shown in Chalmers ZR et al, 2017 
(R17-3824) that the population with squamous skin 
cancer had very high proportion of patients with high 
TMB (~70%). Therefore, the clinical benefit is 
expected to be similar to patients with high TMB 
(R17-3768). Assume the underlying ORR is 50%, the 
probability of observing <3 responders out of 10 and 
stopping at interim is 5%, and the probability of 
observing ≥40% ORR at final analysis is 87%. If the 
underlying ORR is 20%, the probability of stopping 
early is 67%, and the false positive probability of 
observing ≥40% ORR at final analysis is 1%.
New Table 7.4: 1 was added.
Rationale for change
To describe the new interim analysis of efficacy for the 
dose-expansion cohorts.
Section to be changed
Section 7.7.1 Determination of sample size for Phase Ia
Description of change
No formal statistical power calculations to determine 
sample size were performed for this trial. A minimum
ofApproximately 15 patients for the Phase Ia dose
escalation and approximately 30 patients for the Phase Ib 
expansion will beare expected; Ffewer or more patients 
might be needed based on the recommendation of the 
SRC and the actual number of dose cohorts tested.
Rationale for change
To update determination of sample size for Phase Ia 
portion only.
Section to be changed
Section 7.7.2 Determination of sample size for Phase Ib
Description of change
For the cohort of 7 solid tumours (Cohort 4), no 
formal statistical sample size calculations were 
performed. Some efficacy signals are expected to be 
observed from ~30 treated patients.
Several papers demonstrated the association between 
high TMB and better response rates, progression-free 
survival, and overall clinical benefit. In Goodman et 
al., 2017 (R17-3768), response rates were 58% (22/38) 
in patients with ≥20 mutations/mega base compared to 
20% (23/113) in patients with low mutational burden. 
Therefore, in the planning of the TMB-high-tumour 
cohort (Cohort 5), it is deemed clinically meaningful if 
BI 754091 will have an underlying ORR of 35%. With 
30 patients, an ORR of 30% or more would be 

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observed with a probability of 78% assuming a true 
response rate of 35%. The probability of observing a 
false positive signal, e.g., to observe at least an ORR of 
30% if the underlying true ORR is 15%, is around 
3%. Table 7.7.2: 1 summarises the probability of 
observing certain ORRs based on different 
assumptions of the underlying ORR.
New Table 7.7.2: 1 was added.
For the selected squamous tumours cohort (Cohort 6),
probability calculations are provided in Table 7.4: 1 
using the two-stage approach. Depending on the Stage 
I result for the squamous cohort, sample size may vary 
between 20 and 60 patients.
Rationale for change
To update determination of sample size for Phase Ib.
Section to be changed
Table 10.1: 1 Immune-related adverse events of special 
interest
Description of change
This table defines immune-related AEs that must be 
reported as AESIs.
Each subsection was updated as for the following 
example:
Pneumonitis (reported as an AESI if ≥ Grade 2)
Rationale for change
To clarify that all immune related AEs are reportable AEs.  
When they meet the criteria listed in Table 10.1:1, they 
must also be reported as AESIs.
Section to be changed
Table 10.4.1: 2 
Description of change
Footnote removed: *In the event that infusion duration is 
>15 minutes longer than planned, the subsequent time 
point for PK blood collection on the day of drug infusion 
should be adjusted accordingly.
Rationale for change
This footnote is no longer necessary since the sample is 
taken immediately before the end of infusion.
Section to be changed
Table 10.4.2: 1
Description of change
Footnote added for PK sampling:
**The following windows of time are allowed for PK 
sampling:
Predose (PTM -0:05): within 1 hour before next drug 
infusion
Shortly after end of infusion (PTM 1:00): within 5 min 
after the end of infusion
24 through 336 hours post SOI (PTM 24:00 to 336:00): 
±1 hour.
Note: Time windows have been specified for 
procedural reasons; deviations do not automatically 
lead to exclusion of samples from data evaluation.
Rationale for change
To clarify the windows of time allowed for PK 
sampling.

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Number of global amendment
4
Date of CTP revision
15 May 2018
EudraCT number
Not applicable
BI Trial number
1381.1
BI Investigational Product
BI 754091
Title of protocol
An open-label, Phase I trial to 
determine the maximum-tolerated 
dose and investigate safety, 
pharmacokinetics, and efficacy of 
BI 754091 in patients with advanced 
solid tumours
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
X
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Additions to the text are bolded and deletions from the text are crossed
off. Only the parts of sections with changes are presented. Please note 
that formatting changes and minor changes to punctuation, spelling, 

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and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Cover Page
Description of change
EudraCT No. 2017-005043-33
Rationale for change
The trial will expand into the UK where a EudraCT No is 
required
Section to be changed
Synopsis Main criteria for inclusion and Section 3,3.2 
Inclusion Criteria
Description of change
-
Cohort 5: Patients with tumours that are TMB-high:  
any tumour with TMB-high status 
(>1020 mutations/Mb) based on the Foundation 
Medicine assay, excluding those that are MSI-high
based on the Foundation Medicine assay or another 
validated test (TMB and MSI status based on any 
validated test)
Rationale for change
The tumor mutational burden has been changed to >10 
based on recent research. In addition, to allow for more 
flexibility, Foundation Medicine assays will no longer be 
specified in the protocol. 
Section to be changed
Section 4.1.5 Definition of dose-limiting toxicity, 
Section 5.1.1 Primary endpoints (and Synopsis)
Section 5.3 Assessment of Safety (and Synopsis) 
Section 5.3.6.6 Severity of adverse events
Description of change
CTCAE Version 5.04.03
Rationale for change
Adverse events will be graded by the most recent CTCAE 
version. 
Section to be changed
Flow Chart 1 and Flow Chart 2
Description of change
ECOG marked to be assessed on Cycle 3,5,7, 9 etc. 
Rationale for change
Added clarification to the footnote stating that ECOG 
should be assessed every other cycle
Section to be changed
Flow Chart 1 and Flow Chart 2
Description of change
Physical examination ECOG assessment, vital signs, and 
pregnancy added to the PFS follow up. 
Rationale for change
To clarify assessments to be conducted during PFS follow 
up. 
Section to be changed
Flow Chart 1 and Flow Chart 2
Description of change
All cycles are 3 weeks (21 days) in duration. Patients will 
continue treatment with BI 754091 until disease 
progression (PD) by RECIST and/or irRECIST, 
withdrawal of patient consent, an unacceptable toxicity 
occurs, or 1 year of treatment is completed, whichever 
occurs first. Patients will be allowed to stay on treatment 
in the case of initial radiological PD, if the Investigator 
feels that it is in the patient’s best interest and the patient 
signs an informed consent describing this 
circumstance. In addition, patients without PD may stay 

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on trial after 1 year on a case-by-case basis after 
discussion with the Medical Monitor and the sponsor. Day 
1 of Cycle 1 is defined as the day when BI 754091 is first 
administered. During Phase Ia (dose escalation), Cycle 2 
cannot begin without Safety Review Committee approval.
Rationale for change
With the implementation of iRECIST in this protocol, 
patients will be re-consented to remain on treatment 
following PD per RECIST 1.1, until a confirmed 
progression per iRECIST.
Section to be changed
Flow Chart 2 
Description of change
Vital signs, concomitant medications, and adverse events 
will no longer be assessed on Days 2 and 15 of Cycles 4 
and 8. 
Rationale for change
Patients will not need to come to the clinic on these days 
where no blood samples are needed. 
Section to be changed
Flow Chart 2
Description of change
Cycles 10, 11, 13, 14, 16, 17, etc. column added 
Rationale for change
To clarify that patients should return to the clinic every 
cycle for a physical assessment, ECOG assessment (every 
other cycle), vital signs assessment, pregnancy test, 
concomitant medication review, and adverse events 
assessment. 
Section to be changed
Abbreviations
Description of change
irRECIST Immune Related Response Evaluation Criteria 
in Solid Tumours
Rationale for change
iRECIST will replace irRECIST for response assessments
Section to be changed
Section 2.1 Rationale for Performing the Trial
Description of change
More recent data have demonstrated that the 
combination of nivolumab and ipilimumab had better 
efficacy in NSCLC patients with a tumour mutational 
burden of at least 10 mutations per megabase than 
those with < 10 mutations per megabase (R18-1492). 
As such, a ≥ 10 mutation per megabase threshold was 
selected to define patients with high TMB for this trial. 
Rationale for change
The research upon which the change in the mutational 
burden cutoff was provided. 
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Patients will continue treatment with BI 754091 until 
disease progression (PD) according to the Response 
Evaluation Criteria in Solid Tumours (RECIST) and/or 
Immune Related Response Evaluation Criteria in Solid 
Tumours (irRECIST) (R16 0342) and the Guidelines for 
Response criteria for use in trials testing 
immunotherapeutics (iRECIST) (R17-0923),
withdrawal of patient consent, an unacceptable toxicity 
occurs, or 1 year of treatment is completed, whichever 
occurs first.
Rationale for change
iRECIST will replace irRECIST for response assessments
Section to be changed
Description of change

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Rationale for change
Section to be changed
Section 5.2.1 Tumor assessments
Description of change
The tumour response will be evaluated according to 
RECIST Version 1.1 (R09-0262) and irRECIST (R17-
0923 R16-0342).
Rationale for change
iRECIST will replace irRECIST
Section to be changed
Section 5.5 Assessment of Biomarkers
Description of change
∀
Also, genomic profiling maywill be performed when 
possible on pre-treatment biopsies in order to define 
tumour mutational load (unless a similar analysis has 
been performed beforehand).
Rationale for change
To clarify that genomic profiling should be performed on 
pre-treatment tumour biopsies, if possible. 
Section to be changed
Section 6.2.1.1
Description of change
For Cohort 5, the TMB, as well as the microsatellite 
stability (MS) status have to be assessed. Patients that 
have high TMB (defined as ≥1020 mutations/Mb) and are 
MS stable (MSS) will be included. Whereas for MS status 
determinationAany validated assay may be used to 
determine the MS status and TMB., the TMB has to be 
measured by Foundation Medicine (FM). Patients may be 
included that fulfil the criteria (1) having undergone 

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testing by FM previously; (2) if evidence is available that 
the criteria may be fulfilled (or with sponsor approval) 
after providing archival tumour material (as specified in 
the lab manual) and testing by FM; or (3) if evidence is 
available that the criteria may be fulfilled, after providing 
an additional fresh tumour biopsy and testing by FM.  
Options 2 and/or 3 may be discontinued at the sponsor’s 
discretion.
Rationale for change
The tumor mutational burden has been changed to > 10 
based on recent research. In addition, to allow for more 
flexibility, Foundation Medicine assays will no longer be 
specified in the protocol.
Section to be changed
Section 7.7.2 Determination of sample size for Phase Ib
Description of change
Several papers demonstrated the association between high 
TMB and better response rates, progression-free survival, 
and overall clinical benefit. In Hellmann et al., 2018 
(R18-1492) response rates were 45.3% (63/139) in 
patients with ≥10 mutations/mega base.In Goodman et 
al., 2017 (R17 3768), response rates were 58% (22/38) in 
patients with ≥20 mutations/mega base compared to 20% 
(23/113) in patients with low mutational burden.
Rationale for change
The research upon which the change in the mutational 
burden cutoff was provided.
Section to be changed
Section 9.1 Published references 
Description of change
R17-0923
Seymour L, Bogaerts J, Perone A, 
Ford R, Schwartz LH, Mandrekar S, 
et al. RECIST Working Group 
iRECIST: guidelines for response 
criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 
2017;18(3):e143-e152.
R18-1492
Hellmann MD, Ciuleanu TE, 
Pluzanski A, Lee JS, Otterson GA, 
Audigier-Valette C, et al. Nivolumab 
plus ipilimumab in lung cancer with a 
high tumor mutational burden.  N 
Engl J Med. 2018 Apr 16. doi: 
10.1056/NEJMoa1801946.  [Epub 
ahead of print] 
Rationale for change
To provide the relevant references for iRECIST
assessments and the updated tumour mutational burden 
cut-off are added. 
Number of global 
amendment
5
Date of CTP 
revision
14 September 2018
EudraCT number
Not applicable
BI Trial number
1381.1
BI Investigational 
Product
BI 754091
Title of protocol
An open-label, Phase I trial to determine the maximum-tolerated dose and 
investigate safety, pharmacokinetics, and efficacy of BI 754091 in patients with 
advanced solid tumours

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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, 

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and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be 
changed
Synopsis: Objectives
Description of 
change
Phase Ib Dose Expansion: To further evaluate the safety, the PK profile, 
biomarkers, and efficacy of the RP2D in 34 cohorts of patients with selected 
advanced and/or metastatic cancers
Rationale for 
change
To include Cohort 7 
Section to be 
changed
Synopsis: Methodology
Description of 
change
Phase Ib Dose Expansion: Open-label, 34 dose-expansion cohorts
Rationale for 
change
To include cohort 7
Section to be 
changed
Synopsis: No. of Patients
Description of 
change
Approximately 1405 patients, depending on dose-escalation results
Rationale for 
change
To include the patients that will be enrolled in Cohort 7
Section to be
changed
Synopsis: Total Entered
Description of 
change
Phase Ib Dose Expansion at the RP2D: 34 cohorts of approximately 30-40
patients each
Rationale for 
change
To include the patients that will be enrolled in Cohort 7
Section to be 
changed
Synopsis: Diagnosis
Description of 
change
-
Cohort 7: Recurrent human papillomavirus (HPV)-positive, or HPV-
negative (per local testing), vaginal or vulvar squamous cell carcinoma 
(VSCC) not amenable to surgery.
Rationale for 
change
To provide details of Cohort 7 diagnoses 
Section to be 
changed
Synopsis: Main criteria for inclusion
Description of 
change
-
Cohort 7: Patients with recurrent HPV-positive, or HPV-negative, 
vaginal or VSCC.
Rationale for 
change
To provide inclusion criteria for Cohort 7 patients
Section to be 
changed
Synopsis: Endponts
Description of 
change
-
If feasible, the following PK parameters will be calculated: Cmax and AUC0
504 after single and multiple dose of BI 754091, as measured during the first 
and subsequent cycles (administration q3w).

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Rationale for 
change
No PK parameters are needed as a secondary endpoint in the expansion phase.  
Section to be 
changed
Flow Chart 2
Description of 
change
BI 754091 infusion is marked X in the Cycles 10, 11, 13, 14, 16, 17, etc. column 
Rationale for 
change
To correct the flowchart to  clarify that BI 754091 will occur on Day 1 of all 
cycles as noted elsewhere in protocol.
Section to be 
changed
Flow Chart 2
Description of 
change
Footnote l:
The following fresh tumour biopsies will be mandatory for all patients in 
the Phase Ib dose-expansion cohorts of the trial (refer to Section 
6.2.1.1):
-
2 core needle biopsies or 1 punch biopsy (refer to lab 
manual for specifications) from the most recent relapse (if 
within 6 months of trial start with no subsequent therapy); 
otherwise, a minimum of 2 core needle biopsies or 1 punch 
biopsy must be taken between the start of screening and the 
day before first treatment with BI 754091.
Rationale for 
change
To clarify when the fresh tumour biopsies will be collected for Phase Ib dose 
expansion patients
Section to be 
changed
Section 1.1 Medical Background
Description of 
change
Results from anti-PD-1 studies in cervical carcinoma, an HPV- linked 
gynecological cancer, provide rationale for studying immunotherapy in 
vulvar squamous cell carcinoma (VSCC). Preliminary data from the phase 
I/II CheckMate358 study (NCT 02488759), which evaluates nivolumab in 
virus-associated, recurrent or metastatic cervical, vaginal and vulvar 
carcinoma, showed that in the nivolumab-treated cohort, the ORR and the 
disease control rate (ORR + SD) were 20.8% and 70.8%, respectively. 
Rationale for 
change
To provide background information about patients with VSCC.
Section to be 
changed
Section 2.1 Rationale for Performing the Trial
Description of 
change
The second part consists of 34 expansion cohorts at the RP2D that will also 
further evaluate the safety, tolerability, efficacy, PK, and biomarkers of 
BI 754091.
Rationale for 
change
To include Cohort 7.
Section to be 
changed
Section 3.1 Overall Trial Design and Plan
Description of 
change
Following determination of the MTD and/or RP2D from the Phase Ia portion, 
separate cohorts of approximately 30-40 patients each will be conducted in 
patients with select advanced solid malignancies including tumours with 
specific histology/tumour types and/or specific genetic profiles as specified in 
the following cohorts:

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∀
Cohort 7: Recurrent human papillomavirus (HPV)-positive, or HPV-
negative, vaginal or vulvar squamous cell carcinoma (VSCC)
The Phase Ib portion of the trial will further evaluate the safety, tolerability, 
efficacy, PK profile, and biomarkers of BI 754091.
The analysis of the squamous cell tumour cohort (Cohort 6) and the VSCC 
cohort (Cohort 7) will follow a two-stage approach. 
The interim analysis for Cohort 6:
∀
Squamous cervical and/or anal cancer, Stage 1 will include 10 treated 
patients.
∀
Squamous skin tumours, Stage 1 will include 10 treated patients.
The interim analysis for Cohort 7:
∀
Vaginal or VSCC, Stage 1 will include 20 treated patients.
Based on the interim analyses results, the sponsor will determine if recruitment 
into these tumour groups will continue or be terminated (recruitment does not 
have to pause while interim analysis is conducted).
Rationale for 
change
To include Cohort 7.
Section to be 
changed
Section 3.3.2 Inclusion criteria
Description of 
change
4. Phase 1b (dose expansion):
Cohort 7: Recurrent HPV-positive, or HPV-negative (per local testing), 
vaginal or VSCC, not amenable to surgery. 
Rationale for 
change
To provide inclusion criteria for Cohort 7 patients
Section to be 
changed
Section 3.3.2 Inclusion criteria
Description of 
change
7. Females of childbearing potential willing to use adequate contraceptive 
measures from the time of screening until 6 months after trial discontinuation, 
who are not or will not be breast feeding, and agree to have pregnancy tests 
prior to the start of dosing and at regular visits during the trial. Females not of 
childbearing potential must have evidence of such by fulfilling one of the 
following criteria at screening:
-
For women of childbearing potential using a contraceptive pill, an 
additional barrier method is necessary. A list of adequate 
contraception methods is provided in the patient information.  
Acceptable highly effective methods of contraception include total 
sexual abstinence when this is in line with the preferred and usual 
lifestyle of the study participant (periodic abstinence such as 
calendar, ovulation, symptothermal, post-ovulation methods and 
withdrawal are not acceptable methods of contraception), an 
intrauterine device or intrauterine hormone-releasing system, 
bilateral tubal ligation, and vasectomised partner (with post-
vasectomy proof of absence of sperm)
Rationale for 
change
Appropriate contraception methods are defined.  
Section to be 
changed
Section 3.3.3 Exclusion criteria

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Description of 
change
13. Known history of human immunodeficiency virus infection or an active 
hepatitis B or C virus infection. HIV infection is allowed for patients in 
cohort 6 (cervical/anal squamous) and cohort 7 (vulvar).(exception: this 
criteria does not apply to patients with cervical/anal tumours enrolling in Cohort 
6)
Rationale for 
change
To clarify that patients with HIV may enroll on Cohort 6 and Cohort 7. 
Section to be 
changed
Section 4.1.9 Administration of doses for each patient
Description of 
change
Sites will provide normal saline (sodium chloride 0.9%) for the dilution of 
study drug.  For sites in the UK, the saline must be an EU licensed product.
Rationale for 
change
To provide further details about drug dilution
Section to be 
changed
Section 4.2.3.2 Restrictions regarding women of childbearing potential
Description of 
change
Highly-effective methods of contraception include:
∀
Total sexual abstinence when this is in line with the preferred and 
usual lifestyle of the study participant, OR
∀
Bilateral tubal ligation, OR
∀
Vasectomised partner (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate and provided 
that partner is the sole sexual partner of the woman of childbearing 
potential study participant), OR 
∀
Oral, injected, or implanted hormonal methods of contraception, 
ORIntrauterine device or intrauterine hormone-releasing system OR
∀
"Double Barrier" methods of contraception: Male condom in combination 
with female diaphragm/cervical cap plus spermicidal foam/gel/film/cream.
Details of these contraception methods are also described in the patient 
information in the ICF.
Rationale for 
change
To define highly-effective contraception methods.
Section to be 
changed
Section 5.1.2.1 Secondary endpoints of the Phase Ia (dose escalation) portion of 
the trial
Description of 
change
∀
Depending on available data, the same PK parameters calculated during the 
Phase Ia portion of the trial will be calculated for the dose-expansion 
portion.
Rationale for 
change
No PK parameters are needed as a secondary endpoint in the expansion phase.
Section to be 
changed
Description of 
change

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Rationale for 
change
To provide early stopping criteria for Cohort 7
Section to be 
changed
Section 7.7.2 Determination of sample sizes for Phase Ib
Description of 
change
For the vaginal or VSCC cohort (Cohort 7), probability calculations are 
provided in Table 7.4: 1 using the two-stage approach. If the stage 1 result 
is positive (i.e., at least 2 responders out of 20 patients), sample size for this 
cohort will be increased to 40 patients; otherwise, recruitment will be 
stopped in case of negative interim analysis. 
Rationale for 
change
To provide early stopping criteria for Cohort 7
Section to be 
changed
Section 9.1 Published References
Description of 
change
R18-2645
Horowitz NS, Olawaiye AB, Borger DR, Growdon WB, 
Krasner CN, Matulonis UA, Liu JF, Lee J, Brard L, Dizon 
DS. Phase II trial of erlotinib in women with squamous cell 
carcinoma of the vulva. Gynecol Oncol. 2012 
Oct;127(1):141-6. 
R18-2646
Witteveen PO, van der Velden J, Vergote I, Guerra C, 
Scarabeli C, Coens C, Demonty G, Reed N. Phase II study 
on paclitaxel in patients with recurrent, metastatic or 
locally advanced vulvar cancer not amenable to surgery or 
radiotherapy: a study of the EORTC-GCG (European 
Organisation for Research and Treatment of Cancer--
Gynaecological Cancer Group). Ann Oncol. 2009 
Sep;20(9):1511-6.
R18-2647
Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, 
Roman LD. Phase II trial of bevacizumab in the treatment 
of persistent or recurrent squamous cell carcinoma of the 
cervix: a gynecologic oncology group study. J Clin Oncol. 
2009 Mar 1;27(7):1069-74.
R18-2650
Schellens JHM, Marabelle A, Zeigenfuss S, Ding J, Pruitt 
SK, Chung HC. Pembrolizumab for previously treated 
advanced cervical squamous cell cancer: Preliminary 
results from the phase 2 KEYNOTE-158 study. J Clin 
Oncol 35, 2017 (suppl; abstr 5514)
R18-2651
Hollebecque A, Meyer T, Moore KN, Machiels J-PH, De 
Greve J, López-Picazo JM. An open-label, multicohort, 
phase I/II study of nivolumab in patients with virus-
associated tumors (CheckMate 358): Efficacy and safety in 
recurrent or metastatic (R/M) cervical, vaginal, and vulvar 
cancers. J Clin Oncol 35, 2017 (suppl; abstr 5504)
Rationale for 
change
To provide references added for the Cohort 7 background
Section to be 
changed
Section 9.1 Published References

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Description of 
change
R16 0342
Bohnsack O, Hoos A, Ludajic K. Adaptation of the immune 
related response criteria: irRECIST. ESMO 2014. Ann Oncol. 
2014; 25(suppl_4): iv361 iv372. 10.1093/annonc/mdu342.
R17 3651
Castellucci E, He T, Goldstein DY, Halmos B, Chuy J. DNA 
Polymerase ɛ Deficiency Leading to an Ultramutator 
Phenotype: A Novel Clinically Relevant Entity. Oncologist. 
2017;22(5):497 502. doi: 10.1634/theoncologist.2017 0034. 
Epub 2017 May 2.
R17 3767
Nebot Bral L, Brandao D, Verlingue L, Rouleau E, Caron O, 
Despras E, et al.  Hypermutated tumours in the era of 
immunotherapy: the paradigm of personalized medicine. Eur J 
Cancer. 2017;84:290 303. doi: 10. 1016/j.ejca.2017.07.026. 
Epub 2017 Aug 29.
R17 3823
Łuksza M, Riaz N, Makarov V, Balachandran VP, Hellmann 
MD, Solovyov A,et al. A neoantigen fitness model predicts 
tumour response to checkpoint blockade immunotherapy. 
Nature. 2017 Nov 8. doi:10.1038/nature24473. [Epub ahead of 
print]
Rationale for 
change
To remove references no longer used in the CSP.
Number of global amendment
6
Date of CTP revision
08 March 2021
EudraCT number
2017-005043-33
BI Trial number
1381.1
BI Investigational Product
BI 754091 
Title of protocol
An open-label, Phase I trial to determine the 
maximum-tolerated dose and investigate safety, 
pharmacokinetics, and efficacy of BI 754091 in 
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.  Please note 
that formatting changes and minor changes to punctuation or spelling that do not affect 
meaning are not noted in this summary.
Section to be changed
Title page

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Description of change
BI Investigational Product name Ezabenlimab added
Rationale for change
An official name, ezabenlimab, has been assigned to BI 
754091 during the time after the last CTP version update.
Section to be changed
Title page
Description of change
BI Trial Clinical 
 name changed to
Rationale for change
Change in TCM responsibility.
Section to be changed
Synopsis (Endpoints for the Phase Ia Dose Escalation, 
Safety Criteria); Sections: 4.1.5 Definition of dose-
limiting toxicity, 5.1.1 Primary endpoints, 5.3 Assesment 
of Safety, 5.3.6.6 Severity of adverse events, 
Description of change
CTCAE Version 4.03 added along with Version 5. 
Rationale for change
Patients entered before amendment 4 used V4.03 and 
patients entered afterwards used V5.0.
Section to be changed
Synopsis (Endpoints for the Phase Ia Dose Escalation: 
Secondary, Endpoints for the Phase Ia Dose Expansion: 
Primary); 5.1.1 Primary endpoints; 5.1.2.1 Secondary 
endpoints of the Phase Ia (dose escalation) portion of the 
trial; 5.1.3. Further endpoints.
Description of change
Definition of Response (Objective Response) has been 
corrected to Confirmed Response (Confirmed
Objective response) throughout the CTP.
Rationale for change
Clarification of the endpoint definition.
Section to be changed
Synopsis (Endpoints for the Phase Ia Dose Expansion: 
Secondary); 5.1.2.1 Secondary endpoints of the Phase Ia 
(dose escalation) portion of the trial.
Description of change
The following definitions for the safety endpoints were 
added:
-Percentage of subjects with AEs 
-Percentage of subject with SAEs
-Percentage of subjects with clinical relevant 
abnormalities in vital signs, laboratory evaluations or 
ECG parameters (note that clinically relevant 
abnormalities are those which have to be reported by 
the investigator as AEs).
Rationale for change
To clarify the precise definition of the safety endpoints.
Section to be changed
Section 3.3.4.2 Discontinuation of the trial by the 
sponsor.
Description of change
The flowing paragraph was added:
“In case the trial is ended by the sponsor, the 
available clinical trial data will be analysed and 
reported approximately one year after the last patient 
has been enrolled. Patients who are still being treated 
with BI 754091 when the primary report of the trial is 
being prepared, will be kept on treatment in this trial 
and finalize the clinical observation period. Data of 
those patients will then be reported in a revised 
report and it will be noted in the primary report that 
such a revised report will be written.”

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Rationale for change
Clarification of the data handling rules after trial 
discontinuation by the sponsor.
Section to be changed
Flow Chart 2 and Footnote “r”; 
Section 5.5.2.1 Biomarker assessments in blood samples;
Table 10.4.2.1 and foot  note 1.
Description of change
Footnote “r” was added: 
Only patients completed the activity up to until the 
cut of date for the primary report. All remaining 
patients will undergo EOT and 30 days visits safety 
procedures only.
The following test was added:
Only patients completed this activity up to until the 
cut of date for the primary report.
Rationale for change
After the trial discontinuation by the sponsor, PK/PD and 
biomarker sampling will not be collected for patients 
continuing in the study after the cut-off date for primary 
report DBL. These additional data are not anticipated to 
provide significant benefit to the patients or the sponsor.
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 5.4.1 Assessment of pharmacokinetics; 
Section 7.3.5 Pharmacokinetic and pharmacodynamic 
analyses
Description of change
Descriptions of the following BI internal SOPs deleted:

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(001 MCS 36 472_RD 01 [2.0] and Venn Life Sciences 
SOP ‘SOP 1.PKA.03 Non compartmental PK/PD 
Analysis’).
(001 MCS 36 472_RD 01 [actual version] and Venn 
Life Sciences SOP ‘SOP 1.PKA.03 Non compartmental 
PK/PD Analysis’).
Rationale for change
During the trial conduct the SOPs were updated therefore 
the references listed in the CTP are not needed.
Section to be changed
Section 7.1.1 Statistical design – Phase 1a (dose 
escalation)
Description of change
The first cycle dose has been corrected in the paragraph 
below:
“The objective of the Phase Ia portion of the trial is to 
determine the MTD and the RP2D.
first cycle at dose d, d* = 800 3200 mg”
Rationale for change
Mistake in writing has been corrected.
Number of global amendment
8
Date of CTP revision
07 March 2023
EudraCT number
2017-005043-33
BI Trial number
1381.1
BI Investigational Product
BI 754091 
Title of protocol
An open-label, Phase I trial to determine the 
maximum-tolerated dose and investigate safety, 
pharmacokinetics, and efficacy of BI 754091 in 
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

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Additions to the text are bolded and deletions from the text are crossed-off.  Please note 
that formatting changes and minor changes to punctuation or spelling that do not affect 
meaning are not noted in this summary.
Section to be changed
Synopsis – Duration of treatment; 
Flow chart 1 and 2, foot note 1.
Description of change
From: 
BI 754091 will be given on Day 1 of 21-day cycles for 
up to 1 year, or until progressive disease (PD) or 
unacceptable toxicity in the absence of other withdrawal 
criteria. If the patient is benefiting clinically at 1 year, 
he/she may continue after a case by case review with the 
sponsor.
To: 
BI 754091 will be given on Day 1 of 21-day cycles for 
up to 1 year, or until progressive disease (PD) or 
unacceptable toxicity in the absence of other withdrawal 
criteria. If the patient is benefiting clinically at 1 year, 
he/she may continue after a case by case review with the 
sponsor, but no longer than 31 August 2023.
Rationale for change
Treatment duration limitation added due to BI 754091 
monotherapy program discontinuation.
Section to be changed
Section 3.1 Overall trial design and plan
Description of change
Last sentence modified as follows:
In addition, patients without PD may stay on trial after 1 
year on a case-by-case basis after discussion with the 
Medical Monitor and the sponsor, but no longer than 31 
August 2023. After this date treatment with the 
ezabenlimab will no longer be available.
Rationale for change
Treatment duration limitation added due to BI 754091 
monotherapy program discontinuation.
Section to be changed
Section 3.3.4.2 Discontinuation of the trial by the 
sponsor
Description of change
Addition:
5. Termination of the development program by the 
sponsor.
Rationale for change
Trial discontinuation criterium added.
Although a preliminary assessment of the available data 
from the ongoing clinical program for the ezabenlimab 
exhibit signs of antitumour activity and a manageable 
safety profile for an overall positive benefit risk ratio, 
careful review of the full data set performed in the 
context of the current standards of care for the 
indications under study has led to the decision taken by 
the sponsor to discontinue the BI 754091 mono-therapy 
program, and terminate further expansion of the study. 
Section to be changed
Section 4.1.11 Packaging, labelling, and re-supply
Description of change
Addition:
No re-supply will be possible after 31 August 2023.

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Rationale for change
To emphasize that the study medication will not be 
available after 31 August 2023.
Section to be changed
Section 6.2.3.1 End-of-treatment visit.
Description of change
Addition:
For patients still on treatment with ezabenlimab at the 
time point of this protocol amendment, the investigators 
are asked to prepare for discontinuation of patients from 
the current investigational treatment with ezabenlimab 
and to switch them to alternative available treatment 
options outside of the current protocol no later than by 
the final availability of ezabenlimab in August 2023 the 
latest. After this date treatment with the ezabenlimab will 
no longer be available.
For these patients only EOT visit will be performed. 30-
day post-treatment safety visit as well as Progression-free 
survival visits are not applicable.
Rationale for change
To provide an updated guidance for the EOT visit.

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