An Open-label, Phase II, Platform Trial Evaluating Safety and Efficacy of Multiple BI 754091 (Ezabenlimab) Anti-PD-1 Based Combination Regimens in PD-(L)1 naïve and PD-(L)1 Pretreated Patient Populations With Advanced and/or Metastatic Solid Tumours Who Have Had at Least One Line of Systemic Therapy
Phase: PHASE2
Conditions: Neoplasm Metastasis, Advanced Tumors, Metastatic Solid Tumors
Sponsor: Boehringer Ingelheim

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CLINCAL TRIAL PROTOCOL (MASTER)
TITLE PAGE
Document Number:
c23362215-04
EudraCT No.
2018-002344-81
BI Trial No.
1381-0009
BI IMP(s)
Ezabenlimab (BI 754091[anti-PD-1])
Title
An open-label, Phase II, platform trial evaluating safety and 
efficacy of multiple ezabenlimab anti-PD-1 based combination
regimens in PD-(L)1 naïve and PD-(L)1 pretreated patient 
populations with advanced and/or metastatic solid tumours who 
have had at least one line of systemic therapy
Lay Title
Platform trial evaluating safety and efficacy of ezabenlimab
anti-PD-1 based combination therapies in PD-(L)1 naïve and 
PD-(L)1 pretreated patient populations with 
advanced/metastatic solid tumours.
Clinical Phase
Phase II
Clinical Trial 
Leader
 
 
Phone:
Coordinating 
Investigator
Phone:
Status
Final protocol (Revised Protocol [based on Global 
Amendment 3])
Version and Date
Version: 4
Date: 12 JUN 2023
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2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS (MASTER)
Company name
Boehringer Ingelheim International GmbH
Name of finished 
product :
N.A.
Name of active 
ingredient :
Ezabenlimab (BI 754091)
Protocol date
08 AUG 2018
Revision date
12 JUN 2023
BI trial number
1381-0009
Title of trial
An open-label, Phase II, platform trial evaluating safety and efficacy 
of multiple ezabenlimab anti-PD-1 based combination regimens in 
PD-(L)1 naïve and PD-(L)1 pretreated patient populations with 
advanced and/or metastatic solid tumours who have had at least one 
line of systemic therapy
Coordinating 
Investigator
Trial site(s)
This multicentre trial will be conducted in North America and the 
United Kingdom.
Clinical phase
Phase II
Trial rationale
The focus of this study will be to identify biological similarities 
across tumour types to increase the understanding of 
immunobiological prerequisites for different treatment regimens to 
be effective. There may be the potential to identify patterns of 
responsiveness that are not limited to specific tumour types but are 
present across multiple settings. In this study, ezabenlimab will be 
administered to small groups of patients with different tumour types 
in combination with other agents that are expected to increase 
responsiveness to checkpoint inhibitors. The tumour types to be 
included were selected based on high unmet medical need and the 
expectation that the combination therapy planned may be effective
in some patients with these tumour types. This Master protocol 
design document will support the operational aspects of the trial 
while the ‘Modules’ will be applied to specify drug combination. 
Ezabenlimab will be combined with a Boehringer-Ingelheim (BI)
agent(s) for which there is scientific evidence and rationale to 

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support the combination in a specific patient population. Separate 
Modules will be appended to the Master protocol for each of the 
planned ezabenlimab treatment combinations. The Module will
describe the clinical and nonclinical information for the additional 
agent, rationale, benefit/risk, eligibility criteria, treatment
administration, trial assessments and other guidances. Agents 
combined with ezabenlimab will have been previously tested. A 
protocol amendment with relevant clinical and non-clinical data will 
be implemented when a new Module is added prior to enrolling 
patients. 
Trial objective(s)
The main objective of this research trial is to evaluate patient clinical 
response to ezabenlimab in combination with combination partners
presented in individual Modules.
Trial endpoints
Primary Endpoint:

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.
Secondary Endpoints:

Duration of response (DoR), defined as the time from first 
documented CR or PR (RECIST v1.1) until the earlier of 
disease progression or death among patients with OR.

Disease control (DC), defined as best overall response of CR, 
PR, or stable disease (SD) according to RECIST v1.1 as
assessed by the Investigator.

Progression-free survival (PFS), defined as the time from 
first treatment until PD or death from any cause, whichever 
occurs earlier.
Trial design
Open-label, multicentre, Phase II, Master design with treatment-
specific Modules
Total number of 
patients randomised Not applicable
Number of patients 
on each treatment
Patient numbers will be defined in each of the treatment-specific 
Modules. New Modules will be developed and appended as an 
amendment to the Master protocol. 
Diagnosis
Advanced solid tumours as specified in the treatment-specific 
Modules.

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Main inclusion and 
exclusion criteria
Inclusion
For inclusion in the trial, patients must fulfil all of the following 
criteria as well as the inclusion criteria in the treatment-specific 
Module in which eligible solid tumours are defined.
Adult patients at least 18 years of age and a life expectancy of at 
least 12 weeks. 
Eastern Cooperative Oncology Group (ECOG) performance 
status 0 or1.

Patient must agree to a pre-treatment biopsy (if archival tissue is 
not available) and on-treatment tumour tissue biopsy. 
Patients moving from one module to another must have prior
immune-related adverse events (irAEs) resolved to a degree that 
would allow for restart of checkpoint inhibitor therapy according to 
the irAE management guidelines in the protocol.
Exclusion
Patients must not enter the trial if any of the criteria below or any of 
the exclusion criteria described in the treatment-specific Module are 
fulfilled.
Any investigational treatment anti-tumour treatment within 4 
weeks or within 5 half-life periods (whichever is shorter) prior to 
the initiation of trial treatment. 
More than one anti-PD-(L)1-based treatment regimen prior to 
entering study, more specifically defined in the modules. Note: 
Once in a trial Module, patients may crossover to a different 
Module if all other eligibility criteria are met.
Major surgery (‘major’ according to the Investigator’s and/or 
Medical Monitor’s assessment) performed within 12 weeks prior 
to first trial treatment or planned within 12 months after 
screening, e.g., hip replacement.
Inadequate organ function or bone marrow reserve as 
demonstrated by the laboratory values presented in Table 3.3.3: 1
Known history of severe hypersensitivity reactions to other 
monoclonal antibodies (mAbs) or known hypersensitivity to the 
trial drugs or their excipients.
Presence of central nervous system (CNS) metastases, unless 
treated and asymptomatic and off corticosteroids and/or anti-
convulsant therapy for at least 2 weeks prior to start of treatment.
Immunosuppressive corticosteroid doses (>10 mg prednisone 
daily or equivalent) within 4 weeks prior to the first dose of study 
treatment. 
Active autoimmune disease or a documented history of 
autoimmune disease, except vitiligo or resolved childhood 
asthma/atopy, or a patient who was permanently discontinued
from previous anti-PD-1 or anti-PD-L1 therapy because of an 
irAE.

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Test product(s)
Ezabenlimab will be administered in all Modules associated with 
this clinical trial.
Test agents to be administered in combination with ezabenlimab:
specified in the treatment-specific Modules. 
dose(s)
The ezabenlimab dose will be 240mg Q3W
Doses of combination agent will be defined in the treatment-specific 
Modules.
method and route 
of administration
Ezabenlimab intravenous infusion 
Comparator 
product(s)
Not applicable. 
dose
Not applicable.
method and route 
of administration
Not applicable.
Duration of 
treatment
Treatment will continue until progression of disease (PD), according 
to RECIST v1.1 (R09-0262) and/or iRECIST (R15-2005), 
withdrawal of patient consent, an unacceptable toxicity, 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. If the 
patient is benefiting clinically at 1 year from ezabenlimab, he/she 
may continue beyond 1 year of treatment after a case-by-case review 
with the Medical Monitor and the sponsor. The duration of test 
agents to be administered in combination with ezabenlimab will be 
specified in the treatment-specific Modules. Patients that progress on 
treatment in a given Module may be offered treatment in another 
Module if deemed appropriate by the Investigator and Sponsor.  The 
patient must sign an approved ICF for the subsequent Module, be 
screened prior to entering the new Module, and must meet all Master 
and Module-specific inclusion criteria. The transition time between 
Modules (last dose of previous Module and screening visit of 
subsequent Module) will be a maximum of 2 months. Patients will 
be allowed multiple crossovers into subsequent Modules.
Statistical methods
For the response endpoints (i.e., OR, DC), a Bayesian hierarchical 
modelling approach will be used, if applicable. Shrinkage estimators 
per cohort as well as the overall estimate will be considered. The 
shrinkage estimators allow for borrowing information across cohorts 
while taking the multiplicity of the different cohorts into account. 
The details of the specific hierarchical model to be applied as well as 
the related parameters and priors used will be described within each 
Module.
Additionally, descriptive statistics of these endpoints will be 
provided.
Kaplan-Meier estimates will be used to analyse PFS with 95% 
confidence intervals, using Greenwood’s variance estimate.

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FLOW CHART  
Detailed flow charts are located in each Module.
Master flow chart for screening 
Trial Periods
Screeninga 
Visit
1
Assessment (Days)
-28 to -1
Informed Consent 
X
Inclusion/Exclusion Criteria
X
Medical History and Demographics
X
Physical Examination
X
ECOG Performance Status
X
Vital Signs
X
12-Lead Digital Electrocardiogram
Xb
Archival or Fresh Tumour Tissue Required
Xe
Haematology and Clinical Chemistry Laboratory Tests
X
Thyroid panel (TSH, free T4 and free T3)
X
Urinalysis
X
Pregnancy Test for Women of Child-Bearing Potential
Xc
Concomitant Medications
X
Adverse Events
X
Tumour Assessment
Xd
a
Safety laboratory assessments including haematology, serum biochemistry, and urinalysis will be 
performed locally. The screening medical history and demographics, physical examination and Eastern 
Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), 
haematology, clinical chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, albumin, 
total protein, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, 
bilirubin, lactate dehydrogenase, serum glucose, creatine phosphokinase, troponin I (only at screening, 
C1D1, C1D8, C1D15, C2D1, C3D1, C4D1 and anytime CPK is elevated), serum urea nitrogen [or urea], 
serum uric acid, thyroid panel [TSH, free T4, and free T3]), urinalysis, and screening pregnancy test 
should be done ≤14 days prior to initiation of treatment (see Section 5). 
b
Single digitalised ECGs must be done before blood work or other procedures after 5 minutes of rest at 
screening (see Section 5.2.4). 
c
Women of child-bearing potential must have a serum beta human chorionic gonadotropin (βHCG) 
pregnancy test at screening (see Section 5.2.3).
d
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 5.1 for additional details. Tumour assessments 
should be done according to RECIST v1.1 and iRECIST and should include computed 
tomography/positron emission tomography (CT/PET) scans of the chest and abdomen and, if clinically 
indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an 
appropriate method (CT/PET scan or magnetic resonance imaging [MRI]). The same radiographic 
procedure must be used throughout the trial. In case of suspected (but not confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If bone lesions are already known 
or confirmed at screening, correlative imaging (X-ray or CT scan) should be performed.
e
All patients must have tissue samples (fresh or archived [see requirements]) available for retrospective 
central testing (see Section 3.3.2).

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS (MASTER).................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................15
1.2.1
Ezabenlimab ........................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................15
1.4
BENEFIT - RISK ASSESSMENT.....................................................................16
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................18
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........18
2.1.1
Main objective .....................................................................................................18
2.1.2
Primary endpoint................................................................................................18
2.1.3
Secondary endpoint(s) ........................................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................19
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS.........................................................................................20
3.3
SELECTION OF TRIAL POPULATION .......................................................20
3.3.1
Main diagnosis for trial entry ............................................................................20
3.3.2
Inclusion criteria .................................................................................................20
3.3.3
Exclusion criteria ................................................................................................21
3.3.3.1
Withdrawal of patients from treatment or assessments ........................................23
3.3.3.2
Discontinuation of trial treatment .........................................................................24
3.3.3.3
Withdrawal of consent to trial participation .........................................................24
3.3.3.4
Discontinuation of the trial by the sponsor...........................................................24
4.
TREATMENTS...................................................................................................25
4.1
INVESTIGATIONAL TREATMENTS ...........................................................25
4.1.1
Identity of the Investigational Medicinal Products..........................................25
4.1.2
Selection of doses in the trial..............................................................................25
4.1.3
Method of assigning patients to treatment groups...........................................25
4.1.3.1
Method of assigning patients to a second, or subsequent, Module(s)...................25
4.1.4
Blinding and procedures for unblinding...........................................................26
4.1.5
Packaging, labelling, and re-supply...................................................................26
4.1.6
Storage conditions...............................................................................................26

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4.1.7
Drug accountability.............................................................................................27
4.1.8
Dose modifications ..............................................................................................27
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................27
4.2.1
Other treatments and emergency procedures..................................................27
4.2.2
Restrictions ..........................................................................................................28
4.2.2.1
Restrictions regarding concomitant treatment ......................................................28
4.2.2.2
Restrictions on diet and life style..........................................................................28
4.2.2.3
Contraception requirements..................................................................................28
4.3
TREATMENT COMPLIANCE........................................................................29
5.
ASSESSMENTS..................................................................................................29
5.1
ASSESSMENT OF EFFICACY........................................................................29
5.2
ASSESSMENT OF SAFETY.............................................................................30
5.2.1
Physical examination ..........................................................................................30
5.2.2
Vital signs.............................................................................................................30
5.2.3
Safety laboratory parameters ............................................................................30
5.2.4
Electrocardiogram ..............................................................................................31
5.2.5
Other safety parameters.....................................................................................32
5.2.6
Assessment of adverse events.............................................................................32
5.2.6.1
Adverse event........................................................................................................32
5.2.6.2
Adverse event collection and reporting ................................................................37
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................39
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................40
6.
INVESTIGATIONAL PLAN.............................................................................40
6.1
SCREENING PERIOD ......................................................................................40
6.1.1
Baseline conditions..............................................................................................40
6.1.2
Medical history....................................................................................................40
6.1.3
Concomitant therapies........................................................................................40
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................41
7.1
STATISTICAL DESIGN – MODEL ................................................................41
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................41
7.3
PLANNED ANALYSES.....................................................................................41
7.3.1
Primary endpoint analyses.................................................................................42
7.3.2
Secondary endpoint analyses .............................................................................42
7.3.4
Safety analyses.....................................................................................................43
7.4
INTERIM ANALYSES ......................................................................................43
7.5
HANDLING OF MISSING DATA ...................................................................43
7.6
RANDOMISATION ...........................................................................................44
7.7
DETERMINATION OF SAMPLE SIZE .........................................................44

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........44
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................45
8.2
DATA QUALITY ASSURANCE ......................................................................45
8.3
RECORDS...........................................................................................................46
8.3.1
Source documents ...............................................................................................46
8.3.2
Direct access to source data and documents.....................................................47
8.3.3
Storage period of records ...................................................................................47
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................47
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........47
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................48
8.6
TRIAL MILESTONES.......................................................................................48
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................48
9.
REFERENCES....................................................................................................50
9.1
PUBLISHED REFERENCES............................................................................50
10.
APPENDICES.....................................................................................................53
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....53
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS..............56
10.3
PHARMACOKINETIC METHODS AND ANALYSES................................58
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................60
11.1
GLOBAL AMENDMENT 1 ..............................................................................60
11.2
GLOBAL AMENDMENT 2 ..............................................................................68
11.3
GLOBAL AMENDMENT 3 ..............................................................................70

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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastic Time
AST
Aspartate Transaminase 
ßHCG
Beta Human Chorionic Gonadotropin
BHM
Bayesian Hierarchical Model
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
CK
Creatinine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology
Cmax
Maximum Concentration
CML
Clinical Monitor Local
CPK
Creatinine Phosphokinase
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as 
“eCRF”)
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DBL
Database Lock
DC
Disease Control
DILI
Drug Induced Liver Injury
DLT
Dose-Limiting Toxicity
DOiR
Duration of Immune Response
DoR
Duration of Response
EC
Ethics Committee
ECG
Electrocardiogram

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ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FFPE
Formalin fixed and paraffin embedded
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
iCPD
Immune Confirmed Progressive Disease
iCR
Immune Complete Response
iDC
Immune Disease Control
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
iOR
Immune Objective Response
iPR
Immune Partial Response
irAE
Immune-Related Adverse Event
IRB
Institutional Review Board
iRECIST
Immune Response Evaluation Criteria in Solid Tumours
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
i.v.
Intravenous
LPLT
Last Patient Last Treatment
mAb
Monoclonal Antibody
MDSC
Myeloid-Derived Suppressor Cell

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MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
NSCLC
Non-Small-Cell Lung Cancer
OR
Objective Response
ORR
Overall Response Rate
OS
Overall Survival
PD
Progression of Disease
PDc
Pharmacodynamic
PD-1
Programmed Cell Death Protein-1
PD-L1
Programmed Death Ligand-1
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial Response
PT
Prothrombin Time
q3w
Every 3 weeks
QT
ECG interval measured from the onset of the QRS complex to the end 
of the T wave
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
SAE
Serious Adverse Event
SC
Steering Committee
SD
Stable Disease
SOP
Standard Operating Procedure
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
WHO
World Health Organization

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WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
This is a Phase II, open-label, multicentre trial in patients with advanced/metastatic solid 
tumours who may benefit from immune-checkpoint inhibitor therapy. This Master protocol is 
designed with ‘Modules’ which allow for the simultaneous development of ezabenlimab in 
combination with other checkpoint inhibitors or anticancer medications in various tumour 
types.
The Master protocol document contains the operational components common to the conduct 
of the trial regardless of treatment-specific Module (e.g., safety, administrative structure). 
The treatment-specific Modules contain further details particular to each treatment 
combination, such as Module-specific or treatment-specific eligibility criteria, treatment
administration, trial assessments and other guidances.
1.1
MEDICAL BACKGROUND
Despite the recent advancements in cancer treatment, cancer remains a leading cause of death 
globally. Approximately 1,685,210 new cancer cases were expected to be diagnosed in 2016 
(excluding carcinoma in situ [noninvasive cancer] of any site except urinary bladder and 
basal cell or squamous cell skin cancers). Approximately 595,690 people in the United States 
were expected to die of cancer in 2016. 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.
T-cell activation is a highly regulated process that promotes T-cell proliferation, 
differentiation, survival, and cytokine production. Up-regulation of multiple co-regulatory 
receptors on activated T-cells provides a mechanism of fine-tuning the immune response. The 
programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway 
was the first negative immune co-regulatory (immune-checkpoint inhibitor) pathway 
described (R16-2361; R16-2363). Indeed, genetic inactivation of the PD-1/PD-L1 pathway in 
mice resulted in various autoimmune phenotypes (R16-2362; R16-2364). PD-1 expression in 
humans is largely restricted to immune cells (T-cells, B-cells, natural killer T-cells, activated 
monocytes and dendritic cells) and is upregulated upon T-cell activation (R15-6038; R16-
2364), whereas PD-L1 protein is expressed on the surface of a wide range of human cancer 
cells (R16-2371). The physiologic function of the PD-1 pathway is to down-regulate the 
immune response once the antigen that stimulated the response is eliminated, thereby limiting 
collateral tissue damage. The primary study drug in this trial, ezabenlimab, targets the PD-1 
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Treatment of patients with advanced melanoma, non-small-cell lung cancer (NSCLC), renal 
cell carcinoma, and many other tumour types with anti-PD-1 (nivolumab or pembrolizumab) 
or anti-PD-L1 (atezolizumab, durvalumab, and avelumab) monoclonal antibodies (mAbs) has 
resulted in highly durable responses in approximately 15% to 30% of patients (R15-3715; 
R15-3776; R15-3778; R15-6023; R16-0663; R16-0864; R16-0876; R16-1225; R16-1588; 
R16-3547).
For the patients that either lack a response to initial anti-PD-(L)1 therapy or progress 
following an anti-PD-(L)1 response, research efforts to date are focusing on achieving 
clinical benefit using a combination therapy approach. In particular, preclinical and clinical 
research data present strong evidence of tumour regression effects when combining other 
agents, such as immunomodulatory and targeted therapies, with a PD-(L)1 antagonist.
In this study, the planned ezabenlimab treatment combination will include the clinical and 
nonclinical information for the agent being combined and presented in individual Modules. 
The rationale, benefit/risk, treatment-specific eligibility criteria, treatment administration, 
trial assessments and other guidances will be described in the Module. Additional Modules 
and agents may be added to the Master. Agents combined with ezabenlimab will have been 
previously tested.
1.2
DRUG PROFILE
Ezabenlimab will be combined with other agents in each of the Modules. The profiles for the 
agents to be combined with ezabenlimab will be described in the respective Module.
1.2.1
Ezabenlimab
Ezabenlimab is a humanised IgG4Pro mAb that is being developed as an i.v. infusion for the 
treatment of cancer. Ezabenlimab has highly human frameworks and a low predicted 
immunogenicity score.
For a more detailed description of the ezabenlimab profile, please refer to the Investigator’s 
Brochure (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
The aim of this study is to assess the efficacy of ezabenlimab in combination with other 
checkpoint inhibitors or anticancer medications in different tumour types covered by the trial
cohorts, and to identify potential patterns of responsiveness that are not limited to specific 
tumour types but are present across multiple settings. Patients that progress on treatment in a 
given Module may be offered treatment in another Module if deemed appropriate by the 
Investigator and Sponsor. Such patients will help explore potential longitudinal efficacy of
treatment cross-over from one treatment-specific Module to another.  
This Master protocol design document (referred to as the Master) will describe the common 
operational aspects of the trial while the treatment-specific ‘Modules’ (referred to as 
Modules) will contain further details particular to that treatment combination, such as 
eligibility criteria, dose and treatment administration, trial assessments, and other guidances.

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The trial will begin with one treatment Module (ezabenlimab in combination with 
BI 754111); additional Modules will be added by protocol amendment. Clinically ineffective 
or completed Modules will be closed. Patients receiving treatment in one Module with 
disease progression or tolerability issues may be eligible for cross-over to a different Module. 
Ezabenlimab will be combined with anticancer agent(s) with scientific evidence and a 
rationale to support the combination in a specific patient population. Agents combined with 
ezabenlimab will have at least completed dose escalation in combination with ezabenlimab in 
patients with solid tumours in a separate trial prior to inclusion of that treatment-specific 
Module in this study. These agents may be Boehringer Ingelheim-developed agents or other 
agents.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biopsied biospecimens for banking (see the treatment-specific module for details). If 
the patient agrees, banked samples may be used for future biomarker research and drug 
development projects, e.g. to identify patients that are more likely to benefit from a treatment 
or experience an adverse event (AE), or to gain a mechanistic or genetic understanding of 
drug effects and thereby better match patients with therapies. 
The trial populations for the trial (as defined in each module) were selected based on the 
current high unmet medical need with limited treatment options as well as the expectation 
that the combination therapy may be a viable treatment option for these patients.
1.4
BENEFIT - RISK ASSESSMENT
The role of the immune-checkpoints 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-checkpoints also play a major role in promoting 
and maintaining self-tolerance by inactivating auto-reactive T-cells. Therefore, inhibition of 
immune-checkpoint pathways unleashes the immune system and comes with a higher risk of 
inducing immune dysfunction, leading to immune-related adverse events (irAEs). Indeed, 
mice deficient in PD-1 or its ligands (PD-Ll and PD-L2) were found to be highly prone to 
development of autoimmune diseases (R16-2364; R16-2969; R16-2970).
Immune-checkpoint inhibition has been shown to be a promising therapeutic strategy in a 
subset of patients. The limited success achieved with checkpoint-inhibitor monotherapy in 
some studies (up to 80% of treated patients do not respond [R15-3588; R15-3778]) may, in 
part be attributed to redundancy in immune-checkpoint inhibitor pathways. Understanding 
that multiple, diverse mechanisms may contribute to checkpoint-inhibitor resistance, a goal of 
this trial is to improve upon checkpoint-inhibitor monotherapy results thus far, assessing 
multiple novel approaches to therapy.
As of 30-November-2018, 50 patients with advanced/metastatic solid tumours have been 
treated with ezabenlimab as monotherapy in the 1381.1 trial. 
The most frequently reported AEs (reported in >10% of the patients) were fatigue (40%), 
nausea (28.0%), decreased appetite (18.0%), arthralgia (16.0%), cough (16.0%), abdominal 

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pain (14.0%), constipation (14.0%), diarrhoea (14.0 %), vomiting (14.0), back pain (12.0%) 
and dyspnoea (12.0%). Headache, hypokalaemia, muscular chest pain, myalgia, pruritis and 
rash, each occurred at a frequency of 10.0%.  The majority of these AEs were CTCAE Grade 
1 and 2.
Grade 3 and 4 AEs were reported in 38.0% and 4.0% of patients, respectively. Of the Grade 3 
events, only the AST elevation event was reported as related to trial drug.  The reported 
Grade 4 AEs were 1 (2.0%) case of disease progression and 1 (2.0%) case of sepsis, neither 
of which was deemed treatment related. 
Consistent with the similar drug class labels, most irAEs were reported in the GI, skin and 
endocrine system organ class (SOCs). The majority of the irAEs were Grades 1 or 2; the only 
Grade 3 irAE was AST increase.
Preliminary efficacy analyses for study 1381.1 indicate that there have been 6 patients with 
partial response (PR) and 20 patients with stable disease (SD) as best response on 
ezabenlimab monotherapy.  The PRs were reported in two patients with triple negative breast 
cancer, one patient with fallopian tube cancer, one patient with renal cancer, one patient with 
stomach cancer and one patient with endometrial cancer.  All of these PRs occurred in 
patients receiving the 240 mg q3w dose of ezabenlimab.
A similar safety profile of ezabenlimab monotherapy was observed in 6 Japanese patients 
with solid tumours evaluated in the Asian trial 1381.4. 
The details of the preliminary analysis are provided in section 6.2 of the ezabenlimab IB.
Trial procedures such as blood sampling, imaging with contrast media, and tumour biopsies,
are part of standard of care in these advanced cancer patients. The additional blood samplings 
increase the risk for anaemia which can be corrected by appropriate transfusion, if necessary. 
While the imaging performed can bring additional long-term radiation it is the only method to 
detect early progression or early response to avoid unnecessary further treatment or a 
premature stop while the trial treatment would be beneficial to the patient.
There is an added risk for pain, swelling, and bleeding for those patients who will undergo 
tumour biopsies at screening and during the trial, under treatment. Additional treatment-
specific benefit-risk assessments are described in the respective Modules. 
Although rare, the potential for drug-induced liver injury (DILI) is under constant
surveillance by sponsors and regulators. Therefore, this trial requires timely detection,
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters to
ensure patients safety.
A Safety Review Committee (SRC) as described in Section 8.7 will be established for the 
study.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Objectives common across all Modules are described in the following sections. Distinct and 
important objectives applicable to each treatment plan are described in the treatment-specific
Modules.  
2.1.1
Main objective
The aim of this study is to assess the efficacy of ezabenlimab in combination with other 
checkpoint inhibitors or anticancer medications in diverse tumour type cohorts. 
2.1.2
Primary endpoint
The primary endpoint of the trial is objective response (OR), defined as best overall response 
of complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by 
the Investigator. 
2.1.3
Secondary endpoint(s)
The secondary endpoints of the trial will include:

Duration of response (DoR), defined as the time from first documented CR or PR 
(RECIST v1.1) until the earlier of disease progression or death among patients with OR.

Disease control (DC), defined as best overall response of CR, PR, or stable disease (SD) 
according to RECIST v1.1 as assessed by the Investigator.

Progression-free survival (PFS), defined as the time from first treatment until PD or death 
from any cause, whichever occurs earlier.
 

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This Phase II, multi-drug, open-label multi-centre trial will be conducted in North America 
and the United Kingdom. The Master trial design will include several different
ezabenlimab-based combinations, which are defined in treatment-specific Modules appended 
to the Master. Each Module will investigate the anti-PD-1 mAb ezabenlimab combined with
other agents. Within each Module selection criteria will identify patients to be assigned by 
cohort based on their previous exposure or lack of exposure to cancer anti-PD-1 or anti-PD-
L1 treatment and tumour type. The safety, tolerability, PK profile and antitumour activity of 
the treatments in each Module will be determined.
Initial screening assessments are described in the Master protocol. Patients will sign a Master 
informed consent form (ICF) for screening. Upon module assignment, the patient will sign 
the corresponding module ICF. Further screening assessments will be performed to determine 
eligibility for the Module the patient is assigned to.
Once determined eligible for a Module and treatment has begun, the patient will continue 
study treatment in the Module with the study drugs until disease progression (PD) according 
to RECIST 1.1 (R09-0262) and/or iRECIST (R15-2005), withdrawal of patient consent, an 
unacceptable toxicity occurs, or 1 year of treatment is completed, whichever occurs first.
Patients will be allowed to stay on treatment in the case of initial radiological PD, if the 
Investigator feels that it is in the patient’s best interest. In addition, patients without PD may
stay on trial beyond 1 year of treatment on a case-by-case basis after discussion with the 
Medical Monitor and the sponsor. Patients that progress on treatment in a given Module may
be offered treatment in another Module if deemed appropriate by the Investigator and 
Sponsor.  Patients that discontinue for reasons other than PD will not be eligible for other 
Modules. 

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
The primary reason for using this type of design is to answer questions and deliver results 
expeditiously, thus benefitting future patients and the research community. A Master design 
protocol will streamline the exploration of an agent of interest given in combination with 
ezabenlimab, a PD-1 inhibitor, and allow for assessments of patterns of responsiveness across 
multiple tumour types and treatment combinations.
A Safety Review Committee (SRC) as described in Section 8.7 will be established for the 
study.
3.3
SELECTION OF TRIAL POPULATION
The inclusion and exclusion criteria for enrolment in the Master protocol are described 
below. Each Module will have additional inclusion/exclusion criteria to be met prior to 
enrolment into that Module.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients have been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
Patients must fulfil all of the following Master inclusion criteria below and the inclusion 
criteria described in the particular Module to be eligible.
1. Provision of signed and dated, written Master informed consent form (ICF) prior to 
any trial-specific procedures, sampling, or analyses.
2. Several cohorts of patients with various solid tumours have been defined. Details are 
given in the respective treatment-specific Modules.
3. Patient moving from one module to another must have prior irAEs resolved to a 
degree that would allow for restart of checkpoint inhibitor therapy according to the 
irAE management guidelines in the protocol.
4. Patient ≥18 years of age at the time of signature of the ICF.
5. Eastern Cooperative Oncology Group (ECOG) score: 0 or 1.

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6. Patient must agree to a pre-treatment biopsy (if archival tissue is not available) and 
on-treatment tumour biopsy. If archived tumour tissue is available from the last 
treatment failure, sections may be supplied instead of a pre-treatment biopsy. 
7. Life expectancy of at least 12 weeks after the start of the treatment according to the 
Investigator’s judgement.
8. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be willing and able to use highly effective methods of birth control 
(that result in a low failure rate of less than 1% per year when used consistently and 
correctly) during trial participation and for at least 6 months after the last 
administration of trial medication. 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).  Male patients with partners of childbearing potential must 
agree to use condoms and ensure their partners are 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.
3.3.3
Exclusion criteria
Patients must fulfil none of the Master exclusion criteria below or any exclusion criteria 
described in the particular Module to be eligible: 
1. Any investigational treatment, anti-tumour treatment within 4 weeks or within 5 half-
life periods (whichever is shorter) prior to the initiation of trial treatment.
2. More than one anti-PD-(L)1-based treatment regimen prior to entering study, more 
specifically defined in the modules. Note: once in a trial Module, patients may 
crossover to different Module if all other eligibility criteria are met.
3. Major surgery (‘major’ according to the Investigator’s assessment and/or Medical 
Monitor’s) performed within 12 weeks prior to first trial treatment or planned within 
12 months after screening, e.g., hip replacement.
4. 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.
5. Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal 
therapy) at start of treatment in this trial. Patients may be enrolled onto the study 
following an 7-day washout period after the end of systemic treatment for active 
infection.
6. Patient has received allogeneic bone marrow or solid organ transplant.
                                                          
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 

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7. Inadequate organ function or bone marrow reserve as demonstrated by the laboratory 
values presented in Table 3.3.3: 1.
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

Patients with an ejection fraction (EF) <55% or the lower limit of normal of 
the institutional standard (if the lower limit of normal of institutional standard 
is higher than 55%) will be excluded. Only in cases where the Investigator (or 
the treating physician or both) suspects cardiac disease with negative effect on 
the EF will the EF be measured during screening using an appropriate method 
according to local standards to confirm eligibility (e.g., echocardiogram, 
multi-gated acquisition scan). An historic measurement of EF no older than 6 
months prior to first administration of trial 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. Known history of human immunodeficiency virus infection or an active hepatitis B or 
C virus infection.
10. Active autoimmune disease or a documented history of autoimmune disease, except 
vitiligo or resolved childhood asthma/atopy. Patients who were permanently 
discontinued from previous anti-PD-1 or anti-PD-L1 therapy because of an immune-
related adverse event (irAE).
11. Known history of severe hypersensitivity reactions to other mAbs or known 
hypersensitivity to the trial drugs or their excipients.
12. Presence of central nervous system (CNS) metastases, unless treated and 
asymptomatic and off corticosteroids and anti-convulsant therapy for at least 2 weeks 
prior start of treatment.
13. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) 
within 4 weeks prior to the first dose of study treatment.
14. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial.
15. Chronic alcohol or drug abuse or any condition that, in the Investigator’s and/or 
Medical Monitor’s opinion, makes him/her an unreliable trial subject, unlikely to 
complete the trial, or unable to comply with the protocol procedures.
16. Women who are pregnant, nursing, or who plan to become pregnant while in the trial 
and for at least 6 months after the last administration of trial medication.
17. Men who plan to father a child while in the trial and for at least 6 months after the last 
administration of trial medication.

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Table 3.3.3: 1 Laboratory values demonstrating inadequate organ function 
Laboratory Parameter
Values for solid tumours
Absolute neutrophil count
<1.5 x 109/L (<1500/mm3)
Alanine aminotransferase (ALT) 
>2.5 X ULN if no demonstrable liver 
metastases or >5 X ULN in the 
presence of liver metastases
Aspartate aminotransferase (AST)
>2.5 X ULN if no demonstrable liver 
metastases or >5 X ULN in the 
presence of liver metastases
Haemoglobin 
<9 g/dL
International Normalized Ratio (INR) (only 
tested if clinically indicated)
>1.5 X ULN (If treated with anticoagulants, 
prolonged INR is acceptable)
Platelet count
<100 x 109/L
Serum Creatinine
>1.5 X ULN or estimated glomerular filtration 
rate (eGFR) <30 mL/min/1.73 m2
(Chronic Kidney Disease 
Epidemiology [CKD-EPI] 
Collaboration equation); confirmation 
of eGFR is only required when 
creatinine is >1.5 X ULN.
Total bilirubin
>1.5 X ULN, except for patients with Gilbert's 
syndrome who are excluded if total 
bilirubin >3.0 X ULN or direct 
bilirubin >1.5 X ULN
3.3.3.1
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.3.2 and 
3.3.3.3 below.
Every effort should be made to keep the patients in the trial, if possible on treatment, or at 
least post-treatment discontinuation to collect important trial data.
Patients whose disease progresses while receiving therapy in a given Module in this study 
may be offered treatment with a different investigational Module if deemed appropriate by 
the Investigator. A signed Module-specific ICF will be required prior to treatment. The 
transition time between Modules (last dose of previous Module and screening visit of 
subsequent Module) will be a maximum of 2 months.  

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Measures to control the withdrawal rate include careful patient selection and appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If the reason for discontinuation is
death other than due to PD, this should be reported on the SAE form as well, regardless of 
causal relationship.
3.3.3.2
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

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 adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). For pregnancy see Section 5.2.6.2.4.
Even if the trial treatment is discontinued, the patient will remain in the trial and, given 
his/her agreement, will undergo the procedures for early treatment discontinuation and follow 
up (see the treatment-specific module for details).
3.3.3.3
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation (please see Section 3.3.3.2 above).
3.3.3.4
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall, a specific Module, or 
at a particular trial site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk
assessment that could significantly affect the continuation of the trial.
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
4. Completion of treatment by all patients and the sponsor determines that sufficient data 
have been collected.  

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The Investigator/ 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
This is an open-label study. Specific dosing and treatment regimens for each of the 
ezabenlimab combinations are described in the individual Modules. Selection of the 
treatment-specific Module will be determined by the patient’s tumour type, prior treatment, 
and algorithm (such as Interactive Response Technology [IRT]) for patient assignment. 
Patients will sign a Master ICF prior to any Master screening procedures and will sign the 
Module ICF prior to the occurrence of any Module-specific procedures. 
For agents to be combined with ezabenlimab, selection of doses, method of assignment to 
treatment, any dose modification instructions, drug administration, and drug accountability 
are described in the respective Modules of this clinical protocol. 
Dose reductions or escalations of ezabenlimab are not permitted. Treatment administration 
may be delayed to manage AEs by one cycle, plus an additional 3 weeks, following 
discussion with the Medical Monitor.
4.1.1
Identity of the Investigational Medicinal Products
Ezabenlimab will be administered in each of the Modules. The agent to be paired with 
ezabenlimab will be described in detail in the treatment-specific Module.
4.1.2
Selection of doses in the trial
Refer to the treatment-specific Module.
4.1.3
Method of assigning patients to treatment groups
After assessment of all inclusion and exclusion criteria from the Master and the Module, each 
eligible patient will be assigned to a module and the corresponding appropriate medication 
number. Note that the medication number is different from the patient number (the latter is 
assigned directly after informed consent is obtained). The assignment will be determined by 
person(s) independent from the site using predefined algorithm and entered into the 
Interactive Response Technology (IRT) System. Site personnel will enter the medication 
number in the CRF.
4.1.3.1
Method of assigning patients to a second, or subsequent, Module(s)
Patients whose disease progresses while receiving a modular treatment may be offered 
treatment in a different Module if deemed appropriate by the Investigator. The process will 
be the same as if the patient were new to the trial. All the Module-specific inclusion and 
exclusion criteria must be met and the patient must sign an approved ICF for the Module. The 

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assignment will be based on a predefined algorithm if patients are eligible for more than one 
Module. 
The patient must sign an approved ICF for the subsequent Module, be screened prior to 
entering the new Module, and must meet all Master and Module-specific inclusion criteria. 
The transition time between Modules (last dose of previous Module and screening visit of 
subsequent Module) will be a maximum of 2 months. The assignment will be based on 
predefined algorithm if patients are eligible for more than one Module. Patients will be 
allowed multiple crossovers into subsequent Modules.
Patients that cross over to a new Module will not reduce the preplanned number of patients 
allocated to that module (i.e. A Module that is planned to have a specific number of patients 
will have that number of patients recruited irrespective of the number of patients that cross 
over from other modules.)
4.1.4
Blinding and procedures for unblinding
Not applicable in this open-label trial.
4.1.5
Packaging, labelling, and re-supply
The investigational products will be provided by BI. They will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice. Each site will be provided 
with an initial shipment of trial drug supply. The Investigator or designee is responsible 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. The IRT system and DS Team will monitor drug supply at 
site, expiry dates, and upcoming patient visits to ensure adequate supplies. If supply is low at 
a site, the IRT will trigger replacement supplies. Additional details on resupply and setup for 
IRT drug monitoring will be provided in the associated IRT Specific Documentation.
Upon receipt of the request, 
will trigger drug 
supply for the site using an IRT system.
For details of packaging and the description of the label, refer to the Investigator Site File 
(ISF).
4.1.6
Storage conditions  
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.

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4.1.7
Drug accountability
The Investigator, or designee, will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval for the Master protocol, applicable Modules and ICFs 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 for the Master 
protocol and applicable Modules

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 signed and dated Form 1572 (U.S. only).
The Investigator, or designee, must maintain records of the products’ delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or alternative 
disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial patients. The 
Investigator, or designee, will maintain records that document adequately that the patients 
were provided the specified doses and reconcile all investigational products received from the 
sponsor. Unused and partially used trial drugs will be destroyed on site at the end of the trial 
(after relevant reconciliations have been completed and records reviewed by the clinical 
monitor).
4.1.8
Dose modifications
Refer to the treatment-specific Module.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Refer to the treatment-specific Modules.
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. Recommendations for the management of immune-related AEs 
can be found in Appendix 10.2.
Rescue medications to reverse the actions of ezabenlimab are not available. Therefore, 
potential side effects of ezabenlimab have to be treated symptomatically. Rescue medications 
for other investigational medicinal products will be described in the respective Module.

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Appropriate measures according to institutional standards should be taken to limit any risk of 
bleeding for patients who are on full anti-coagulation therapy.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
No other investigational therapy or anticancer agent should be given to patients. If such 
agents are required for a patient, then the patient must first be withdrawn from the trial.
4.2.2.2
Restrictions on diet and life style
No restrictions to diet or life style have been identified for ezabenlimab.
Refer to each Module for any additional restrictions.
4.2.2.3
Contraception requirements
Women of childbearing potential and men able to father a child must use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly. A list of contraception methods meeting these 
criteria is provided below.
WOCBP and men able to father a child must use medically approved methods of birth control 
throughout the trial, and for a period of at least 6 months after last trial drug intake. 
Male patients: 
Male patients with partners of childbearing potential must agree to use condoms and ensure 
their partners are using an additional highly-effective method of birth control, during the trial 
and until at least 6 months after the end of the trial treatment.
Female patients: 
WOCBP must use highly effective methods of birth control per ICH M3 (R2) that results in a 
low failure rate of less than 1% per year when used consistently and correctly during the trial, 
and for a period of at least 6 months after the last dose of trial drug.
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 WOCBP 
CT participant), OR 

Intrauterine device or intrauterine hormone-releasing system

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4.3
TREATMENT COMPLIANCE
Study drug will be administered 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 in the applicable Module. Missed or interrupted doses 
will be recorded in the eCRF with the associated reasons. The method of collecting dosing 
information assures that total exposure can be calculated programmatically taking into 
account any missing doses.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The tumour response in patients with solid tumours will be evaluated according to RECIST 
Version 1.1 (R09-0262) for the primary endpoin
The assessment by the Investigator and/or the local radiologist will be the basis for 
continuation or discontinuation of the trial medication in an individual patient (in addition to 
safety). The baseline imaging must have been performed within 4 weeks prior to treatment 
with the trial medication and the Investigator will record the target and non-target lesions in 
the eCRF. The same method of assessment and the same technique must be used to 
characterise each reported lesion at baseline and during treatment. Lesions in previously 
irradiated areas may not be used as target lesions. Tumour assessments will be performed at 
screening (as close as possible to the treatment start and no more than 28 days before the start 
of study treatment), every 6 weeks (±3 days) for the first 6 months, then every 9 weeks (±3 
days) thereafter, and at the EOT visit (if not performed within the previous 4 weeks). The 
length of cycles will be defined in the respective Modules. 
If the patient stops trial medication intake for a reason other than PD based on RECIST, the 
tumour assessment according to RECIST and iRECIST will be performed according to 
standard of care until the last follow-up needed according to the protocol (PD, death, lost to 
follow-up, end of the trial).
Patients will continue treatment with the study drugs until disease progression (PD) by 
RECIST and/or iRECIST, withdrawal of patient consent, an unacceptable toxicity occurs, or 
1 year of treatment is completed, whichever occurs first. Patients will be allowed to stay on 
treatment in the case of initial radiological PD, if the Investigator feels that it is in the 
patient’s best interest. In addition, patients without PD may stay on study drug (s) beyond 
1 year of treatment on a case-by-case basis after discussion with and approval by the Medical 
Monitor and the sponsor. 
Digital copies of disease evaluation scans (CT/MRI/PET) are to be collected by the sponsor
and stored centrally for later radiomics assessment. It is planned to explore the potential for 
enhanced and improved baseline and on-treatment markers/patterns of early efficacy based 
on comprehensive quantitative CT metrics, i.e., radiomics features, assessed in standard-of-
care medical imaging data.

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5.2
ASSESSMENT OF SAFETY
The safety of ezabenlimab in combination with other agents will be assessed by a descriptive 
analysis of incidence and severity of AEs graded according to CTCAE (version 5.0), 
laboratory data, and results of physical examinations. Safety will be assessed in a descriptive 
way without confirmatory analysis.
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified within each 
module (see the treatment-specific module for details). It includes at a minimum general 
appearance, neck, lungs, cardiovascular system, abdomen, extremities, skin, and neurological 
systems. 
Measurement of height and body weight will be performed at the specific time points (see the 
treatment-specific module for details).
During the physical examination, the patient should be assessed for possible adverse events.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified to the modules, prior to blood 
sampling and trial treatment administration (see the treatment-specific module for details). 
This includes body temperature, systolic and diastolic blood pressure and pulse rate 
(electronically or by palpation count for 1 minute). All except body temperature need to be 
taken in a seated position after 5 minutes of rest. Oxygen saturation will be measured, if 
needed.
Blood pressure and heart rate may also be measured after infusion of ezabenlimab or at any 
time that the Investigator deems it is necessary.
5.2.3
Safety laboratory parameters
Safety laboratory testing will occur at the time points specified in the respective modules (see 
the treatment-specific module for details). All analyses will be performed locally. Patients do 
not have to be fasted for the blood sampling for the safety laboratory tests.
Instructions regarding sample collection, sample handling / processing and sample shipping 
are provided in the Laboratory Manual in the ISF.
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.3 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.

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Safety laboratory tests will include the following parameters:
Haematology
The standard haematology panel will consist of: haemoglobin, red blood cell count, 
haematocrit, mean corpuscular volume, white blood cell count, differential blood count 
(preferably expressed in absolute values), and platelets.
Biochemistry
The standard biochemistry panel will consist of glucose, sodium, potassium, chloride, 
calcium, phosphate, urea, creatinine, AST, ALT, alkaline phosphatase, lactate 
dehydrogenase, bilirubin (direct and indirect bilirubin in case of elevated total bilirubin 
values), total protein, albumin, urea nitrogen, uric acid, Troponin I (only at screening, C1D1, 
C1D8, C1D15, C2D1, C3D1, C4D1 and anytime CPK is elevated), and creatinine kinase 
(CK). A thyroid panel (TSH, free T4, and free T3) will be done during at the time of each 
standard biochemistry panel.
If symptoms of pancreatitis are observed, amylase and lipase should be tested at the 
discretion of the Investigator.
Coagulation
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) (expressed either in 
seconds or as a percentage) will be tested according to the treatment-specific module.
Urine
Urine (pH, glucose, erythrocytes, leukocytes, protein, and nitrite) will be analysed by dipstick 
(semi-quantitative measurements).
Pregnancy test
A beta human chorionic gonadotropin (β-HCG) pregnancy test in serum will be performed 
for women of childbearing potential (WOCBP) at screening. Thereafter, this test may be done 
in serum or urine on Day 1 of each cycle, at the EOT visit, and at the 30-day safety follow-up 
visit.
If laboratory safety investigations have been performed >72 hours prior to the first trial 
treatment, the results of the new safety laboratory investigations performed within 72 hours 
of first treatment must be available to reconfirm eligibility.
5.2.4
Electrocardiogram
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting electrocardiograms (ECGs) will 
be obtained and digitally recorded. See the treatment-specific modules for details outlining 
which visits will require single ECGs. 
The ECG should be obtained after the patient has been resting supine for at least 5 minutes.
All ECGs should be recorded with the patient in the same physical position. If necessary, 
additional ECGs may be recorded for safety reasons.

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The ECG recordings must also be analysed and checked for abnormality by the Investigator 
(or designated physician) who will also calculate the QTcF. Particular attention must be paid 
to T wave inversions. Clinically relevant abnormal findings will be reported either as baseline 
condition (if identified at the screening visit) or otherwise as adverse events and will be 
followed up and/or treated as medically appropriate. CTCAE version 5.0 will be used for the 
grading of prolonged QTcF intervals.
In case of related ECG changes and whenever the Investigator deems necessary, additional 
ECG monitoring will be performed in the respective and later courses of treatment.
In case of QTcF prolongation to >500 ms AFTER receiving therapy, the Investigator will 
initiate further ECG monitoring and diagnostics (e.g., check electrolytes and check 
concomitant therapy that may be contributing to QTcF prolongation) and if required provide 
adequate treatment according to medical standards. The patient will be discharged from the 
investigational site only after resolution of ECG findings as assessed by the Investigator.
In case of occurrence of symptoms suggestive of arrhythmia related to QTcF prolongation, a 
cardiologic evaluation will be performed, and treatment will be provided according to 
medical standards at the discretion of the Investigator.
5.2.5
Other safety parameters
Refer to the treatment-specific Modules.
5.2.6
Assessment of adverse events
5.2.6.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of pre-existing conditions.

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.

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5.2.6.1.1
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
Patients may be hospitalised for administrative reasons during the trial, including 
hospitalisation for respite care. These as well as hospitalisations/surgical procedures which 
were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalisation/surgical procedure has not 
changed/worsened after signing informed consent).
5.2.6.1.2
AEs considered ‘Always Serious’
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since the discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above. The latest list of ‘Always Serious AEs’ can be found in the electronic 
document system. These events should always be reported as SAEs as described above.
5.2.6.1.3
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.

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For this trial, infusion-related AEs, potential DILI events, hepatic injury, and qualifying 
irAEs, as defined in the treatment-specific Modules and Appendix 10.1, are AESIs.
Immune-related adverse events (irAEs)  
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. All immune-related events are to be reported as AEs. Some irAEs also 
need to be reported as AESIs as defined by the sponsor in Appendix 10.1. If an Investigator 
determines a Grade 3 event of an AE that is not mentioned on the list of immune-related AEs, 
the Investigator should also report that event as an AESI.
Recommendations for the management of irAEs are presented in Appendix 10.2.
Infusion-related reactions
In the event of an infusion-related reaction ≤ Grade 2, treat the symptoms accordingly with 
antihistamine or corticosteroids if needed. The infusion rate of ezabenlimab may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate. If an infusion-
related reaction to trial medications is Grade 3 or higher in severity at any point during the 
study, permanently discontinue study drug(s).
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional 
standard may be administered prior to subsequent infusions at the discretion of the 
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the study, treatment with 
ezabenlimab will be permanently discontinued.
As with any mAb, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and trial personnel must be trained to recognise and treat anaphylaxis. The trial site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability 
to admit patients to an intensive care unit if necessary.

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The following terms describe those events that are to be considered potential infusion-related 
AEs. Regardless of grade, these events are considered as AESIs and must be reported to the 
Safety group within 24 hours of the event:

Allergic reaction

Anaphylaxis

-release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential infusion-
related AE, the Investigator may also report that event as an AESI.
Hepatic injury and potential drug-induced liver injury (DILI)
During the course of the trial the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets the 
hepatic injury definition or potential Hy’s Law criteria at any point during the trial.
The Investigator participates, together with 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:
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or 

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “Potential DILI Checklist” provided in 
the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the “Potential DILI Checklist” (Figure 
5.2.6.1.3: 1) should be followed. 

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Lab values meeting the hepatic injury definition will need to be reported as an AESI. Please 
follow the flowchart below for reporting hepatic injury / potential DILI cases.
Figure 5.2.6.1.3: 1 Potential DILI Cases in Oncology
Hy’s Law cases have the following 3 components:

The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST

Among trial subjects showing such aminotransferase elevations, often with elevations 
much greater than 3 times ULN, one or more also show elevation of serum total bilirubin 
to >2 times ULN, without initial findings of cholestasis (elevated serum ALP)

No other reason can be found to explain the combination of increased aminotransferase 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury.
5.2.6.1.4
Severity of AEs
The severity of AEs should be classified and recorded in the eCRF according to the CTCAE 
Version 5.
5.2.6.1.5
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

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
The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

There was an indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is reduced).
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.

The event disappeared even though the trial drug treatment continued or remained 
unchanged.

There may be additional arguments amongst those stated before, like alternative 
explanation (e.g. situations where other drugs or underlying diseases appear to provide a 
more likely explanation for the observed event than the drug concerned).
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files. The 
following must be collected and documented on the appropriate CRF(s) by the investigator:

From signing the ICF onwards until the end of treatment (including the residual effect 
period (REP); a period of 30 days after the last dose of trial medication) - all AEs (non-
serious and serious) and all AESIs.

After the end of treatment, including REP until the individual patient’s end of trial - all 
related SAEs and all related AESIs and any occurrence of cancer of new histology.

After the individual patient’s end of trial, the Investigator does not need to actively 
monitor the patient for new AEs but should only report related SAEs and related AESIs 
and any occurrence of cancer of a new histology of which the investigator may become 
aware of by any means of communication, e.g. phone call. Those AEs should however, 
not be reported in the CRF.
The rules for AE reporting exemptions still apply, please see Section 5.2.6.2.5.

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All AEs which occurred through the treatment phase and throughout the REP will be 
considered as on treatment; please see Section 7.3.4. Events which occurred after the REP 
will be considered as post-treatment events.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via secure e-mail connection or via fax 
immediately (within 24 hours) to 
Safety
Department:

Secure email 
 mailbox: 
 or 

Fax 
safety fax number):
For sites outside of the US, country-specific fax numbers will be provided in the ISF/study
reference manual.
The same timeline applies if follow-up information becomes available. On specific occasions, 
the Investigator can inform 
Safety 
Department upfront via telephone by calling 
 
 reporting phone number (
). This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information about these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.  
5.2.6.2.3
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and on the BI SAE form (if applicable).
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.
5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner; 

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Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.6.2.5
Exemptions to AE/SAE reporting
Disease progression is a trial endpoint for analysis of efficacy and as such is exempted from 
reporting as an AE or SAE. Progression of the subject's underlying malignancy will be 
recorded on the appropriate pages of the eCRF as part of efficacy data collection only and 
will not be reported on the SAE Form. It will therefore not be entered in the safety database 
(ARISg) and hence not get expeditiously reported. Death due to disease progression is also to 
be recorded on the appropriate eCRF page and not on the SAE Form. However, when there is 
evidence suggesting a causal relationship between the study drug or study drugs and the 
progression of the underlying malignancy, the event must be reported as an SAE on the SAE 
Form and on the eCRF.
Examples of exempted events of PD may be:

Progression of underlying malignancy (progressive disease [PD]): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria.

Hospitalisation/procedures due solely to the progression of underlying malignancy (PD)

Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g., imaging, clinical measurement): if the symptom can exclusively be determined to be 
due to the progression/relapse of the underlying malignancy and does meet the expected 
pattern of progression for the disease under study.
Exempted events are collected and tracked following a protocol specified monitoring plan. 
Exempted events are monitored at appropriate intervals throughout the study at Safety 
Review Meetings.
Lab values meeting the hepatic injury definition as defined in Section 5.2.6.1.3 will need to 
be reported as AESI. PD reporting exemption does not apply to hepatic injury.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Refer to the treatment-specific Modules.

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5.6
APPROPRIATENESS OF MEASUREMENTS
Refer to the treatment-specific Modules.
6.
INVESTIGATIONAL PLAN
6.1
SCREENING PERIOD
Screening procedures in the Master protocol apply to all patients (See Master flow chart). 
Refer to the treatment-specific Modules as well.
6.1.1
Baseline conditions
Demographics (sex, birth date, race, and ethnicity where allowed), information on tobacco 
and alcohol use, and baseline conditions will be collected during the screening visit.
6.1.2
Medical history
History of the patient’s cancer and concomitant disease, other diseases, and operations will be 
obtained. The type of cancer, the date of the first histological diagnosis (month and year may 
be sufficient), and the primary tumour site will be reported on the eCRF. The differentiation 
grade (not specified, undifferentiated, poorly differentiated, moderately differentiated, well 
differentiated) obtained at the time of diagnosis and the location of metastatic sites as well as 
the stage according to the tumour, (lymph) node, and metastasis (TNM) classification will be 
provided as obtained at diagnosis and at trial screening. Previous surgeries will be reported.
Previously administered chemotherapy, tyrosine kinase inhibitor treatment, vaccine therapy, 
antibodies therapy, immune therapy, and hormone therapy will be reported, including start 
and end dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
lines of treatment will be recorded, if known. Baseline PD-L1 expression level, microsatellite 
instability (MSI), and tumour mutation burden (TMB) information will be collected in eCRF, 
if locally available.
6.1.3
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. Post-trial therapy for advanced or metastatic disease will also 
be documented.

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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
To effectively use the information from these patients’ cohorts in the assessment of the 
efficacy, a Bayesian hierarchical model (BHM) approach (R13-4803), which assumes full 
exchangeability of model parameters and allows borrowing information across patients’ 
cohorts, will be used to analyse the response rate endpoints (i.e., objective response rate, 
disease control rate). For cases where the initial assumption of exchangeability may not be 
valid more general approaches will be considered like the EXNEX (R17-3435). If that is the 
case the primary model will be described explicitly in the respective Module.
The BHM has 2 main components: a data model and a parameter model, as well as priors for 
the parameter model. The data model is a binomial sampling model
|~	

 , , j = 1, 2, 3, …
where  and  are the number of patients and the corresponding number of patients with 
response in each patient cohort. The parameter model for the log-odds parameters, including 
an adjustment for the target rates 
 =  

1 −
 − 

1 −

is specified as
| , τ ~ (, τ), j = 1, 2, 3, …
where  is the target response rate, μ denotes the “overall” mean of  and τ determines the 
inter-cohort heterogeneity. A non-informative normal prior is used for the mean parameter μ. 
For the inter-cohort heterogeneity parameter τ, a prior distribution will be specified in each of 
the Modules. Based on this model the cohort specific shrinkage estimators for will be 
evaluated.
7.2
NULL AND ALTERNATIVE HYPOTHESES
This trial is an exploratory trial. No formal hypothesis testing is planned in this trial. Only 
descriptive analysis will be performed.
7.3
PLANNED ANALYSES
Only one analysis population will be considered for efficacy and safety analyses: the treated 
set (i.e., patients treated with at least one dose of trial medications). 
In the case that a patient switches to another available treatment in the study, the detailed 
handling rule will be described in the TSAP.
The data from each module will be analysed and reviewed together with the data from other 
studies in the same combination project to evaluate the safety and efficacy benefit in explored 
indications/patient populations. Decisions on further development will be made based on an 
analysis of the aggregated data for each combination via a meta-analytic approach 
implementing quantitative Go-NoGo rules. Results of the meta-analytic approach will be 

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summarised as an internal research report and will be used to support the rationale and the 
benefit-risk assessment for future development trials, if applicable.
7.3.1
Primary endpoint analyses
Overall response will be analysed in terms of ORR, defined as the proportion of patients with 
best overall response of CR or PR determined according to RECIST v1.1 until the earliest of 
disease progression, death or last evaluable tumour assessment before start of subsequent 
anti-cancer therapy. A BHM approach will be used to derive the posterior distribution of the 
response rate endpoints of each patient cohort within each Module if applicable. The median 
and 95% credible interval will be used to summarize the posterior. It will be evaluated and 
described in the Trial Statistical Analysis Plan (TSAP) which cohorts will be included in the 
model. Data from other trials may be included as well if deemed appropriate. If a different 
primary model is chosen for a specific Module, e.g. the EXNEX method etc., the details of 
the analysis method will be illustrated in that Module.
Descriptive statistics regarding e.g., observed response rates will be displayed additionally.
In the case that a patient meets the inclusion and exclusion criteria for more than one cohorts 
within a Module, the handling rule will also be documented in the TSAP.
The primary analysis will include patients who received only one anti-PD-(L)1 based 
treatment regimen prior to entering the trial, and additional analyses may be performed taking 
into account the patients who cross-over from different Modules and therefore will have had 
more than one prior anti-PD-(L)1 based therapy.
7.3.2
Secondary endpoint analyses
The same method for the analysis of primary endpoint will be used for the analysis of disease 
control. All the other endpoints will be analysed separately for each cohort.
Descriptive analysis will be performed for DoR.
Kaplan-Meier estimates will be used to analyse PFS with 95% confidence intervals, using 
Greenwood’s variance estimate.
The censoring rules for PFS and DoR (i.e., outcome and the date of outcome) are described in 
the TSAP.
 

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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, defined in each Module, will be 
assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all AEs occurring between start of treatment and end of the REP. AEs that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA
at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.4
INTERIM ANALYSES
Interim analysis will be performed when deemed necessary. Final/primary analysis for a 
specific treatment combination or cohort will be considered as interim analysis. A cohort or 
Module may be closed, if determined to be appropriate based on results on interim analyses. 
Note that interim analysis will not lead to any modifications within the running trial unless 
otherwise stated in a Module.
Details will be described in the Trial Statistical Analysis Plan (TSAP).
7.5
HANDLING OF MISSING DATA
In general, no imputation will be performed on missing efficacy data. For PFS data, every 
effort will be made to obtain date of progression for patients known to have progressed. 
Detailed censoring rules will be specified in the TSAP. Missing baseline laboratory values 
will be imputed by the respective values from the screening visit. No other imputations will 
be performed on missing data although every effort will be made to obtain complete 
information on all AEs. For partial or missing AE onset and/or end dates, BI internal rules 
will be followed.

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7.6
RANDOMISATION
The treatment assignment will be determined by person(s) independent from the site using 
predefined criteria and entered into the Interactive Response Technology (IRT) System. If not 
stated differently in a Module, a balanced randomisation across available treatment groups is 
the aim.
7.7
DETERMINATION OF SAMPLE SIZE
As sample sizes are in particular depending on assumptions regarding cohort-specific 
response rates and the number of cohorts to be investigated they will be determined in each of 
the treatment-specific Modules. Sample sizes are selected to ensure reasonable probabilities 
of reaching the pre-specified response rate under a wide range of scenarios.
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations. Investigators and site staff must adhere to 
these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
Patients will sign a Master informed consent form (ICF) for screening. Upon module 
assignment, the patient will sign the corresponding module ICF. Further screening 
assessments will be performed to determine eligibility for the Module the patient is assigned 
to. 
Patients that progress on treatment in a given Module may be offered treatment in another 
Module if deemed appropriate by the Investigator and Sponsor, and must sign the ICF for the 
newly-assigned Module. 

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8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This Master protocol and each treatment-specific Module (the trial will begin with one 
module, Module A) will be initiated only after all required legal documentation has been 
reviewed and approved by the respective IRB / Independent Ethics Committee (IEC and 
competent authority (CA) according to national and international regulations. The same 
applies for the implementation of changes such as additional Modules which will be 
introduced by amendments. Clinically ineffective or completed Modules will be closed.  
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The investigator or delegate obtains written consent of the patient’s 
own free will with the informed consent form after confirming that the patient understands 
the contents. The investigator or
 delegate must sign (or place a seal on) and date the 
informed consent form. If a trial collaborator has given a supplementary explanation, the trial
collaborator also signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
It is initiated by the assessment of critical data and processes for trial subject protection and 
reliability of the results as well as identification and assessment of associated risks. An 
Integrated Quality and Risk Management Plan documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.

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8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.7.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents necessary for tumour assessment will be provided to the sponsor.
Before sending or uploading those copies, the investigator must ensure that all patient
identifiers (e.g. patient’s name, initials, address, phone number, social security number) have 
properly been removed or redacted from any copy of the patients’ source documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient
was informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date [mandatory], and end date [if 
available])

Serious adverse events (onset date (mandatory), and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 

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meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
Exemptions from expedited reporting are described in Section 5.2.6.2.5, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised 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 at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.

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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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
Independent milestones will be defined in each individual Module. Milestones for the Master 
are not necessary since it is the launching point for each Module.
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent for the Master protocol and treatment-specific Module.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(‘Last Patient Completed’). 
The ‘Last Patient Last Treatment’ (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site. 
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).

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A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A Steering Committee (SC) consisting of independent experts and sponsor representatives
will be established to support the Coordinating Investigator who will be the chair of the SC. 
The composition of the SC will be documented in the Trial Master File (TMF). The tasks and 
responsibilities will be agreed in contracts between the SC members and the sponsor and also 
summarised in a SC charter.
The safety of all patients will be under surveillance by the Safety Review Committee (SRC).  
The SRC will be responsible for assessing the progress of the clinical trial, including making 
safety and efficacy assessments at specified intervals.  The SRC will have unblinded access 
to data from this trial.  
Members of the SRC will include:

Medical Monitor for the trial

Principal Investigators, or delegates, from investigational sites

BI Safety Physician, or delegate

BI Clinical Program Leader responsible for the project

BI Project or Trial Statistician.
The BI Safety Physician, BI Clinical Program Leader, or delegate, should always attend the 
SRC, if there are safety issues for discussion. 
, 
, Medical Monitor, or delegate, should always be present at the SRC. 
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 (e.g. their curricula 
vitae) will be filed in the ISF.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
An IRT vendor will be used in this trial. Details will be provided in the IRT Manual are 
available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES  
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009;45:228-47.
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.
R15-2005
Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response 
criteria: irRECIST. 39th Ann Cong of the European Society for Medical 
Oncology (ESMO), Madrid, 26-30 Sep 2014 (Poster).
R15-3588
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, 
et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. 
N Engl J Med. 2012;366(26):2443-54.
R15-3715
Brahmer J, et al. Nivolumab versus docetaxel in advanced squamous-cell non-
small-cell lung cancer. N Engl J Med. 2015;373(2):123-35.
R15-3776
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. 
KEYNOTE-006 Investigators Pembrolizumab versus ipilimumab in advanced 
melanoma. N Engl J Med, 2015;372(26):2521-32.
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.
R15-6023
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.
R15-6038
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. 
Colocalization of inflammatory response with B7-H1 expression in human 
melanocytic lesions supports an adaptive resistance mechanism of immune 
escape. Sci Transl Med. 2012;4(127):127ra37.
R16-0663
Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et 
al. Safety and antitumour activity of durvalumab plus tremelimumab in non-
small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016; 
(online publication):1-10.
R16-0864
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.
R16-0868
Koyama S, et al. Adaptive resistance to therapeutic PD-1 blockade is 
associated with upregulation of alternative immune checkpoints. Nat 
Commun. 2016;7:10501.
R16-0876
Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, 
advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet. 2016;387(10027):1540-50.

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R16-1225
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, 
Mazieres J, et al. POPLAR Study Group Atezolizumab versus docetaxel for 
patients with previously treated non-small-cell lung cancer (POPLAR): a 
multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016; 
(online publication). 00587-95.
R16-1588
Rosenberg J, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, 
Neechi A, et al. Atezolizumab in patients with locally advanced and metastatic 
urothelial carcinoma who have progressed following treatment with platinum-
based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 
(online publication): 00561-4.
R16-2360
Francisco LM, Sage PT, Sharpe AH. The PD-I Pathway in Tolerance and 
Autoimmunity. Immunol Rev. 2010;236:219-42.
R16-2361
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. 
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
member leads to negative regulation of lymphocyte activation. J. Exp. Med. 
2000;192(7):1027-34.
R16-2362
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.
R16-2363
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a 
novel member of the immunoglobulin gene superfamily, upon programmed 
cell death. The EMBO Journal. 1992;11(11):3887-95.
R16-2364
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.
R16-2371
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. 
Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of 
immune evasion. Nature Med. 2002;8(8):793-800.
R16-2968
Dong H, Zhu G, Tamada K, Flies DB, Deursen JMA van, Chen L. B7-H1 
determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. 
Immunity. 2004;20(3):327-36.
R16-2969
Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in 
peripheral tolerance. Trends Immunol. 2001;22(5):265-68.
R16-2970
Okazaki T, Okazaki I, Wang J, Sugiura D, Nakaki F, Yoshida T, et al. PD-1 
and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity 
in mice. J Exp Med. 2011;208(2):395-407.
R16-3547
Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety 
and Efficacy of Durvalumab (MEDI4736), an Anti–Programmed Cell Death 
Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial 
Bladder Cancer. J Clin Oncol. 2016;34:1-9.
R16-4925
American Cancer Society. Cancer facts & figures 2016. 
http://www.cancer.org/acs/groups/content/@research/documents/document/acs
pc-0470 79.pdf (access date: 20 October); Atlanta: American Cancer Society 
2016.
R16-5335
Huang RY, Francois A, McGray AJR, Miliotto A, Odunsi K. Compensatory 
upregulation of PD-1, LAG-3 and CTLA-4 limits the efficacy of single agent 
checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2016.

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R16-5356
Workman CJ, Vignali DAA. Negative regulation of T cell homeostasis by 
lymphocyte activation gene-3 (CD223). J Immunol. 2005;174(2):688-95.
R16-5357
Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-
Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related 
to CD4. J Exp Med. 1990;171(5):1393–1405.
R16-5358
Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. 
Characterization of the major histocompatibility complex class II binding site 
on LAG-3 protein. Proc Natl Acad Sci USA. 1997;94:5744-49.
R17-3435
Neuenschwander B, Wandel S, Roychoudhury S, Bailey S. Robust 
exchangeability designs for early phase clinical trials with multiple strata. 
Pharm Stat 2105; 15:123-134. 

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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

Diarrhoea
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)

Allergic reaction

Anaphylaxis

 release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
Neurologic (reported as an AESI)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as an AESI if ≥ Grade 2 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)

Uveitis

Iritis
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)

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Immune-related adverse events of special interest
Skin (reported as an AESI)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (reported as an AESI if ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (reported as an AESI)

Myocarditis

Pancreatitis

Pericarditis

Any other Grade 3 event that is considered immune-related by the physician

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

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

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
Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with i.v. or oral corticosteroids
o
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 28 days.
o
Ezabenlimab should be permanently discontinued for any recurrent Grade 3-4 AE, 
transaminase >5 times ULN or total bilirubin >3 times ULN (unless unequivocally 
attributably to another cause), inability to taper steroids to 10 mg or less 
prednisone or equivalent within 12 weeks, or persistent Grade 2-3 AEs that do not 
recover to Grade 1 or less within 12 weeks.

Renal failure or nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
o
Ezabenlimab should be permanently discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Adrenal insufficiency
o
Ezabenlimab should be permanently discontinued for Grade 3-4 adrenal 
insufficiency or persistent Grade 2 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Rash
o
Ezabenlimab should be permanently discontinued for Grade 4 rash, any recurrent 
Grade 3 AE or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Encephalitis
o
Ezabenlimab should be permanently discontinued for any grade encephalitis.

Infusion reactions:
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. In the event of an infusion-
related reaction ≤ Grade 2, treat the symptoms accordingly with antihistamine or 
corticosteroids if needed, the infusion rate of study drug(s) may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 50% of the initial rate until 
completion of the infusion. In patients experiencing infusion-related reactions ≤ Grade 2, 
subsequent infusions may be administered at 50% of the initial rate. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the study, permanently 
discontinue study drug(s).
10.3
PHARMACOKINETIC METHODS AND ANALYSES
Methods and procedure for handling blood samples are presented in the Laboratory Manual 
for the individual Modules.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
7 MAY 2019
EudraCT number
EU number
2018-002344-81
BI Trial number
BI 1381-0009
BI Investigational 
Medicinal Product(s)
See Modules
Title of protocol
An open-label, Phase II, platform trial evaluating safety and 
efficacy of multiple BI 754091 anti-PD-1 based 
combination regimens in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced and/or 
metastatic solid tumours who have had at least one line of 
systemic therapy
To be implemented 
only after approval of 
the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / Competent 
Authority to be 
notified of change with 
request for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Section to be changed
Synopsis - Main inclusion and exclusion criteria
Description of change
Patients moving from one module to another must have 
prior irAEs resolved to a degree that would allow for restart 
of checkpoint inhibitor therapy according to the irAE 
management guidelines in the protocol.
Rationale for change
An additional inclusion criteria was added and included in 
the list of main inclusion and exclusion criteria to highlight 
it. 

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Section to be changed
Synopsis - Main inclusion and exclusion criteria
Description of change
More than A maximum of one anti-PD-(L)1-based 
treatment regimen prior to entering study, more specifically 
defined in the modules.
Rationale for change
To help clarify the criteria
Section to be changed
Synopsis - Main inclusion and exclusion criteria
Description of change

Active autoimmune disease or a documented history of 
autoimmune disease, except vitiligo or resolved 
childhood asthma/atopy, or a patient who was 
permanently discontinued removed from previous 
anti-PD-1 or anti-PD-L1 therapy because of a severe
immune-related adverse event (irAE).
Rationale for change
To help clarify the criteria
Section to be changed
Synopsis - Duration of Treatment
Description of change
The patient must sign an approved ICF for the 
subsequent Module, be screened prior to entering the 
new Module, and must meet all Master and Module-
specific inclusion criteria. The transition time between 
Modules (last dose of previous Module and screening 
visit of subsequent Module) will be a maximum of 2 
months. Patients will be allowed multiple crossovers 
into subsequent Modules.
Rationale for change
The additional text provides further detail about how a 
crossover to another Module after progression on their 
previous treatment Module.
Section to be changed
1.2 Drug Profile
Description of change
BI 754091 will be combined with other agents in each of 
the multiple Modules.
Rationale for change
“Multiple” was removed from the description of modules to 
avoid implying there would be an unlimited number of 
modules in the study.
Section to be changed
1.4
BENEFIT – RISK ASSESSMENT
Description of change
BI 754091 is currently being tested in patients in the BI 
1381.1 clinical trial. Preliminary clinical safety information 
indicates that BI 754091 monotherapy in 39 patients with 
advanced metastatic cancer is well tolerated with no 
reported dose limiting toxicities (DLTs), treatment related 
SAE or treatment related deaths. Preliminary efficacy 
analyses indicate that there are 5 patients with partial 
response (PR) and 17 patients with disease stabilization on 
BI 754091 monotherapy in the trial 1381.1. The PRs were 
reported in two patients with triple negative breast cancer, 

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one patient with ovarian cancer, one patient with renal 
cancer, and one patient with stomach cancer. All of these 
PRs occurred in patients receiving the 240 mg q3w dose of 
BI 754091 (BI 754091 Investigator Brochure).
As of 30-November-2018, 50 patients with 
advanced/metastatic solid tumours have been treated 
with BI 754091 as monotherapy in the 1381.1 trial. 
The most frequently reported AEs (reported in >10% of 
the patients) were fatigue (40%), nausea (28.0%), 
decreased appetite (18.0%), arthralgia (16.0%), cough 
(16.0%), abdominal pain (14.0%), constipation (14.0%), 
diarrhoea (14.0 %), vomiting (14.0), back pain (12.0%) 
and dyspnoea (12.0%). Headache, hypokalaemia, 
muscular chest pain, myalgia, pruritis and rash, each 
occurred at a frequency of 10.0%.  The majority of 
these AEs were CTCAE Grade 1 and 2.
Grade 3 and 4 AEs were reported in 38.0% and 4.0% of 
patients, respectively. Of the Grade 3 events, only the 
AST elevation event was reported as related to trial 
drug.  The reported Grade 4 AEs were 1 (2.0%) case of 
disease progression and 1 (2.0%) case of sepsis, neither 
of which was deemed treatment related. 
Consistent with the similar drug class labels, most 
irAEs were reported in the GI, skin and endocrine 
system organ class (SOCs). The majority of the irAEs 
were Grades 1 or 2; the only Grade 3 irAE was AST 
increase.
Preliminary efficacy analyses for study 1381.1 indicate 
that there have been 6 patients with partial response 
(PR) and 20 patients with stable disease (SD) as best 
response on BI 754091 monotherapy.  The PRs were 
reported in two patients with triple negative breast 
cancer, one patient with fallopian tube cancer, one 
patient with renal cancer, one patient with stomach 
cancer and one patient with endometrial cancer.  All of 
these PRs occurred in patients receiving the 240 mg 
q3w dose of BI 754091.
A similar safety profile of BI 754091 monotherapy was 
observed in 6 Japanese patients with solid tumours 
evaluated in the Asian trial 1381.4. 

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The details of the preliminary analysis are provided in 
section 6.2 of the BI 754091 IB.
Rationale for change
More recent safety and efficacy information has been added 
to update the benefit-risk section of the protocol. 
Section to be changed
1.4
BENEFIT – RISK ASSESSMENT
Description of change
Trial procedures such as blood sampling, imaging with e.g.
contrast media, and tumour biopsies, are part of standard of 
care in these advanced cancer patients. 
Rationale for change
The text was clarified to better describe the standard of care 
for advanced cancer patients. 
Section to be changed
3.3.2 Inclusion Criteria
Description of change
3
Patient moving from one module to another must 
have prior irAEs resolved to a degree that would allow 
for restart of checkpoint inhibitor therapy according to 
the irAE management guidelines in the protocol.
Rationale for change
Text has been added to provide safety guidance when a 
patient moves from one Module to another.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Male patients with partners of childbearing potential 
must agree to use condoms and ensure their partners 
are 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.
Rationale for change
The additional language provides guidance for male 
patients with partners of childbearing potential. This also 
aligns the text with the contraception requirements found in 
Section 4.2.2.3.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
2
More than A maximum of one anti-PD-(L)1-based 
treatment regimen prior to entering study, more specifically 
defined in the modules.
Rationale for change
To help clarify the criteria
Section to be changed
3.3.3 Exclusion Criteria
Description of change
6.
Patient has received allogeneic bone marrow or 
solid organ transplant.
Rationale for change
To address UK regulatory concern.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
10
Active autoimmune disease or a documented history 
of autoimmune disease, except vitiligo or resolved 

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childhood asthma/atopy, or a patient who was 
permanently discontinued removed from previous anti-
PD-1 or anti-PD-L1 therapy because of a severe immune-
related adverse event (irAE).
Rationale for change
To help clarify the criteria
Section to be changed
3.3.3.1 Withdrawal of patients from treatment or 
assessments
Description of change
The transition time between Modules (last dose of 
previous Module and screening visit of subsequent 
Module) will be a maximum of 2 months.
Rationale for change
The additional text provides further detail about transition 
timelines between Modules after progression on a previous 
treatment Module.
Section to be changed
4.1.3.1 Method of assigning patients to a second or 
subsequent, Module(s)
Description of change
The patient must sign an approved ICF for the 
subsequent Module, be screened prior to entering the 
new Module, and must meet all Master and Module-
specific inclusion criteria. The transition time between 
Modules (last dose of previous Module and screening 
visit of subsequent Module) will be a maximum of 2 
months. The assignment will be based on predefined 
algorithm if patients are eligible for more than one 
Module. Patients will be allowed multiple crossovers 
into subsequent Modules.
Rationale for change
The additional text provides further detail about how to 
cross a patient over to another Module after they have had 
progression on their previous treatment Module.
Section to be changed
Section 4.2.2.3 Contraception requirements
Description of change
WOCBP and men able to father a child must use two
medically approved methods of birth control throughout the 
trial, and for a period of at least 6 months after last trial 
drug intake.
WOCBP must use two highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly 
during the trial, and for a period of at least 6 months after 
the last dose of trial drug.
Rationale for change
The text was updated to correct the number of highly 
effective methods of birth control that should be used by a 
patient.

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Section to be changed
Section 4.2.2.3 Contraception requirements
Description of change
Acceptable methods of birth control for this trial are:
Highly-effective methods of contraception include:
Rationale for change
Redundant language was removed from the text. 
Section to be changed
5.2.6.1.3
Adverse events of specific interest
Description of change
For this trial, infusion-related AEs, potential DILI events, 
hepatic injury, and qualifying irAEs, as defined in the 
treatment-specific Modules and Appendix 10.1, are AESIs.
Rationale for change
Language about drug-induced liver injury has been updated 
per BI revised template text to clarify that all liver 
elevations meeting potential Hy’s Law criteria require 
expedited reporting as an AESI on the SAE form.
Section to be changed
5.2.6.1.3
Adverse events of specific interest
Description of change
In the event of an infusion-related reaction ≤ Grade 2, 
thetreat the symptoms accordingly with antihistamine 
or corticosteroids if needed. The infusion rate of BI 
754111 and/or the combination of BI 754111 plus 
BI 754091 may be decreased by 50% or interrupted until 
resolution of the event and re-initiated at 50% of the initial 
rate until completion of the infusion. In patients 
experiencing infusion-related reactions ≤ Grade 2, 
subsequent infusions may be administered at 50% of the 
initial rate. If an infusion-related reaction is Grade 3 or 
higher in severity at any point during the study, 
permanently discontinue study drug(s).
Rationale for change
Pre-treatment medication has been added to the study prior 
to administration of the study treatment in order to reduce 
the risk of infusion related reactions. In addition, more 
detail has been provided on what to do in the event of a 
Grade 3 or higher infusion related reaction.
Section to be changed
5.2.6.1.3
Adverse events of specific interest
Description of change
Hepatic injury and potential drug-induced liver injury 
(DILI)
Rationale for change
Language about drug-induced liver injury has been updated 
per BI revised template text to clarify that all liver 
elevations meeting potential Hy’s Law criteria require 
expedited reporting as an AESI on the SAE form.
Section to be changed
5.2.6.1.3
Adverse events of specific interest

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Description of change
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.
A hepatic injury is defined by the following alterations 
of hepatic laboratory parameters: 

an elevation of AST (Aspartate Aminotransferase) 
and/or ALT (Alanine Aminotransferase) ≥3 fold 
ULN combined with an elevation of total bilirubin 
≥2 fold ULN measured in the same blood draw 
sample, or 

aminotransferase (ALT and/or AST) elevations ≥10 
fold ULN.
These lab findings constitute a hepatic injury alert and 
the patients showing these lab abnormalities need to be 
followed up according to the “Potential DILI Checklist” 
provided in the ISF. 
In case of clinical symptoms of hepatic injury (icterus, 
unexplained encephalopathy, unexplained 
coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) 
available, the investigator should make sure these 
parameters are analysed, if necessary in an unscheduled 
blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the 
“Potential DILI Checklist” (Figure 5.2.6.1.3: 1) should 
be followed. 
Lab values meeting the hepatic injury definition will 
need to be reported as an AESI. Please follow the 
flowchart below for reporting hepatic injury / potential 
DILI cases.

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Rationale for change
A decision tree is provided to illustrate when the Potential 
DILI Checklist is initiated and when it can be considered 
complete.
Section to be changed
5.2.6.2.4
Pregnancy
Description of change
Similarly, potential drug exposure during pregnancy 
must be reported if a partner of a male trial participant 
becomes pregnant. This requires a written consent of 
the pregnant partner; Reporting and consenting must 
be in line with local regulations. The ISF will contain 
the trial specific information and consent for the 
pregnant partner.
Rationale for change
Guidance for the pregnant partner of a male trial participant 
was added. 
Section to be changed
5.2.6.2.5
Exemptions to SAE Reporting
Description of change
5.2.6.2.5
Exemptions to AE/SAE Reporting
Rationale for change
The header has been corrected to reflect the section content.
Section to be changed
5.2.6.2.5
Exemptions to AE/SAE Reporting
Description of change
Lab values meeting the hepatic injury definition as 
defined in section 5.2.6.1.3 will need to be reported as 
AESI. PD reporting exemption does not apply to 
hepatic injury.
Rationale for change
Text stating that PD reporting exemptions do not apply to 
hepatic injury reporting was added for clarification.  
Language added to clarify that liver injury is to be reported 
as an AESI.
Section to be changed
6.1.2
Medical history

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Description of change
Baseline PD-L1 expression level, microsatellite 
instability (MSI), and tumour mutation burden (TMB) 
information will be collected in eCRF, if locally 
available. 
Rationale for change
Additional baseline data for a deeper analysis was added. 
Section to be changed
7.3 Planned Analyses
Description of change
The data from each module will be analysed and 
reviewed together with the data from other studies in 
the same combination project to evaluate the safety and 
efficacy benefit in explored indications/patient 
populations. Decisions on further development will be 
made based on an analysis of the aggregated data for 
each combination via a meta-analytic approach 
implementing quantitative Go-NoGo rules. Results of 
the meta-analytic approach will be summarised as an 
internal research report and will be used to support the 
rationale and the benefit-risk assessment for future 
development trials, if applicable.
Rationale for change
The text clarifies how the data from each module will 
contribute to the overall development plan for each 
potential combination and how the data from each module 
will be used going forward.
Section to be changed
10.2
MANAGEMENT OF IMMUNE-RELATED 
ADVERSE EVENTS
Description of change
In the event of an infusion-related reaction ≤ Grade 2, 
treat the symptoms accordingly with antihistamine or 
corticosteroids if needed, the infusion rate of study 
drug(s) may be decreased by 50% or interrupted until 
resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients 
experiencing infusion-related reactions ≤ Grade 2, 
subsequent infusions may be administered at 50% of 
the initial rate. If an infusion-related reaction is Grade 3 
or higher in severity at any point during the study, 
permanently discontinue study drug(s).
Rationale for change
More detail has been provided on what to do in the event of 
an infusion related reaction.
11.2
GLOBAL AMENDMENT 2
Number of 
Amendment
2
Date of amendment
14 JUL 2021
EudraCT number
EU number
2018-002344-81

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BI Trial number
BI 1381-0009
BI Investigational 
Medicinal Product(s)
See Modules
Title of protocol
An open-label, Phase II, platform trial evaluating safety and 
efficacy of multiple BI 754091 anti-PD-1 based 
combination regimens in PD-(L)1 naïve and PD-(L)1 
pretreated patient populations with advanced and/or 
metastatic solid tumours who have had at least one line of 
systemic therapy
To be implemented 
only after approval of 
the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / Competent 
Authority to be 
notified of change with 
request for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Section to be changed
Title page/ BI IMP(s)
Description of change
Added ezabenlimab
Rationale for change
BI 754091’s INN is “ezabenlimab”.  The section was 
updated to show the new name associated with BI 754091
Section to be changed
Coordinating Investigator
Description of change
, 
Rationale for change
 
will replace 
 
 as the coordinating 
investigator.
Section to be changed
Synopsis Main Inclusion and Exclusion Criteria and 
Section 3.3.2 Inclusion Criteria
Description of change
5
Eastern Cooperative Oncology Group (ECOG) 
score: 0 to or 1.
Rationale for change
To clarify that patients with either an ECOG of 0 or 1 may
be enrolled onto the study.

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Section to be changed
Synopsis Main Inclusion and Exclusion Criteria and 
Section 3.3.2 Inclusion Criteria and Section 3.3.3 Exclusion 
Criteria
Description of change
….the Investigator’s and/or Medical Monitor’s….
Rationale for change
To clarify that the Medical Monitor plays a role in 
determining if a patient meets the enrollment criteria. 
Section to be changed
Synopsis Main Inclusion and Exclusion Criteria and 
Section 3.3.3 Exclusion Criteria
Description of change
12. Known pPresence of symptomatic central nervous 
system (CNS) metastases, unless treated and 
asymptomatic and off corticosteroids and anti-convulsant 
therapy for at least 2 weeks prior start of treatment.
Rationale for change
To clarify that known, untreated, asymptomatic CNS 
metastases will also be an exclusion criteria.
Section to be changed
Section 3.3.2 Inclusion Criteria
Description of change
6
Patient must agree to a pre-treatment biopsy (if 
archival tissue is not available) and on-treatment tumour 
biopsy. If archived tumour tissue is available from the last 
treatment failure, sections may be supplied instead of a pre-
treatment biopsy. If the patient does not have archival 
tumour tissue and is not biopsiable because of a safety 
concern the patient could be considered for study after 
discussion with the Medical Monitor to potentially allow 
for inclusion of a patient with for a tumour type of interest.
Rationale for change
To prevent the enrollment of ineligible patients. 
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
5.
Active infection requiring systemic treatment 
(antibacterial, antiviral, or antifungal therapy) at start of 
treatment in this trial. Patients may be enrolled onto the 
study following an 7-day washout period after the end 
of systemic treatment for active infection.
Rationale for change
To clarify how soon after an active infection a patient 
would be allowed to enrol. 
11.3
GLOBAL AMENDMENT 3
Date of amendment
12 JUN 2023
EudraCT number
EU number
2018-002344-81
BI Trial number
1381-0009
BI Investigational Medicinal 
Product(s)
See Modules

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Title of protocol
An open-label, Phase II, platform trial evaluating 
safety and efficacy of multiple ezabenlimab 
anti-PD-1 based combination regimens in PD-(L)1 
naïve and PD-(L)1 pretreated patient populations 
with advanced and/or metastatic solid tumours who 
have had at least one line of systemic therapy
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Section to be changed
Title Page/Clinical Trial Leader
Description of change
Trial Clinical MonitorClinical Trial Leader
Phone: 
 
Phone: 
Rationale for change
Role of ‘Trial Clinical Monitor’ changed to 
‘Clinical Trial Leader’ due to update in role title 
within BI; role changed over to 
 
.
Section to be changed
Title Page/Coordinating Investigator and Synopsis
Description of change
, 
  
Phone: 

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Rationale for change
Updated company name.
Section to be changed
Title page and throughout the document
Description of change
BI 754091 was changed to its INN, ‘ezabenlimab’. 
Rationale for change
Change was communicated with Global 
Amendment 2 (14 Jul 2021) but was not introduced 
to the study title or replaced throughout the 
document.
Section to be changed
Throughout the document
Description of change
 updated 
to 
Rationale for change
Updated to legal name.
Section to be changed
Section 4.1 Investigational Treatments
Description of change
Selection of the treatment-specific Module will be 
determined by the patient’s tumour type, prior 
treatment, and algorithm (such as IVRSInteractive 
Response Technology [IRT]) for patient 
assignment.
Rationale for change
Terminology corrected for consistency with rest of 
the document.
Section to be changed
Section 8.7 Administrative Structure of the Trial
Description of change
‘BI Team Member Medicine’ changed to ‘BI 
Clinical Program Leader’:
Members of the SRC will include:

BI Team Member MedicineBI Clinical 
Program Leader responsible for the project
The BI Safety Physician, BI Team Member 
MedicineBI Clinical Program Leader, or 
delegate, should always attend the SRC, if there are 
safety issues for discussion.
Rationale for change
Role of ‘BI Team Member Medicine’ changed to 
‘BI Clinical Program Leader’ due to update in role 
title within BI.

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23362215
4.0
clinical-trial-protocol-version-04-master
An open-label, Phase II, platform trial evaluating safety and efficacy of multiple
ezabenlimab anti-PD-1 based combination regimens in PD-(L)1 naïve and PD-(L)1
pretreated patient populations with advanced and/or metastatic solid tumours who
have had at least one line of systemic therapy
Author-Clinical Trial Leader
12 Jun 2023 13:05 CEST
Approval-Team Member Medicine
12 Jun 2023 13:10 CEST
Author-Trial Statistician
12 Jun 2023 13:17 CEST
Verification-Paper Signature
Completion
27 Jun 2023 09:47 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23362215
4.0