Clinical trial NCT05446129
Conditions: Colorectal Cancer
Sponsor: Boehringer Ingelheim
Start date: 2022-09-27; Completion date: 2023-11-08
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to people with newly diagnosed colorectal cancer. People who are scheduled for surgery can participate. People either get a medicine called BI 765063 combined with ezabenlimab or combined with pembrolizumab in preparation of the upcoming surgery. The tested medicines in this study are antibodies that may help the immune system fight cancer.

The purpose of this study is to find out how well people with early colorectal cancer can tolerate treatment with these medicines. The study also looks at whether the tumor changes.

Participants are put into 2 groups. One group gets ezabenlimab and BI 765063. The other group gets pembrolizumab and BI 765063. All participants receive the study medicines as 2 subsequent infusions into a vein on a single day.

Participants are in the study for about 4 months. During this time, they visit the study site about 5 times. The doctors check the health of the participants and note any health problems that could have been caused by ezabenlimab, pembrolizumab, or BI 765063. The doctors also check whether these health problems lead to a delay of the planned surgery.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Ezabenlimab intervention 2: BI 765063 intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Ezabenlimab intervention 2: BI 765063 intervention 3: Pembrolizumab

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (20.0) / Saved on: 20 Apr 2021
Clinical Trial Protocol
 
Document Number:
c36932219-03
BI Trial No.
1502-0001
BI Investigational 
Medicinal Product(s)
Ezabenlimab 
BI 765063
Title
A Phase I open label study to assess safety, feasibility, efficacy, 
and biological activity of single administration of Ezabenlimab in 
combination with BI 765063 and Pembrolizumab in combination 
with BI 765063 as neoadjuvant treatments in patients with newly 
diagnosed surgically-resectable, locoregional colorectal cancer
Lay Title
A study in people with colorectal cancer to test whether 
ezabenlimab or pembrolizumab in combination with BI 765063 
lead to side effects or delays in surgery
Clinical Phase
Phase I
Clinical Trial Leader
Phone:
Investigator
Current Version and 
Date
Version 3.0; 24 January 2022
Original Protocol 
Date
2 November 2021
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Proprietary confidential information.
! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
2 November 2021
Revision date
21 January 2022
BI trial number
1502-0001
Title of trial
A Phase I open label study to assess safety, feasibility, efficacy, and 
biological activity of single administration of Ezabenlimab in 
combination with BI 765063 and Pembrolizumab in combination 
with BI 765063 as neoadjuvant treatments in patients with newly 
diagnosed surgically-resectable, locoregional colorectal cancer
Investigator 
Trial site(s)
Clinical phase
Phase I
Trial rationale
Anti-SIRPα antibodies are a potential new tool for cancer 
immunotherapy. Preclinical data suggests that the combination of 
anti-SIRPα and anti-PD-1 antibodies may lead to better tumor control 
than either alone.
There are preclinical and clinical data to suggest that neoadjuvant 
immunotherapy in early stages of disease may be more effective than 
later.
A better understanding of the biological and clinical activity of 
combining PD-1 and SIRPα blockade in colorectal cancer (CRC), 
including the effect on infiltrating myeloid and lymphoid 
populations, is needed to inform more rational approaches to 
incorporating immunotherapy and other active agents in the treatment 
of CRC.
Trial objective(s)
Primary objective
To investigate safety and feasibility of single administration of 
ezabenlimab in combination with BI 765063 and single 
administration of Pembrolizumab in combination with BI 765063 in 
patients with early stage resectable colorectal cancer in neoadjuvant 
setting.
Secondary objectives


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∀
To investigate efficacy of the study treatments
∀
To investigate biology activity of the study treatments
Further objectives
To define the immunodynamic effect of the combined immunotherapy 
regimens systemically and on the tumor immune microenvironment
Trial endpoints
Primary endpoint(s)
The primary endpoint is a composite endpoint which estimates 
proportion of patients with at least one occurrence of safety or 
feasibility. The detailed definitions of safety and feasibility are as 
follows. 
Safety 
Safety is defined as any grade 3 or higher adverse events (according to 
NCI CTCAE v5.0) related to study treatments at any point within the 
follow up period following the administration of study treatments.
Feasibility (delay in surgery)
Feasibility or delay in surgery is defined as any treatment related 
adverse events (AE) leading to delays in surgery.
Patients’ surgery is scheduled to take place between 2 weeks and up 
to 6 weeks following the administration of study treatment. Any 
treatment related AE leading to a delay in surgery beyond the 6 
weeks period following study treatment administration will be 
considered as a relevant AE for this endpoint. 
Secondary endpoint(s)
∀
Pathologic response (PR) defined as at least 50% or more 
tumor regression classified as per Mandard tumor regression 
grading system (R21-1544), in viable adenocarcinoma cells in 
the surgical specimen, including lymph nodes. Pathological 
response includes complete pathology response (CR), near 
complete pathological response (near CR) and partial 
pathological response (R21-0915). 
∀
Time from administration of trial treatment to surgery, 
defined as the time in days that elapses between administration 
of neoadjuvant trial therapy and surgical resection. 
∀
Radiographic response on pre-surgical imaging, following 
receipt of the neoadjuvant therapy, as per RECIST v1.1. 


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Trial design
This is an open-label, two-arm, parallel group, single-center Phase 1 
trial of Ezabenlimab in combination with BI 765063 (Cohort A) and 
Pembrolizumab in combination with BI 765063 (Cohort B) in 
patients with early stage resectable colorectal cancer in neoadjuvant 
setting.
Total number of 
patients
A total of approximately 50 patients will be treated in this trial
Number of patients per
treatment group
25 patients per treatment group in 2 treatment groups.
∀
25 patients in Cohort A (Ezabenlimab/BI 754091) + BI 
765063
∀
25 patients in Cohort B (Pembrolizumab + BI 765063
Diagnosis
Resectable colorectal cancer (CRC)
Main inclusion and 
exclusion criteria
Key inclusion criteria
Patients must satisfy all the following criteria for entry into the trial 
(protocol): 
1. Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.  
Ability to understand and the willingness to sign a written 
informed consent.
2. Male or female aged ≥ 18 years at the time of Informed 
Consent Form (ICF) signature.
3. Patients with histological diagnosis of resectable CRC, or 
radiographic/visual findings highly suggestive, with planned 
confirmatory biopsy.
4. CRC lesions must be at least 1 cm in largest diameter and 
amenable to endoscopic biopsy.
5. Patient must be willing and able to have endoscopic biopsy 
(Goal 3-6 core-needle or surgical/endoscopic biopsies, final 
number to be determined by the physician performing the 
procedure as safe) of tumor prior to initiation of therapy. 
6. Eastern Cooperative Oncology Group (ECOG) performance 
status 0-1. The exception will be patients with long term 
disability (such as cerebral palsy) that is unlikely to
significantly affect their response to therapy.
7.
Patient is determined to be a surgical candidate for resection 
of their tumor.


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8. Adequate organ and marrow function as defined below in 
Table 3.3.2:1.
9. Women of childbearing potential (WOCBP) must be ready 
and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly, from signature 
of ICF until 6 months after administration of trial treatment. A 
list of contraception methods meeting these criteria is 
provided in the patient information. For further detail refer to 
Section 4.3.2.3. 
Key exclusion criteria
Patients must not enter the trial if any of the following exclusion 
criteria are fulfilled:
1. Patients who are deemed to be at high risk for colonic 
obstruction and/or perforation per investigator assessment.
2. Patients eligible for neoadjuvant therapy (chemotherapy, 
radiotherapy, chemoradiotherapy) as standard of care.
3. Major surgery (major according to the investigator’s 
assessment) performed within 4 weeks prior to administration 
of trial medication.
4. Patients who must or wish to continue the intake of restricted 
medications (see section 4.3.2.1) or any drug considered
likely to interfere with the safe conduct of the trial.
5. Patients not expected to comply with the protocol 
requirements or not expected to complete the trial as 
scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator’s opinion, makes the patient 
an unreliable trial participant).
6. Previous enrolment in this trial. 
7. Currently enrolled in another investigational device or drug 
trial, or less than 30 days since ending another investigational 
device or drug trial(s) or receiving other investigational 
treatment(s).
8. Patients who have had chemotherapy or radiotherapy within 6 
months prior to entering the study for a different primary 
tumor, or those that have received locoregional therapy 
(radiation, chemoembolization, etc.) for the target lesion that 
will be biopsied and subsequently resected. Previous therapy 
for a different cancer (a different primary) is acceptable. 
9. Prior immune checkpoint inhibitor therapy. 


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10. Patients with metastatic or recurrent disease, for which the 
intent of surgery would not be curative.
11. Uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection requiring antibiotics (except 
antibiotics to be completed 4 weeks before initiation of 
treatment), symptomatic congestive heart failure, unstable 
angina pectoris, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
12. Patients who are pregnant or nursing or who plan to become 
pregnant while in the trial.
13. Has a diagnosis of primary immunodeficiency or is receiving 
systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the 
administration of trial treatment. Patients on chronic steroids 
(more than 4 weeks at stable dose) equivalent to ≤ 10mg 
prednisone will not be excluded. 
14. Has active autoimmune disease that has required systemic 
treatment in the past 1 year (i.e. with use of disease modifying 
agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is acceptable. 
15. Has any hematological malignancy.
16. Has a known additional somatic malignancy that is 
progressing and/or requires active treatment. Exceptions 
include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative 
therapy or in situ cervical or anal cancer, non-metastatic 
prostate cancer on stable dose of hormonal therapy without 
rising PSA, and breast cancer patients who have been treated 
with curative intent, who may be on hormonal therapy.
17. Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the 
trial, interfere with the patient’s participation for the full 
duration of the trial, or is not in the best interest of the patient 
to participate, in the opinion of the treating Investigator. 
18. Patients with history of human immunodeficiency virus (HIV) 
infection who meet one or more of the following criteria;
a.
CD4+ count < 350 cells/μL
b. Viral load > 200 copies/μL (local lab assessment)
c.
Not receiving antiretroviral therapy


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d. Receiving established antiretroviral therapy for less 
than four weeks prior to the start of study treatment
e.
History of AIDS-defining opportunistic infections 
within 12 months prior to start of study treatment
Patients with a history of HIV who do not meet any of the 
criteria above are eligible to participate but the patient must 
be under the care of a HIV/Infectious Diseases specialist or a 
HIV/Infectious Diseases specialist must be consulted prior to 
inclusion.
19. Patients with a history of Hepatitis C (HCV) infection who 
meet one or both of the following criteria.
a.
Curative antiviral treatment is not complete
b. HCV viral load is above the limit of quantification 
(HCV RNA positive)
20. Patients with chronic Hepatitis B (HBV) infection with active 
disease who meet the criteria for anti HBV therapy (according 
to local / institutional standard) who have not been adequately 
treated with suppressive antiviral therapy prior to initiation of 
study treatment.
21. History of allogeneic hematopoietic cell transplantation or 
solid organ transplantation.
22. Documented allergic or hypersensitivity response to any 
protein therapeutics (e.g., recombinant proteins, vaccines, 
intravenous immune globulins, monoclonal antibodies, 
receptor traps).
23. Neuropathy # grade 2.
24. Principal Investigator believes that for one or multiple reasons 
the patient will be unable to comply with all study visits, or if 
they believe the trial is not clinically in the best interest of the 
patient.
Test product(s)
Ezabenlimab (BI 754091)
BI 765063
Pembrolizumab 
Dose
Ezabenlimab (BI 754091) 240 mg, IV, Day 1
BI 765063 
Pembrolizumab 200 mg, IV, Day 1
Mode of 
administration
Intravenous (i.v.) for all compounds
Duration of treatment
Single dose administration of the combination in both cohorts
Statistical methods


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A Bayesian framework will be used to calculate the posterior 
probability that the Pathological Response (PR) rate is at least 15%. 
The 95% credible interval of the PR rate along with observed 
response rate and 95% confidence interval will be constructed.




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3 - All screening labs should be performed or repeated within 10 days prior to treatment initiation. (Refer to 
Section 5.2.3)
4 - Biopsies to include (target) 3-6 endoscopic biopsies of tumor, or as determined as safe by surgeon and/or 
gastroenterologist.
5 - *Resected tumor collection: Tumor tissue will be a sample from the tumor removed during the surgery. (*Note: 
“Resected tumor collection” is listed under V03 in the flow chart for practical reasons and should occur at the day 
of the surgery. All other activities will be performed prior to the surgery.)
6 - All eligible patients will be enrolled in the trial, genotyping will be performed retrospectively.
7 - Stool samples will be collected at Screening and V03 or on the day of before the surgery in a specified tube.
8 - Study treatment administration – to be given to the patient after the study required procedures for V01/D1have 
been completed.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................9
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS AND DEFINITIONS...........................................................................15
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.1.1
Colorectal Cancer (CRC)...................................................................................18
1.2
DRUG PROFILE................................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................22
1.4.1
Benefits.................................................................................................................22
1.4.2
Risks .....................................................................................................................23
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........26
2.1.1
Main objectives....................................................................................................26
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
3.1
OVERALL TRIAL DESIGN.............................................................................29
3.1.1
Data review committee (DRC)...........................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................31
3.3.1
Main diagnosis for trial entry ............................................................................31
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Discontinuation of patients from treatment or assessments ...........................35
3.3.4.1
Discontinuation of trial treatment .........................................................................36
3.3.4.2
Withdrawal of consent to trial participation .........................................................36
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................36
4.
TREATMENTS...................................................................................................36
4.1
INVESTIGATIONAL TREATMENTS ...........................................................36
4.1.1
Identity of the Investigational Medicinal Products..........................................37
4.1.2
Selection of doses in the trial and dose modifications......................................38
4.1.3
Method of assigning patients to treatment groups...........................................38


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4.1.4
Drug assignment and administration of doses for each patient......................39
4.1.5
Blinding and procedures for unblinding...........................................................39
4.1.5.1
Blinding.................................................................................................................39
4.1.5.2
Unblinding and breaking the code ........................................................................39
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................40
4.2
CONCOMITANT MEDICATIONS .................................................................40
4.2.1
Acceptable Concomitant Medications...............................................................40
4.2.2
Prohibited Concomitant Medications ...............................................................41
4.2.3
Pre-medication ....................................................................................................41
4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................41
4.3.1
Other treatments and emergency procedures..................................................41
4.3.2
Restrictions ..........................................................................................................41
4.3.2.1
Restrictions regarding concomitant treatment ......................................................41
4.3.2.2
Restrictions on diet and lifestyle...........................................................................42
4.3.2.3
Contraception requirements..................................................................................42
4.4
TREATMENT COMPLIANCE........................................................................42
5.
ASSESSMENTS..................................................................................................43
5.1
ASSESSMENT OF EFFICACY........................................................................43
5.2
ASSESSMENT OF SAFETY.............................................................................43
5.2.1
Physical examination ..........................................................................................43
5.2.2
Vital signs.............................................................................................................43
5.2.3
Safety laboratory parameters ............................................................................43
5.2.4
Electrocardiogram ..............................................................................................45
5.2.5
Other safety parameters.....................................................................................45
5.2.6
Assessment of adverse events.............................................................................45
5.2.6.1
Definitions of AEs ................................................................................................45
5.2.6.1.1
Adverse event........................................................................................................45
5.2.6.1.2
Serious adverse event............................................................................................46
5.2.6.1.3
AEs considered “Always Serious”........................................................................46
5.2.6.1.4
Adverse events of special interest.........................................................................46
5.2.6.1.5
Intensity (severity) of AEs....................................................................................49
5.2.6.1.6
Causal relationship of AEs....................................................................................49
5.2.6.2
Adverse event collection and reporting ................................................................50
5.2.6.2.1
AE reporting to the sponsor and timelines............................................................51
5.2.6.2.2
Pregnancy..............................................................................................................51
5.2.6.2.3
Exemptions to SAE reporting ...............................................................................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................52
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................52
5.4.1
Biomarkers planned to be assessed in this trial ...............................................52
5.4.2
Methods of Sample Collection, Handling of Samples and Biomarker 
Results ..................................................................................................................53


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5.5
BIOBANKING ....................................................................................................54
5.5.1
Methods and timing of sample collection..........................................................54
5.6
OTHER ASSESSMENTS...................................................................................54
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................54
6.
INVESTIGATIONAL PLAN.............................................................................54
6.1
VISIT SCHEDULE.............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................55
6.2.1
Screening and run-in period(s)..........................................................................55
6.2.2
Treatment period(s)............................................................................................56
6.2.3
Follow-up period and trial completion, End of Study (EOS) Visit ................58
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................58
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................59
7.2
PLANNED ANALYSES.....................................................................................59
7.2.1
General considerations .......................................................................................59
7.2.2
Handling of Intercurrent Events .......................................................................59
7.2.3
Primary objective analyses.................................................................................59
7.2.3.1
Sensitivity Analyses..............................................................................................60
7.2.3.2
Subgroup Analyses ...............................................................................................60
7.2.3.3
Supplementary Analyses.......................................................................................60
7.2.4
Secondary objective analyses.............................................................................60
7.2.5
Further objective analyses..................................................................................61
7.2.6
Safety analyses.....................................................................................................61
7.2.7
Other Analyses ....................................................................................................62
7.2.8
Interim Analyses .................................................................................................62
7.3
HANDLING OF MISSING DATA ...................................................................62
7.4
RANDOMIZATION...........................................................................................62
7.5
DETERMINATION OF SAMPLE SIZE .........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........63
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................64
8.2
DATA QUALITY ASSURANCE ......................................................................64
8.3
RECORDS...........................................................................................................65
8.3.1
Source documents ...............................................................................................65
8.3.2
Direct access to source data and documents.....................................................66
8.3.3
Storage period of records ...................................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................66
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........66
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................67


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8.6
TRIAL MILESTONES.......................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................68
9.
REFERENCES....................................................................................................69
10.
APPENDICES.....................................................................................................73
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................73
10.2
TIME SCHEDULE FOR PHARMACODYNAMIC AND BIOMARKER 
SAMPLING.........................................................................................................73
10.3
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....73
10.4
ECOG PERFORMANCE STATUS..................................................................76
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................76


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ABBREVIATIONS AND DEFINITIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIDS
Acquired Immuno Deficiency Syndrome
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Products
AST
Aspartate Aminotransferase
BI
Boehringer Ingelheim
CA
Competent Authority
CBC
Complete Blood Count
CD172
SIRP Alpha monoclonal antibody
CI
Confidence Interval
CRA
Clinical Research Associate
CRC
Colorectal Cancer
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CR
Complete response (complete pathological response)
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CTLA - 4 
Cytotoxic T-Lymphocyte associated protein 4
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report 
CyTOF
Cytometry by Time of Flight
DBL
Database Lock
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
dMMR
deficient Mismatch Repair
DRC
Data Review Committee
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form


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eDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EOS
End of Study (corresponds with End of Trial)
FC
Flow Chart
FIH
First In Human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HA
Health Authority
HAART
Highly Active Antiretroviral Therapy
HBV
Hepatitis B
HCC
Hepato Cellular Carcinoma
HCV
Hepatitis C
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG4
Immunoglobulin G4
IMP
Investigational Medicinal Product
irAEs
Immune Related Adverse Events
IRB
Institutional Review Board
iRECIST
Guidelines for Response Criteria in Immunotherapies
IRR
Infusion Related Reactions
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
i.v.
Intravenous
IV
Intravenous
LPLT
Last patient last treatment
mAb
Monoclonal Antibody
MDSC
Myeloid Derived Suppressor Cell
MICSSS
Multipexed Immunohistochemical Cosecutive Staining on a Single Slide


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MedDRA
Medical Dictionary for Drug Regulatory Activities
MoA
Mechanism of action
MSI-H
Microsatellite Instability - High
MSI-L
Microsatellite Instability – Low 
MSS
Microsatellite Stable
OE
Outcome Events
ORR
Overall Response Rate
PCR
Polymerase Chain Reaction
PD-1
Programmed Cell Death 1
PI
Principal Investigator
pMMR
proficient Mismatch Repair
PK
Pharmacokinetics
PR
Pathological Response
q3W
Every 3 weeks
RA
Regulatory Authority
RMP
Risk Management Plan
RNASeq
RNA sequencing
SAE
Serious Adverse Event
scRNASeq
Single cell RNASeq
SIRPα 
Signal Regulotory Protein Alpha
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TAM
Tumor associated macrophages
TCR
T-Cell Receptor
TMB
Tumor Mutational Burden
TME
Tumor Microenvironment
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
VEGF
Vascular Endothelial Growth Factor
WES
Whole Exome Sequencing
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
1.1.1
Colorectal Cancer (CRC)
Colorectal cancer is one of the most common and deadly cancers worldwide, with over 1.5 
million new cases and over 800,000 deaths annually (R21 1422). In the US, 75% of patients 
are diagnosed with locoregional disease, while the remainder are diagnosed with advanced or 
metastatic disease (R21-1418). Five-year survival for locoregional disease is over 70%, while 
five-year survival of metastatic disease is just 14% (R21-1418). 
Surgery is the indicated procedure for eligible patients with locoregional disease. Histological 
assessment of the resected specimen and regional lymph nodes aid in risk stratification. Stage 
II and Stage III disease are distinguished by the presence of involved lymph nodes. Adjuvant 
chemotherapy after surgery is generally recommended for those with Stage III disease and 
those with high-risk Stage II disease, as determined by clinical and histological factors. 
Nevertheless, a significant portion of patients relapse after surgery, and adjuvant chemotherapy 
only confers a modest absolute survival benefit of 5-10% (R21-1553). 
Advanced and metastatic CRC is treated with systemic chemotherapy. Frontline chemotherapy 
typically consists of a fluoropyrimidine-based doublet with or without a targeted anti-VEGF or 
anti-EGFR agent. Anti-PD-1 antibodies are an option for patients with deficient mismatch 
repair or microsatellite instability-high (dMMR/ MSI-H) status. Clinical trials have 
demonstrated that dMMR/ MSI-H CRC has a response rate of 30-50% to anti-PD-1 
monotherapy, while those with proficient mismatch repair or microsatellite instability-low 
(pMMR/MSI-L) do not respond to any immunotherapy monotherapy or combinatorial 
approaches (R16-1497, R18-1746). Combination therapy with an anti-PD-1 and anti-CTLA-4 
agent is approved in the dMMR/MSI-H population (R18-1746, R21-1971).
1.2
DRUG PROFILE
BI 765063 (anti-SIRPα mAb)
BI 765063 is a humanized IgG4 monoclonal antibody that targets the human SIRPα (CD172) 
protein, thus antagonizing the CD47/SIRPα interaction. 
SIRPα is a receptor protein expressed primarily on myeloid cells (including macrophages and 
dendritic cells). When activated by its ligand, the surface marker CD47 inhibits phagocytosis 
of the signaling cell. CD47 is expressed in normal tissue cell types and is often overexpressed 
by many types of tumor cells. The interaction of CD47 with SIRPα is considered a “do not eat” 
signal and induces tumorigenic environment, polarizing intratumoral myeloid cells towards a 
more regulatory/immunosuppressive phenotype. 
BI 765063 is being investigated in the dose escalation/dose expansion trial 1443-0001 in 
patients with advanced cancer. The dose escalation part of the trial 1443-0001 has been fully 
enrolled. BI 765063 was well tolerated, both as a single agent up to 
 and in 


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combination with ezabenlimab up to 
, with no reported Dose Limiting Toxicities 
(DLTs) and a dose of
 was identified for further study. BI 765063 
was well tolerated as a monotherapy with the exception of IRR (infusion related reaction) 
occurring during the first infusion in approximately 47% of the patients. These IRR were 
mostly G1/G2 with the exception of a single Grade 3 event and were easily manageable with 
antihistamines and acetaminophen. Limited safety data from Phase I clinical development have 
not raised any safety concerns for BI 765063 monotherapy or the combination with 
ezabenlimab. The safety profile of the combination therapy has been consistent with what is 
expected based on the safety profiles of both monotherapies. 
Preliminary anti-tumor activity was observed, with 1 patient with heavily pre-treated HCC
experiencing a durable response (significant PR > 1 year) after monotherapy with 
 
 BI 765063. Two additional PRs in patients with microsatellite stable (MSS) endometrial 
cancer and a third iRECIST PR in a patient with MSS colorectal cancer were observed in the 
combination portion of the study. 
 
 
dose forward for further study.
There are two major alleles of SIRPα, V1 and V2, and BI 765063 strongly binds to V1 alleles, 
while it only weakly binds to V2 alleles. In pre-clinical experiments, BI 765063 antagonizes 
CD47 binding to SIRPα on V1/V1 and, to much lower extent, V1/V2 on human monocytes; 
the magnitude of the effect was much greater for SIRPα V1/V1. No effect is expected on V2/V2 
allele combination. SIRPα V1 and V2 allele frequencies can differ by geographic location. For 
the US population, the expected V2/V2 allele frequency is approximately 24%, The allele 
frequency for V1/V2 and V1/V1 is expected to be 36% and 40%, respectively.
For a more detailed description of the BI 765063 profile, please refer to the current 
Investigator’s Brochure (c29693380).
Ezabenlimab (anti-PD-1 mAb)
Ezabenlimab is an IgG4 antibody which binds to PD-1 expressed on T cells. Ezabenlimab 
binding disrupts PD-1 interaction with the inhibitor ligand, PD-L1, which is expressed on a 
variety of cells including cancer cells. 
As of July 2021, 117 patients with advanced/metastatic solid tumors have been treated with 
single agent Ezabenlimab. Of these, 108 patients were treated with the recommended Phase II 
dose of 240 mg every three weeks. Ezabenlimab demonstrated preliminary efficacy (ORR of 
approximately 15%) and was very well tolerated in this heterogeneous late stage patient 
population with a safety profile similar to other immune checkpoint inhibitors. Additionally, 
more than 800 patients have been treated with ezabenlimab in combination with other agents. 
The currently available ezabenlimab clinical data demonstrate that ezabenlimab is well 
tolerated. Recommended dose for further investigation was determined to be 240 mg once 
every 3 weeks 
For a more detailed description of the ezabenlimab profile, please refer to the current 
Investigator’s Brochure (c07895879).


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Pembrolizumab (brand name Keytruda, anti-PD-1 mAb) 
Pembrolizumab also binds to PD-1 expressed on T cells. It is approved for medical use in the 
United States and in other countries to treat several kinds of cancers.
For this trial, locally commercially available pembrolizumab will be used by the 
investigational site. 
For a more detailed description for pembrolizumab, please refer to the US Package Insert.
Follow up period
The follow up period of ezabenlimab in combination with BI 765063 and pembrolizumab in 
combination with BI 765063 is 90 days. This is the period after the single dose administration 
that measurable drug levels and/or pharmacodynamic effects are still likely to be present.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
Anti-PD-1 checkpoint inhibitors have demonstrated efficacy in a variety of cancer types, 
including CRC. However, the role of anti-PD-1 agents in CRC is currently confined to a narrow 
subset of patients—namely, those with unresectable tumors with dMMR/MSI-H status. The 
prevalence of dMMR/MSI-H status among CRC patients is about 10 - 15% overall, while the 
prevalence is just 5% among those with Stage IV disease (R21-1420). In fact, the majority of 
CRC are pMMR/MSI-L, a category of tumors which have negligible response rates to 
anti-PD-1 monotherapy in the metastatic setting (R16-1497). However, data from patients with 
non-metastatic colon cancer (stage I, II, or III) indicate that patients with MMR-proficient 
tumors may benefit from a neoadjuvant treatment with ipilimumab and nivolumab (R21-0915). 
Additionally, though significant radiographic responses are not seen in clinical trials, it remains 
to be shown whether there are dynamic and/or beneficial changes to the tumor immune 
microenvironment in patients treated with PD-1 blocking antibodies. A better understanding of 
the activity of PD-1/PD-L1 blockade in CRC, and the effect on infiltrating myeloid and 
lymphoid populations, is needed to inform more rational approaches to incorporating 
immunotherapy and other active agents in the treatment of CRC.
The cancer-immune cycle provides a framework for conceptualizing how tumors evade the 
immune system, and where therapeutic interventions may restore effective anti-cancer 
immunity (R14-5099). It has been observed, for example, that dMMR/MSI-H CRCs are 
heavily infiltrated by cytotoxic T lymphocytes, but that they also overexpress inhibitory 
immune checkpoints such as PD-1 and PD-L1 (R21_1610). Thus, PD-1 blockade may be 
particularly effective for unleashing the pre-existing immune response against this tumor 
subtype, if immunosuppressive effects of the tumor can also be disrupted.
Tumor associated macrophages (TAMs) have come to light as an influential, heterogeneous, 
immune cell subclass within the tumor microenvironment (TME). Earlier studies identified 
conflicting associations between TAMs and prognosis in CRC (R21-1688, R21 1609). More 
recent work has recognized that macrophage subtypes matter; pro-inflammatory M1-like 
macrophages are associated with improved outcomes, while anti-inflammatory M2-like 
macrophages are associated with worse outcomes (R21-1607, R21-1608, R21-1616). The TME 
appears to promote polarization of macrophages towards pro-tumor phenotypes which 
contribute to several of the hallmarks of cancer, including angiogenesis (R21 1615), metastasis 
(R21-1614), and an immunosuppressive TME replete with inhibitory checkpoints (R21_1613, 
R21-1612), and regulatory T cells (R10-5119). Consequently, TAMs and pathways regulating 
their polarization between pro- and anti-tumor phenotypes have become targets of interest in 
cancer immunotherapy (R21-1611, R18_3350, R21-1601). 
Signal regulatory protein α (SIRPα) is a transmembrane protein expressed by macrophages 
which binds to CD47 expressed by target cells—the so-called “don’t eat me” signal—and 
inhibits phagocytosis. In preclinical models, anti-CD47 antibody induced phagocytosis of 
cancer cells by macrophages, led to increased priming of cytotoxic T lymphocytes and 
enhanced anti-cancer immunity (R18 3292, R21-1600). Clinical trials of an anti-CD47 
antibody combined with rituximab and azacitidine have shown promising results in lymphoma 
(R20-0311) and myelodysplastic syndrome/acute myeloid leukemia (R21-1681), respectively. 
In a preclinical study of an anti-SIRPα antibody, investigators demonstrated that the antitumor 
effect of the antibody was mediated by macrophages, and that the effect of the antibody was to 




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combinations. It is hoped that any efficacy from this treatment,
 
.
1.4.2
Risks
Table 1.4.2: 1 displays the anticipated side effects of the study drugs, based on the 
mechanism of action, observed clinical data from ongoing studies, and published clinical data 
for drugs targeting SIRPα and PD-1 as well as the risk of trial procedures. 
Table 1.4.2:1
Overview of trial related risks 
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Products BI 765063 and ezabenlimab
Unexpected adverse events 
and laboratory abnormalities 
Due to limited clinical 
experience of the drugs.
Close monitoring of the data 
to ensure timely detection and 
reporting of any unexpected 
event. A Data Review 
Committee (DRC) will 
evaluate safety, feasibility,
efficacy and biomarker results 
as available. 
Immune-related adverse 
events (irAEs)
irAEs are associated with 
immune mediated mode of 
action and can be potentially 
severe. 
Recommendations for the 
management of irAEs are 
provided according to 
international guidelines and 
product labels of approved 
PD-1 inhibitors [P19-00269]
Infusion related reactions 
(IRR)
As with any mAb, 
hypersensitivity reactions to 
study medication 
administration are possible 
and they are potentially 
severe.
Patients with history of severe 
hypersensitivity reactions to 
other mAbs are excluded. 
Recommendations for the 
management of infusion 
related reactions are given in
Section 5.2.6.1.4
Drug Induced Liver Injury 
(DILI)
Rare but can be a potentially 
severe event, thus, under 
constant surveillance by 
sponsors for all drugs in 
development.
Timely detection, evaluation, 
and follow-up of laboratory 
alterations in selected liver 
laboratory parameters to 
ensure patients’ safety.
Trial procedures
Biopsies
Patients may experience 
biopsy related AEs such as 
pain or bleeding.
Site has to be selected based 
on ability and experience in 
performing all required trial 
procedures.


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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
The risks are clearly 
explained in the informed 
consent document.
Delay in surgery
Treatment related adverse 
events leading to delays in 
surgery
Patient will be monitored on 
an ongoing basis by the DRC 
for safety including treatment 
related events that may lead to 
a delay in surgery. The 
frequency of these events will 
be monitored, and enrolment 
will be adapted accordingly.
Potential risks related to BI 765063:
Based on its characteristic or mechanism of action, the primary safety concerns of SIRPα 
antagonism by BI 765063 are immune-related adverse events, infusion reactions and embryo-
fetal toxicity. The 1443-0001 study is the FIH study to investigate BI 765063. Preliminary 
clinical safety information indicates that BI 765063 monotherapy in patients with advanced 
metastatic cancer is well tolerated with no reported DLTs or treatment related death. 
Infusion-related reactions (IRRs) were reported by approximately half of the patients in the 
BI 765063 monotherapy dose escalation part of trial 1443-0001, when premedication prior to 
cycle 1 was not allowed. The majority of the IRRs were grade 1 to grade 2 and were well 
manageable. Pre-medication with an antihistamine and acetaminophen or paracetamol prior 
to cycle 1 resulted in a markedly reduction of IRR (as observed in the BI 765063 dose 
escalation in combination with fixed dose ezabenlimab part of trial 1442-0001). 
Potential risks related to ezabenlimab:
Based on its mechanism of action, the primary safety concerns of PD-1 antagonism by 
ezabenlimab are immune-mediated adverse reactions, infusion reactions, and embryo fetal
toxicity. Preliminary clinical safety information indicates that ezabenlimab monotherapy in 
patients with advanced metastatic cancer is well tolerated with no reported dose limiting 
toxicities (DLTs), treatment related SAE or treatment related deaths.
The available safety data from these patients suggests that treatment with ezabenlimab is 
anticipated to have a similar adverse events pattern to the currently marketed anti-PD-1 
mAbs, with immune related adverse events (irAEs) as the most common AEs. These side 
effects are well manageable with validated guidelines.
Developmental and reproductive toxicology studies have not been conducted with 
ezabenlimab. Based on animal models, the PD-1/PD-L1 pathway is involved in the induction 
of maternal immune tolerance to allogenic fetal tissue, and therefore, is important in the 
maintenance of pregnancy. Administration of ezabenlimab is not expected to affect fertility 


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but may increase the risk of abortion and premature infant death if administered to pregnant 
women. Therefore, pregnant women are to be excluded from clinical trials and contraception 
measures as described in the informed consent have to be observed.
Potential risks related to pembrolizumab:
Potential risks related to pembrolizumab have been described. Please refer to the US Package 
Insert.
Potential risks related to the combination of BI 765063 and ezabenlimab / 
pembrolizumab:
Owing to the mechanism of action of each product and given that BI 765063 may potentiate 
the effect of ezabenlimab / pembrolizumab by increasing the adaptive immune effectors, 
special attention will be given to potential increase in irAEs in patients receiving the 
combination treatment.
Immune-related AE management guidance will be provided in the Section 5.2.6.1.4.
Infusion-related reactions have been reported with checkpoint inhibitor treatment (as for all 
protein therapeutics). These reactions occur infrequently and are typically managed based on 
symptoms using treatments ranging from treatment with histamine antagonists, in mild cases,
to administration of epinephrine, when symptoms of anaphylaxis are detected.
Potential risks related to COVID-19:
Based on their mode of action, the trial drugs are not expected to have a relevant impact on 
the susceptibility to or the course of an infection.
In case of a confirmed infection, trial treatment will not be provided and appropriate 
measures for monitoring, treatment and quarantine will be implemented. The patient may be 
treated following recovery from a SARS-CoV-2 infection if the patient is expected to derive 
clinical benefit, as agreed between the investigator and sponsor. 
In case of an increased risk of SARS-CoV-2 infection due to the physical visits to the sites, 
the visits should be avoided where the investigator judges that this is the safest course of 
action. These measures ensure the safety of the patients throughout the trial, maintain the 
integrity of the trial and will not affect the benefit-risk ratio of BI 765063 given in 
combination with ezabenlimab or pembrolizumab.
1.4.3
Discussion
The risk-benefit relationship has been carefully considered in the planning of the trial. Based 
on the pre-clinical and clinical data available to date on the Investigational Medicinal 
Products (IMPs), the conduct of the trial is considered justifiable using the doses and dose 
regimens of the IMPs as specified in this CTP.
Patients will receive a single administration of trial medication (either a single dose 
ezabenlimab in combination with BI 765063 or a single dose pembrolizumab in combination 


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with BI 765063). Therefore, temporary or permanent discontinuation of trial treatment is not 
applicable in this trial. However, there is a remaining possibility that the administration of 
trial medication will be temporary or permanently discontinued during the infusion 
(administration) of trial medication or between the administration of the two combination 
drugs due to safety reasons or due to withdrawal of informed consent. It is expected that the 
safety risks associated with repeated exposure will not be a factor in this trial. 
Respective risk mitigation measures, with regard to the expected potential adverse drug 
reactions to the IMPs and study procedures, have been implemented in the current clinical 
study. The measures taken during the trial to mitigate the risks are: 
A Data Review Committee (DRC) will be established to oversee and assess the progress of 
the clinical trial, specifically for safety, feasibility, efficacy and biomarker results as 
available. Please see section 3.1
∀
The safety of the patients will be monitored continuously. All SAEs, irAEs, and
adverse events of special interest (AESI) will be closely followed and reviewed with
the DRC as necessary.
∀
Guidance in case of irAEs have been defined in the trial protocol.
∀
Regular clinical and biological monitoring of patients and their data will be performed 
during the study period by the investigators and the sponsor.
∀
In order to avoid a delay in surgery, study treatment will be provided as soon as 
possible. The results from the biomarker assessments will not be immediately 
available. Study treatment will be provided as soon as possible and will not be 
delayed by the availability of the biomarker assessment results (e.g. genotyping).
Considering the medical need for the development of a better tolerated and more effective 
treatment for patients with CRC,
 
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
Primary objective: 
The primary objective of the trial is to investigate safety and feasibility of single 
administration of ezabenlimab in combination with BI 765063 and single administration of 
pembrolizumab in combination with BI 765063 in patients with early stage resectable 
colorectal cancer in neoadjuvant setting.
The proportion of patients experiencing a safety and feasibility event at any time will be 
estimated for each arm. This is defined as a composite of whether treated patients experience 
one or more treatment-related events of the following types: grade 3 and higher adverse event 




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For more details please refer to the flow chart and section 6.2. 
Table 3.1:1 Study treatments and schedules
Study Treatments
Agent
Cohort
Dose
Route
Schedule
Ezabenlimab
Cohort A
240 mg
IV
Day 1 only 
Pembrolizumab
Cohort B
200 mg
IV
Day 1 only 
BI 765063
Cohort A and B
IV
Day 1 only
3.1.1
Data review committee (DRC)
A total of approximately 50 patients will be treated in this trial, i.e. approximately 25 patients 
in each arm. A Data Review Committee (DRC) will be established to oversee and assess the 
progress of the clinical trial, specifically for safety, feasibility, efficacy and biomarker results 
as available. The DRC will operate according to specifications defined in a separate DRC 
charter. 
The DRC will consist of the following members: 
∀
Principal Investigator (PI), decision maker
∀
BI Safety physician (pharmacovigilance officer), decision maker
∀
BI Clinical Program Leader (CPL), decision maker,
∀
BI Statistician (Stat), participates if needed
∀
BI Clinical Trial Leader (CTL), participates if needed
All members can be represented by a deputy. 
The first scheduled DRC meeting to review data will take place after approximately 5 
patients in each arm have been treated, and while recruitment continues. A second meeting of 
the DRC will be scheduled to review the data after approximately 15 patients have been 
treated in each arm. After each of these meetings the DRC will recommend to continue, to 
modify, or to stop the trial due to any safety concern. The DRC may meet to review data any 
other time if deemed necessary.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The above described trial design is appropriate for a trial with exploratory intent. 
In order to avoid a delay in surgery, study treatment will be provided as soon as possible. 
Since biomarker assessment needs time for processing, study treatment will be provided 
without having the results of biomarker assessment (e.g. SIRPα genotype status) available. 
SIRPα genotype status will be assessed retrospectely. For details please see section 7.2.5


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3.3
SELECTION OF TRIAL POPULATION
This trial is planned as a single center trial at Icahn School of Medicine at Mount Sinai, US. 
Further investigational sites may be added as appropriate. Screening for the trial will stop at 
the site/all sites at the same time once a sufficient number of patients have been screened. 
The investigator/s will be notified about screening completion and will then not be allowed to 
screen additional patients for this trial. Patients already in screening at the time that screening 
has stopped will be allowed to continue if eligible.
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 retrospectively it is found that a patient has been treated with study drug in error (e.g. did
not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or delegate 
should be contacted immediately to assess the safety of the patient. 
3.3.1
Main diagnosis for trial entry
Patients with diagnosis of resectable CRC will be included. Please refer to section 8.3.1
(Source Documents) for the documentation requirements pertaining to the in- and exclusion 
criteria.
3.3.2
Inclusion criteria
Patients must satisfy all the following criteria for entry into the trial (protocol): 
1. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial. Ability to understand and the willingness to 
sign a written informed consent.
2. Male or female aged ≥ 18 years at the time of ICF signature.
3. Patients with histological diagnosis of resectable CRC, or radiographic/visual findings 
highly suggestive, with planned confirmatory biopsy.
4. CRC lesions must be at least 1 cm in largest dimeter and amenable to endoscopic 
biopsy.
5. Patient must be willing and able to have endoscopic biopsy (Goal 3-6 core-needle or 
surgical/endoscopic biopsies, final number to be determined by the physician 
performing the procedure as safe) of tumor prior to initiation of therapy. 


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6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. The exception 
will be patients with long term disability (such as cerebral palsy) that is unlikely to 
significantly affect their response to therapy.
7.
Patient is determined to be a surgical candidate for resection of their tumor.
8. Adequate organ and marrow function as defined below in Table 3.3.2:1.
9. Women of childbearing potential (WOCBP)1 must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly, from signature of ICF
until 6 months after administration of trial treatment. A list of contraception methods 
meeting these criteria is provided in the patient information. For further detail refer to 
Section 4.3.2.3. 
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming postmenopausal 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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Table 3.3.2: 1
Adequate organ and marrow function for inclusion
3.3.3
Exclusion criteria
Patients must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Patients who are deemed to be at high risk for colonic obstruction and/or perforation 
per investigator assessment.
2. Patients eligible for neoadjuvant therapy (chemotherapy, radiotherapy, 
chemoradiotherapy) as standard of care.
3. Major surgery (major according to the investigator’s assessment) performed within 4 
weeks prior to administration of trial medication.
4. Patients who must or wish to continue the intake of restricted medications (see section
4.3.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
5. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other 
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
≥1,500 /mcL (1,000 /mcl for African American patients) 
Platelets
≥100,000 /mcL
Hemoglobin
≥10 g/dL
Renal*
Serum creatinine OR
Measured or calculateda creatinine clearance (GFR 
can also be used in place of creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) 
OR
≥60 mL/min for patient with creatinine levels > 1.5 X 
institutional ULN
Hepatic*
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for patients with total bilirubin levels > 
1.5 ULN
AST and ALT
≤ 2.5 X ULN 
Albumin
>2.5 mg/dL
Coagulation*
International 
Normalized 
Ratio 
(INR) 
or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X ULN unless patient is receiving anticoagulant therapy as 
long as PT is within therapeutic range of intended use of 
anticoagulants
≤1.5 X ULN unless patient is receiving anticoagulant therapy as 
long as PTT is within therapeutic range of intended use of 
anticoagulants
a Creatinine clearance should be calculated per institutional standard.
* If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s 
syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. 
elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not 
be used to exclude patient from this trial. Similarly, for patients with elevated bilirubin due to biliary obstruction 
from tumor, this will not serve as an exclusion criterion. This determination will be made by PI.


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condition that, in the investigator’s opinion, makes the patient an unreliable trial 
participant).
6. Previous enrolment in this trial.
7. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s) or receiving other 
investigational treatment(s).
8. Patients who have had 
 prior to 
entering the study for a different primary tumor, or those that have received 
locoregional therapy (radiation, chemoembolization, etc.) for the target lesion that 
will be biopsied and subsequently resected. Previous therapy for a different cancer (a 
different primary) is acceptable. 
9. Prior immune checkpoint inhibitor therapy. 
10. Patients with metastatic or recurrent disease, for which the intent of surgery would not 
be curative.
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection requiring antibiotics (except antibiotics to be completed 4 weeks before 
initiation of treatment), symptomatic congestive heart failure, unstable angina 
pectoris, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
12. Patients who are pregnant or nursing or who plan to become pregnant while in the 
trial.
13. Has a diagnosis of primary immunodeficiency or is receiving systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to the 
administration of trial treatment. Patients on chronic steroids (more than 4 weeks at 
stable dose) equivalent to ≤ 10mg prednisone will not be excluded. 
14. Has active autoimmune disease that has required systemic treatment in the past 1 year 
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable. 
15. Has any hematological malignancy.
16. Has a known additional somatic malignancy that is progressing and/or requires active 
treatment. Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical or anal cancer, non-metastatic prostate cancer on stable dose of hormonal 
therapy without rising PSA, and breast cancer patients who have been treated with 
curative intent, who may be on hormonal therapy.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation 
for the full duration of the trial, or is not in the best interest of the patient to 
participate, in the opinion of the treating Investigator. 
18. Patients with history of human immunodeficiency virus (HIV) infection who meet 
one or more of the following criteria:


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o
CD4+ count < 350 cells/μL
o
Viral load > 200 copies/μL (local lab assessment)
o
Not receiving antiretroviral therapy
o
Receiving established antiretroviral therapy for less than four weeks prior to 
the start of study treatment
o
History of AIDS-defining opportunistic infections within 12 months prior to 
start of study treatment
Patients with a history of HIV who do not meet any of the criteria above are eligible 
to participate but the patient must be under the care of a HIV/Infectious Diseases 
specialist or a HIV/Infectious Diseases specialist must be consulted prior to inclusion.
19. Patients with a history of Hepatitis C (HCV) infection who meet one or both of the 
following criteria:
o
Curative antiviral treatment is not complete
o
HCV viral load is above the limit of quantification (HCV RNA positive)
20. Patients with chronic Hepatitis B (HBV) infection with active disease who meet the 
criteria for anti HBV therapy (according to local / institutional standard) who have not 
been adequately treated with suppressive antiviral therapy prior to initiation of study 
treatment.
21. History of allogeneic hematopoietic cell transplantation or solid organ transplantation.
22. Documented allergic or hypersensitivity response to any protein therapeutics (e.g., 
recombinant proteins, vaccines, intravenous immune globulins, monoclonal 
antibodies, receptor traps).
23. Neuropathy # grade 2.
24. Principal Investigator believes that for one or multiple reasons the patient will be 
unable to comply with all study visits, or if they believe the trial is not clinically in the 
best interest of the patient.
3.3.4
Discontinuation of patients from treatment or assessments
Patients will receive a single administration of trial medication (either single dose 
ezabenlimab in combination with BI 765063 or single dose pembrolizumab in combination 
with BI 765063). 
If a patient is considered eligible for trial participation, but cannot be treated with trial 
medication for any reason, this patient will be replaced by another patient.
Patients which have received treatment will not be replaced (regardless whether the treatment 
is administered completely or not).
Please refer to section 3.3.4.2 regarding withdrawal of consent to trial participation. 
Please refer to section 6.1 regarding situations where a patient is unable or unwilling to attend 
a clinic visit. 


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3.3.4.1
Discontinuation of trial treatment
This is a single dose trial. Trial medication will be given one time on Day 1 of the study and 
will not be given any more throughout the study. Patients will continue to be followed as 
described in the flowchart and in section 6.
3.3.4.2
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 discontinuation of administration of the 
single trial treatment (e.g. after one infusion dose), and withdrawal of consent to trial 
participation, as well as explain the options for continued follow-up safety assessments.
Measures to control the withdrawal rate include careful patient selection, 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 administration of the trial treatment or withdraw consent to trial 
participation and the reason must be documented in the patient files and CRF. If applicable, 
consider the requirements for Adverse Event collection reporting (please see section 5.2.6.2).
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
On Day 1 (treatment day) 




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Unit strength:
Posology:
Rate controlled infusion on Day 1 
Route of administration:
Duration of use:
One time
Pembrolizumab
Table 4.1.1:3  Pembrolizumab
Substance:
Pembrolizumab
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
To be taken from the market by the investigator
Unit strength:
Pembrolizumab 200 mg, IV, Day 1
Posology:
Rate controlled infusion on Day 1 
Route of administration:
i.v.
Duration of use:
One time
4.1.2
Selection of doses in the trial and dose modifications
Cohort A: Ezabenlimab in combination with BI 765063:
On Day 1 only, patients assigned to the Cohort A will all receive the recommended Phase II 
dose (RP2D) of ezabenlimab i.e. a flat dose of 240 mg 
 
.
Cohort B: Pembrolizumab in combination with BI 765063:
On Day 1 only, patients assigned to the Cohort B will receive pembrolizumab flat dose of 
200 mg 
.
4.1.3
Method of assigning patients to treatment groups
Patients will be assigned alternatingly (sequentially one by one) to either of the cohorts and 
will receive one-time either of the combination treatments with the first patient allocated to 
Cohort A and the second patient allocated to Cohort B. All eligible patients will be enrolled 
in the trial and genotyping will be performed retrospectively.  Assignments will be conducted 
at the site and recorded in the eCRF. 


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4.1.4
Drug assignment and administration of doses for each patient
Each patient will receive the appropriate dose for their assigned cohort. The trial drug will be 
prepared and handled according to the ‘Medication Handling Instruction’ which will be filed 
in the ISF. Upon notification of the treatment cohort of the patient, the pharmacy will prepare 
the trial drugs for administration to the patient.
Pembrolizumab, Ezabenlimab (BI 754091), and BI 765063 will be given as an intravenous 
infusion by authorised site staff in a specialised unit where emergency care can be provided 
(e.g. intensive care unit available, medical personnel trained in advanced life support). The 
maximum infusion duration including the interruption time, the infusion rate and storage 
conditions are indicated in the ISF.  
The pembrolizumab will be administered per the US package insert information.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
eCRF will contain information on allocated treatment.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).  Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA, as provided in the list of contacts) must be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee,
∀
Availability of a signed and dated clinical trial contract between the sponsor or delegate 
and the investigational site,
∀
Approval / notification of the regulatory authority (RA), e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
Availability of the proof of a medical license for the Principal Investigator, 
∀
Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial 
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
CONCOMITANT MEDICATIONS
Medications specifically prohibited (see section 4.2.2) are not allowed during the ongoing trial. 
If there is a clinical indication for one of these or other medications or vaccinations specifically 
prohibited during the trial, discontinuation from the trial may be required. The Investigator 
should discuss any questions regarding this with the Study PI and Sponsor. The final decision 
on any supportive therapy or vaccination rests with the Investigator and/or the patient's primary 
physician. 
4.2.1
Acceptable Concomitant Medications
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. Regarding pre-medication please refer to section 4.2.3. All concomitant 
medication will be recorded on the case report form (CRF) including all prescription, over-the-


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counter (OTC), herbal supplements, and intravenous medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
4.2.2
Prohibited Concomitant Medications
Patients are prohibited from receiving the following therapies during the Screening and 
Neoadjuvant Treatment Phase of this trial:
∀
Antineoplastic systemic chemotherapy or biological therapy 
∀
Immunotherapy not specified in this protocol
∀
Radio-therapy
∀
Systemic glucocorticoids for any purpose other than those used to modulate symptoms 
from an AE of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the PI, and patients on long-
term steroids equivalent to 10mg or less of prednisone daily may be enrolled.
∀
Live attenuated vaccines are prohibited during the trial and for 90 days after the 
administration of trial treatment.
Any standard of care therapy is allowed in the adjuvant (post-operative setting) that is 
deemed clinically indicated by the treating physician.
Patients may receive other medications that the Investigator deems to be medically necessary.
4.2.3
Pre-medication
Infusion-related reactions (IRRs) were reported by approximately half of the patients when 
premedication prior was not allowed. Pre-medication with an antihistamine and
acetaminophen or paracetamol resulted in a markedly reduction of IRR (for details please 
refer to section 1.4.2, subsection “Potential risks related to BI 765063”).
Therefore, pre-medication with an antihistamine and acetaminophen or paracetamol to reduce 
the risk of IRRs is recommended prior to drug administration of BI 765063. Pre-medication 
should be administered at sufficient time prior to initiation of infusion to allow the agents to 
exert their effect. Corticosteroids will not be allowed in pre-medication regimens.
4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.3.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.3.2
Restrictions
4.3.2.1
Restrictions regarding concomitant treatment
Please see section 4.2.2 “Prohibited Concomitant Medications”


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4.3.2.2
Restrictions on diet and lifestyle
The usual restrictions on diet and lifestyle that were already applicable for a given patient 
before entry into the trial, according to his/her medical condition, have to be continued.
4.3.2.3
Contraception requirements
WOCBP (for the definition please refer to section 3.3) must use medically approved methods 
of birth control as described below. 
WOCBP must use a highly effective method 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 if their sexual 
partner is a man able to father a child.
Highly effective methods of contraception:
∀
Combined (estrogen and progestogen containing) hormonal birth control that prevents
ovulation (oral, intravaginal, transdermal).
∀
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).
∀
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
∀
Bilateral tubal occlusion.
∀
Vasectomised partner (provided that this partner is your sole sexual partner and that 
your vasectomised partner has received medical assessment of the surgical success).
∀
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period (stated above) of risk associated with the study treatments. This is 
defined as being in line with the only lifestyle of the patient. Periodic abstinence e.g. 
calendar, ovulation, symptothermal, post-ovulation methods; declaration of abstinence 
for the duration of exposure to study drug; and withdrawal are not acceptable.
Although use of a contraceptive pill and Intrauterine device (IUD) are considered a highly-
effective method of birth control, women of childbearing potential taking a contraceptive pill 
must use an additional barrier method from signature of ICF until 6 months after the 
administration of trial treatment.
4.4
TREATMENT COMPLIANCE
The trial drug products should only be used as directed in this protocol. The treatments will 
be taken at the investigational site under the supervision of the investigator and/or authorized 
and trained designee. Therefore, actual dosing is expected to precisely follow the assigned 
dose which will be administered as an intravenous infusion at the clinical site under the 
supervision of trained site personnel. The dose administered will be recorded in the eCRF and 
any irregularities in dosing will also be documented in the eCRF by the investigator or 
designee.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Pathological response (PR), will be assessed as per Mandard tumor regression grading system 
(R21-1544). Please see also section (please see section 2.1.2)
Tumor assessments must be performed according to RECIST 1.1 comparing screening and 
pre-surgery assessments. The same radiographic procedure(s) (e.g. CT scan, MRI) should be 
used throughout the trial. Tumor assessments performed prior to informed consent as part of 
routine clinical practice will be accepted if they meet the requirements of the protocol and are 
performed within the Screening visit window (within 21 days prior toof Day 1).
Clinical imaging data acquired in this trial might also be analysed further to build diagnostic, 
prognostic and predictive models using radiomics. This exploratory analysis might be 
performed in collaboration with an independent third party nominated by the Sponsor.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
Measurement of height (in cm, only at screening), body weight (in kg), and the evaluation of 
the ECOG performance score (see Appendix 10.4) will be performed at the time points 
specified in the flow chart.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flow chart, prior to blood 
sampling.  This includes systolic and diastolic blood pressure and pulse rate (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must 
be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters will be analysed at a local laboratory.  Safety laboratory 
examinations will include tests as listed in Table 5.2.3:1 and should be obtained at the time 
points specified in the flow chart.
All analyses will be performed by the site’s local laboratory, the respective reference ranges 
will be provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 


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Instructions regarding sample collection, sample handling / processing and sample shipping 
are provided in the Laboratory Manual (to be filed ISF). 
The local laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. 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) and the DILI Checklist provided in the ISF system. 
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The laboratory will transfer the results of the analysis to the sponsor or delegate.
Table 5.2.3:1 
Safety laboratory tests
Category
Parameters
Haematology
Haemoglobin, haematocrit, platelet count, reticulocytes, red blood cell count, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, erythrocytes distribution width, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
preferably expressed in absolute values.
Biochemistry
Glucose, sodium, potassium, chloride, calcium, magnesium, phosphate, venous 
bicarbonate HCO3, total protein, albumin, uric acid and creatinine kinase (CK; if 
CK is elevated, then CK-MB [cardiac], Troponin I or T, and myoglobin should be 
reactively tested).
A thyroid panel (TSH, free T4, and free T3) will be done 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.
Liver function 
AST, ALT, alkaline phosphatase, lactate dehydrogenase, bilirubin (direct and 
indirect bilirubin in case of elevated total bilirubin values)
Renal function
Blood urea or blood urea nitrogen, and creatinine.
Note: Creatinine can be assessed by any of these methods: CREE (enzymatic serum 
creatinine assay), CREJIDMS (IDMS standardized Jaffe), or CREJ (non-IDMS
standardized Jaffe).
Coagulation
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) 
(expressed either in seconds or as percentage) or International Normalised Ratio 
(INR)
Urinalysis
pH, glucose, erythrocytes, leukocytes, protein, and nitrite analysed by dipstick 
(semi-quantitative measurements). The result will be kept in source document, but 
not entered in the CRF/database and will not be reported in the CTR. Clinically 
relevant abnormal findings will be reported either as baseline condition (if 
identified at the Screening visit) or otherwise as adverse event.
Pregnancy
Beta human chorionic gonadotropin (β-HCG) pregnancy test in serum performed 
for women of childbearing potential at Screening.
Urine or serum test performed within 72 hours before study treatment on Day 1.
For patients with 
history of HIV or
HCV infection only:
For patients with history of HIV infection: CD4+ count, Viral load, according to 
local standard.


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For patients with a history of HCV infection: HCV viral load according to local 
standard as needed.
Additional testing for infectious diseases can be added as required.
The result will be kept in source document, but not entered in the CRF/database and 
will not be reported in the CTR. Clinically relevant abnormal findings will be 
reported either as baseline condition (if identified at the Screening visit) or 
otherwise as adverse event.
Tests performed no more than 4 weeks prior to screening (day of blood collection) 
can be used and do not need to be repeated for screening.
All screening labs should be performed or repeated within 10 days prior to treatment 
initiation with the exception of the urine pregnancy test which should be conducted within 72 
hours of initiating treatment; all other screening assessments are performed within 21 days of 
initiation of study treatment (Day 1).
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist as scheduled in the 
flowchart. The investigator or a designee will evaluate whether the ECG is normal or 
abnormal and assess clinical relevance. ECGs may be repeated for quality reasons.
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record. Clinically relevant abnormal 
findings will be reported either as baseline condition (if identified at the screening visit) or 
otherwise as AEs and will be followed up and / or treated as medically appropriate.
5.2.5
Other safety parameters
None 
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀
Worsening of the underlying disease if certain conditions are met – refer to section 
5.2.6.2.3


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∀
Worsening of pre-existing conditions other than the underlying disease
∀
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation (except 
planned hospitalization for tumor resection),
-
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 
medial 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. 
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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 eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
Every occurrence of cancer of new histology must be classified as a serious event regardless 
of the time since the administration 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”.
5.2.6.1.4
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 


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Pharmacovigilance Department within the same timeframe that applies to SAEs. Please see 
section 5.2.6.2.1.
The following are considered as AESIs:
Infusion related reactions
As with any mAb, hypersensitivity reactions to the administration of IMP are possible. 
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and trial personnel must be trained to recognize and treat anaphylaxis. 
The trial site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit patients to an intensive care unit if necessary.
The following terms describe those events that are to be considered potential infusion-related 
AEs. Regardless of grade, these events are considered as AESIs and must be reported to the 
Sponsor Drug Safety Department within 24 hours of the knowledge of the event (refer to 
Section 5.2.6.2):
∀
Allergic reaction
∀
Anaphylaxis
∀
Cytokine-release syndrome
∀
Serum sickness
∀
Infusion reactions
∀
Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential infusion-
related AE, the Investigator may also report that event as an AESI.
Management of infusion related reactions (IRR):
As a routine precaution, patients enrolled in this trial must be observed for at least 4 hours 
post-infusion of study drugs, with immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit patients to an intensive care unit if necessary.
Monitoring will include measurement of body temperature, heart rate, and blood pressure at 
regular intervals. Patients will be assessed for signs or symptoms of IRR, e.g. hypotension, 
hypoxia, tachycardia, fever, nausea, fatigue, headache, myalgias, and malaise.
Patients will be informed about possible signs and symptoms of IRR during, or after, 
administration of study drugs.
The following recommendations for the management of IRR regarding administration of 
study drugs should be considered by the Investigator as guidance:


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∀
Regarding premedication please see section 4.1.3.
∀
Grade ≤ 2: In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of 
study drug(s) may be decreased by 50%, or interrupted, until resolution of the event 
and resumed at 50% of the initial rate until completion of the infusion. In case 
infusion must be stopped due to infusion related reactions (IRR) or similar situation, 
the duration of infusion can be prolonged up to 6 hours for BI 765063, or to 3 hours 
for ezabenlimab. Infusion duration for BI 765063 beyond 6 hours may be possible on 
a case-by-case bases after discussion with the sponsor. The details of dose preparation 
as well as the infusion duration are specified in “Instruction for Pharmacists”.
∀
Grade 3 or higher in severity at any time point during the infusion of study drug, the 
infusion has to be permanently discontinued. 
Immune-related adverse event (irAE)
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. The sponsor has defined a list of potential irAEs which need to be 
reported as irAEs in Section 10.3. If an investigator determines another event (not on the list) 
should be a potential irAE, the investigator may also report that event as an AESI.
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
∀
For patients with abnormal liver function at baseline (AST and/or ALT>ULN) 
o
an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of 
total bilirubin ≥2 fold ULN measured in the same blood draw sample, with the 
exclusion of the causes due to underlying diseases, and/or
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN
∀
For patients with normal liver function at baseline (ALT, AST, and bilirubin within 
normal limits at baseline):
o
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of 
total bilirubin ≥2 fold ULN measured in the same blood draw sample, and/or 
o
Marked peak 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 “DILI checklist” provided in the ISF 
and EDC. 


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Figure 5.2.6.1.4:1 
Potential severe DILI reporting –in case of a DILI please follow the 
above procedure on how to report the DILI as an AESI.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF
according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, 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 trial drug.
∀
The event is known to be caused by or attributed to the drug class.


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∀
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).
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 trial 
drug concerned).
∀
Continuation of the event despite the withdrawal of the medication, considering the 
pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned.
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial
(including the Follow up Period):
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial drug related SAEs and trial drug related AESIs 
of which the investigator may become aware of by any means of communication, e.g. 
phone call. Those AEs should be reported on the BI SAE form (see section 5.2.6.2.1), but 
not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see section 5.2.6.2.3.


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5.2.6.2.1
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 
hours of becoming aware of the event, the country specific process will be specified in the 
ISF. The same timeline applies if follow-up information becomes available. In specific 
occasions, the investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.6.2.2
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and / or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE 
form is to be completed. If there is an SAE and / or AESI associated with the pregnancy an 
SAE form must be completed in addition.
5.2.6.2.3
Exemptions to SAE reporting
The outcome “disease progression” is used to assess trial endpoints for the analysis of 
efficacy and as such is exempted from AE/SAE reporting. Signs and symptoms of disease 
progression which can exclusively be determined to be due to the progression of the 
underlying malignancy and meet the expected pattern of disease progression for the disease 
under study are also exempted from AE/SAE reporting.
Disease progression of the patient’s underlying malignancy will be recorded on the 
appropriate pages of the eCRF as part of efficacy data collection only. It will not be recorded 
on the AE page in the eCRF and will not be reported on the SAE Form even when it meets 
standard seriousness criteria.
Lab values meeting the potential severe DILI definition in section must always be reported as 
AESI, even if the most likely cause is disease progression. No exemption to AE reporting 
applies.


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When there is evidence suggesting a causal relationship between the trial drug(s) and the 
progression of the underlying malignancy, the event must be recorded as an SAE on the AE 
page in the eCRF and reported as an SAE on the SAE Form.
Exempted events are monitored at appropriate intervals
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable
5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in sections 5.1 and 5.2.
Exploratory biomarkers will be analysed to provide clinical evidence of the biological mode 
of action of the combination of BI 765063 and ezabenlimab or BI 765063 and Pembrolizumab
(i.e., pharmacodynamic biomarkers), to molecularly characterize an individual patient’s 
cancer in neoadjuvant setting. Biomarker maybe useful to retrospectively correlate patient 
subgroups with differential responses to treatment and/or to prognosis. These analyses are 
hypothesis generating and will be used to expand the current understanding of the trial drugs
and the disease. Participation in the biomarker testing is mandatory and is a prerequisite for 
participating in the study. 
Should other tissues or blood-based biomarkers beyond those exploratory biomarkers in the 
Flowchart become relevant, these may also be explored. The list of biomarkers planned to be 
studied during the trial may change based on new information in the scientific literature or 
early trial analysis. 
Any remaining samples or derived material from pre-specified analyses (RNA, DNA) will be 
destroyed no later than 5 years after the final trial report is archived.
The following biomarkers are planned to be examined in this trial (for detailed sampling 
times, refer to the Flowchart).
5.4.1
Biomarkers planned to be assessed in this trial
∀
Assessment of biomarkers of potential predictive value
o
SIRPα genotype (V1/V1, V1/V2, V2/V2), through WES/PCR
o
Baseline SIRPα and CD47 expression in tumor, through bulk RNAseq and 
scRNAseq
o
Baseline MMR/MSI status, TMB status, PD-L1 expression, T cell and 
macrophage infiltration in tumor through WES, bulk RNAseq, and MICSSS
∀
Pharmacological modulations of key MoA biomarkers upon Ezabenlimab/BI 765063 
combination


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o
Macrophage reprograming in tumor (changes in macrophage phenotype from 
baseline) through bulk RNAseq and scRNAseq
o
CD8 T cell infiltration in tumor, through MICSSS, bulk RNAseq and 
scRNAseq
o
Changes of lymphoid/myeloid populations in tumor and in blood through 
CyTOF
o
TCR clonality for clonal expansion/enrichment analysis in tumor and in blood 
through TCR sequencing on tissue and blood
o
Longitudinal mutation analysis, baseline TMB from ctDNA analysis in blood 
o
MoA-related cytokine modulation
o
Changes of microbiome in stool through 16s sequencing
5.4.2
Methods of Sample Collection, Handling of Samples and Biomarker Results
Detailed instructions for handling, storage, and shipment of the biomarker samples will be 
provided in the laboratory manual. All tumor and blood samples will be obtained at time 
points as defined in the Flow Chart. Biomarker data performed by the laboratory could be 
reported to investigators upon request.


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5.5
BIOBANKING
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling time points see Flow Chart.
The following biomarker samples specified in section 5.4, Assessment of Biomarkers, will be 
banked: pre-treatment and surgery tumor tissue, fixed in formalin and embedded in paraffin.
5.6
OTHER ASSESSMENTS
Not applicable
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor patients’ safety and to determine biological activity and 
efficacy in an appropriate way. The scheduled measurements will allow monitoring of 
changes in vital signs, standard laboratory values, and ECG parameters that might occur as a 
result of administration of trial medication. The safety assessments are standard, are accepted 
for evaluation of safety and tolerability of an intravenously administered drug, and are widely 
used in clinical trials.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and exclusion criteria who have signed a written ICF are
eligible for participation in the trial. Patients will visit the clinical site at the time points
specified in the Flowchart. All patients should adhere to the visit schedule as specified in the 
Flowchart. The allowed windows for each visit and assessment are specified in the 
Flowcharts. Additional flexibility (e.g. to allow for public holidays and patient unavailability) 
may be allowed if agreed between the investigator and the sponsor.
If a patient misses a visit during which there is no treatment administration planned, the visit 
should be rescheduled as soon as possible, and the delayed visit documented with the actual 
date and the reason for the delay. The scheduling of subsequent visits must not be altered, so 
if it is not possible to reschedule prior to the next planned visit, the missed visit should be 
skipped.
If a patient is hospitalised for administrative reasons this will not be considered an SAE, 
unless any other criteria for an SAE are fulfilled.
In addition to the scheduled assessments, unscheduled visits and unscheduled assessments for 
safety reasons may be performed at any time according to clinical need.  


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In situations where a patient is unable or unwilling to attend a clinic visit, the investigator 
must assess the risk-benefit for the individual patient and may decide to perform a visit 
remotely if this is in the best interests of the patient and if agreed with the sponsor. Patient 
safety must be ensured when determining if a visit may be remote.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the flowchart will be performed at the respective visits.
Specific details to conduct of physical examination, collection of vital signs, including blood 
pressure measurement, laboratory investigations, assessment of ECG, and other safety 
parameters can be found in the subsections of section 5.2.2.
6.2.1
Screening and run-in period(s)
Screening Period
Patients may be consented to the clinical trial if they have imaging or other findings highly 
suggestive of a diagnosis of CRC. Such patients should subsequently undergo diagnostic and 
research biopsies in parallel, during screening, in order to avoid repeating procedures. 
Consented patients found to have a diagnosis other than CRC will be considered as screen-
fail. Such patients will be replaced.
Following informed consent, the patient will undergo screening assessments as indicated in 
the flowchart. The assessments must fall within the acceptable Screening visit window but do 
not need to be performed on the same day. Screening assessments may be repeated as long as 
they fall within the Screening visit window of 21 days. If more than one screening assessment 
is available, the latest assessment prior to the start of treatment must be used to assess 
eligibility. 
Tumor assessments performed prior to informed consent as part of routine clinical practice 
will be accepted if they meet the requirements of the protocol and are performed within the 
Screening visit window of 21 days.
There is no mandatory order of assessments, but the biopsy must only be performed on 
patients who are expected to be eligible. Where applicable, the pre-treatment/baseline biopsy 
must be obtained prior to the dose.
If the patient meets the eligibility criteria during screening, the treatment visit should be 
scheduled. Any baseline conditions which are present at the Screening visit should be 
reported in the eCRF. 
Re-screening of patients who have previously failed screening will be permitted. In this 
situation patients will be allocated a new patient number.
∀
During the screening visit, demographics information will be collected. This includes: 
age on the day of informed consent (in years) 
∀
Sex (male, female in order to describe the subject`s sex at birth) 


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∀
Gender identity (male, female, other in order to describe how the subject self-
identifies regardless of their genotypic or phenotypic sex)
∀
For women: of childbearing potential yes / no in order to characterize the patient 
population and as a basis for contraception requirements 
∀
Pregnancy testing - serum
∀
Ethnicity and race in order to sufficiently characterize the patient population, to 
support possible subgroup analyses if needed unless not acceptable according to local 
regulations.
∀
Information on tobacco use
Baseline Conditions
Any baseline conditions which are present at the screening visit should be reported in the 
eCRF.
Demographics
Demographics (sex, birth year, race, and ethnicity [where allowed]), and baseline medical 
conditions will be collected during the screening visit.
Medical History of Cancer:
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumor site will be 
reported on the eCRF. The differentiation grade, i.e. not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated, obtained at screening, as well as 
the stage according to the tumor, lymph node, and metastasis (TNM) classification, will be 
provided as obtained at trial screening. 
Other Medical History
Past diseases and/or concomitant diagnoses relevant to the patient's safety during the trial, 
assessment of biomarker such as PD-L1 expression, microsatellite instability (MSI), TMB 
information, and efficacy, as judged by the Investigator, will be recorded in eCRF.
Concomitant Medication
Past medications relevant to the patient's safety during the trial, as judged by the
Investigator, will be recorded in the eCRF. From the date of signature of the main ICF, all
concomitant medications will be recorded.
Please refer to the Flowchart for a detailed presentation of the Screening visit.
6.2.2
Treatment period(s)
In this trial the investigational combination treatment will be provided as single 
administration. Eligible patients will be administered study medication on Day 1.  




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∀
*Resected tumor collection: Tumor tissue will be a sample from the tumor removed 
during the surgery. (*Note: “Resected tumor collection” is listed under visit 3 in the 
flow chart for practical reasons and should occur at the day of the surgery. All other 
activities will be performed prior to the surgery.)
Please refer to the Flow Chart for a detailed presentation of each visit during Visits 1 through 
Visit 3.
6.2.3
Follow-up period and trial completion, End of Study (EOS) Visit 
After the patient completes visit 1 through visit 3, there is a single visit to be conducted at ≥ 
91 days and no later than 120 days from Day 1. The following procedures need to be 
performed at the End of Study (EOS) Visit:
∀
Physical exam
∀
ECG
∀
ECOG determination
∀
Adverse Events assessments
∀
Research blood samples
After EOS visit, the patient has completed the trial and no further data collection is required.
If needed in the opinion of the investigator, after EOS visit, additional visits may be 
scheduled for continued safety monitoring. For information on follow-up period, see section 
7.2.6.
Abnormal assessments or lab values judged clinically relevant by the investigator will be 
monitored until they returned to a medically acceptable level. 
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This is an open-label, two-arm, parallel group, single-center Phase 1 trial of ezabenlimab in 
combination with BI 765063 and Pembrolizumab in combination with BI 765063 in patients with 
early stage resectable colorectal cancer in neoadjuvant setting. Patients will be assigned 
alternatingly (sequentially one by one) to either of the cohorts and will receive one-time either of 
the combination treatments. 
This is an exploratory study where the primary objective is to assess safety of patients treated 
with both the treatments in the neoadjuvant setting and also to ensure that the neoadjuvant 
treatment does not delay the recommended surgery. In addition, this trial will investigate efficacy 
as secondary objective and biological activity (including immunodynamic effect of the combined 
immunotherapy regimens systemically and on the tumor immune microenvironment) as further 
objectives.


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7.1
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. All the analyses in this trial are descriptive 
and exploratory. Results collected will be used for potential hypothesis generation. A Bayesian 
framework will be used to assess safety and feasibility. Any other analyses will be described in 
the Trial Statistical Analysis Plan (TSAP).
7.2
PLANNED ANALYSES
7.2.1
General considerations
For analyses of primary and secondary endpoints, all patients in the treated set (i.e., patients 
treated with one dose of trial medication) will be used if not specified differently. No per 
protocol set will be used in the analysis. However, important protocol violations will be 
identified and listed. Any other analysis set will be defined in the TSAP.
7.2.2
Handling of Intercurrent Events
Considering that patients will be treated with one-time treatment in both cohorts, no major
intercurrent event is anticipated in this trial.
7.2.3
Primary objective analyses
The primary endpoint of the trial is a composite endpoint, safety and feasibility. Primary 
evaluation of safety and feasibility will be reported for all treated patients and will be 
measured as proportion of patients (along with 95% CI) who will meet the criterion of safety 
or feasibility (or both) defined in section 2.1.2. Safety and feasibility will be summarized 
separately for each arm.
In addition, safety and feasibility will be monitored, at interim and at final, using a Bayesian 
method. The incidence of complications after surgery for colorectal cancer is assumed 
approximately 20%. We consider that a neoadjuvant therapy with one of the regimens is not 
feasible if at least 20% of the patients with 85% or higher probability experience treatment 
related grade 3 or higher adverse events or have delay in surgery due to treatment related 
adverse events. Interim and final assessments for safety and feasibility will be conducted, 
separately, approximately after 5, 15 and 25 (final) patients being treated in each arm. 
With a conservative prior probability of unfavorable “safety/feasibility” as Beta (0.1,0.4), the 
stopping boundaries are defined as seeing unfavorable “safety/feasibility” in ≥ 3 of first 5 
patients, ≥ 5 of first 15, 8 or more out of 25 patients (Table 7.2.3:1). In case one arm needs to 
be closed due to unfavorable “safety/feasibility”, accrual to the remaining arm will continue. 
The calculation was performed using the Shiny Application: Bayesian Toxicity Monitoring 
version 2.2.1.0.


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Table 7.2.3: 1
Early stopping boundary for unfavorable “safety/feasibility
# of patients (inclusive) per 
cohort 
# of patients with related 
grade ≥ 3 AE or surgery 
delay 
Decisions
5
3-5
Stopping
15
5-15
Stopping
25
8-25
Reached to final sample size
7.2.3.1
Sensitivity Analyses
Currently no sensitivity analysis is planned for the primary endpoint.  Any additional 
sensitivity analysis will be described in the TSAP.
7.2.3.2
Subgroup Analyses
No subgroup analysis is planned for the primary endpoint.
7.2.3.3
Supplementary Analyses
No supplementary analysis is planned for the primary endpoint.
7.2.4
Secondary objective analyses
Pathological response (PR) will be assessed as per Mandard tumor regression grading 
system (R21-1544). The study will apply a Bayesian framework to calculate the posterior 
probability of PR rate for each arm separately. The 95% credible interval of the PR rate will 
be constructed along with observed PR (naïve estimate) and corresponding 95% confidence 
interval. In addition, at the final analysis, posterior probability, for each arm, that the PR rate 
is at least 15% will be calculated (i.e., suggesting that drug is efficacious) under the beta-
binomial model with a weakly informative prior: Beta (0.15, 0.85).
Any additional analysis (including sensitivity analysis) to assess pathological responses will 
be separately described in the Trial Statistical Analysis Plan (TSAP).
Time from administration of trial treatment to surgery will be calculated as [Date of 
surgery – Date of first treatment administered + 1]. Time from administration of trial therapy 
to surgery will be summarized descriptively.
Radiographic response will be summarized descriptively along with 95% confidence interval.




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7.2.7
Other Analyses
Not applicable.
7.2.8
Interim Analyses
Two interim analyses are planned to assess safety and feasibility of the treatments. A 
Bayesian framework will be used to assess safety and feasibility after, approximately, 5 and 
15 patients are treated in each arm. A Data Review Committee (DRC) will review the overall 
data along with the results from Bayesian calculation at interim. 
7.3
HANDLING OF MISSING DATA
In general, no imputation will be performed on missing efficacy data. 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 (see Reference Document 001-MCG-156_RD01 “Handling of 
missing and incomplete AE dates”)
7.4
RANDOMIZATION
No randomization will be performed. Patients will be assigned alternatingly (sequentially one by 
one) to either of the cohorts and will receive one-time either of the combination treatments.
7.5
DETERMINATION OF SAMPLE SIZE
No formal statistical assumption is used for the sample size calculation. A total sample size of 
50 (25 in each arm) evaluable patients is planned to enroll in this trial. With a sample size of 
25 patients in each arm, the study will have a very low probability (0.01) to wrongly declare 
that the study shows unfavorable “safety/feasibility” when the true rate is 10%, while it will
have a high probability of 89% to identify a high true unfavorable “safety/feasibility” rate of 
40% (Table 7.5:1).
The simulation was performed using the Shiny Application: Bayesian Toxicity Monitoring 
version 2.2.1.0.


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Table 7.5:1
Operating characteristic, based on 10000 simulated trials, for 
Bayesian monitoring for unfavorable “safety/feasibility”
Scenario
True
Rate of 
unfavorable 
“safety/feasibility”
Probability of 
Early Stop
Probability of
Declaring 
unfavorable 
“safety/feasibility”
Average 
No of 
patients
Average No of 
unfavorable 
“safety/feasibility”
Observed rate of 
unfavorable 
“safety/feasibility”
1
0.1
0.01
0.02
24.72
2.47
0.10
2
0.2
0.18
0.21
22.57
4.51
0.22
3
0.3
0.50
0.60
18.31
5.49
0.35
4
0.4
0.79
0.89
13.88
5.55
0.47
5
0.5
0.94
0.98
10.55
5.27
0.57
For pathological response (PR), a weakly informative prior for PR as Beta (0.15, 0.85) along
with an observed PR of 5 out of 25 patients will provide a posterior probability of 70% that 
PR rate is more than 15%.
Table 7.5:2
Posterior probability of true pathological response
# of observed PR out of 25
Posterior 
probability that 
(PR > 0.05)
Posterior probability 
that (PR > 0.10)
Posterior 
probability that 
(PR > 0.15)
4
0.97
0.78
0.49
5
0.99
0.91
0.70
6
0.99
0.97
0.85
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).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor or delegate 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


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with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report
(CTR).
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator 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
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan (RMP) or alternative plan, in line with the guidance provided by ICH Q9 
and ICH-GCP E6, for fully outsourced trials, 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.


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Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit / inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.2.1.
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 at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Certified copies of source documents necessary for data review and monitoring are accepted.  
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 (OE) (onset date (mandatory), and end date (if 
available))


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∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion / exclusion criteria does not make 
the patient eligible for the clinical trial.
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 always be available 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 or delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site:
The trial site 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. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook. 
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. In case patient’s records will be forwarded to the sponsor (e.g. for SAE processing or 
adjudication committees) personal data that can identify the patient will be redacted by the 


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site prior to forwarding. Access to the patient files and clinical data is strictly limited: 
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.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.
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 must be in accordance with the separate biobanking informed 
consent
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials
∀
An appropriate sample and data management system, including 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
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered trial treatment (as 
scheduled per protocol). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 90 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
(HA) request.


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A DRC will be established as described in section 3.1.1. and section 7.2.8. 
Relevant documentation on the participating (Principal) Investigator (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor (if applicable).
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), and Clinical Research Associates (CRAs).
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 available 
in the ISF.


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combined with azacitidine is well-tolerated and effective in AML patients: 
phase 1b results. 62nd Ann Mtg of the American Society of Hematology 
(ASH) Virtual, 5 - 8 Dec 2020 . Blood 2020 ; 136(Suppl 1)
R21-1681
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, 
Veeriah S, et al, TRACERx Consortium. Tracking the evolution of non-
small-cell lung cancer. N Engl J Med 2017; 376(22) ; 2109-2121. 
R21-1682
Liu J, Blake SJ, Yong MCR, Harjunpaa H, Ngiow SF, Takeda K, et al. 
Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to 
eradicate metastatic disease. Cancer Discov 2016 ; 6(12) ; 1382-1399. 
R21-1683
Blank CU, Rozeman EA, Fanchi LF, Sikorska K, Wiel B van de, Kvistborg 
P, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in 
macroscopic stage III melanoma. Nature Med 2018 ; 24; 1655-1661. 
R21-1684
Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, et al. 
T-cell invigoration to tumour burden ratio associated with anti-PD-1 
response. Nature 2017 ; 545; 60-65. 
R21-1688
Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. 
High macrophage infiltration along the tumor front correlates with 
improved survival in colon cancer. Clin Cancer Res 2007 ; 13(5) ; 1472-
1479. 
R21-1971
Opdivo (nivolumab) injection, for intravenous use (Bristol-Myers Squibb) 
(U.S. prescribing information, revised: 01/2021). 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl
.pdf (access date: 20 May 2021); 2021.
P19-00269
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino 
JM, et al. National Comprehensive Cancer Network Management of 
immune-related adverse events in patients treated with immune checkpoint 
inhibitor therapy: American Society of Clinical Oncology clinical practice 
guideline. J Clin Oncol 2018. 36(17): 1714.


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P21-08940
Kotecki N, Champiat S, Delord JP, Vinceneux A, Jungels C, Marabelle A 
et al. Phase I dose escalation study in patients with advanced solid tumours 
receiving first-in-class BI 765063, a selective signal-regulatory protein 
alpha (SIRPalpha) inhibitor, in combination with ezabenlimab (BI 754091), 
a programmed cell death protein-1 (PD-1) inhibitor. 46th Ann Cong of the 
European Society for Medical Oncology (ESMO), Virtual, 16 Sep 2021 -
21 Sep 2021. 2021 (Poster #983P)
c29693380
Investigator's Brochure BI 765063 version 1.0 dated 28 May 2021.
c07895879
Investigator's Brochure BI 754091 version 5.0 dated 08 Feb 2021
001-MCG-
156_RD01
“Handling of missing and incomplete AE dates”)


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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Not Applicable
10.2
TIME SCHEDULE FOR PHARMACODYNAMIC AND BIOMARKER 
SAMPLING
Please see the Flowchart
10.3
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST
This table defines immune-related AEs that must be reported as AESIs if they occur after 
exposure to the trial treatment. For each category examples are provided, but these are not 
exhaustive.
Table 10.3: 1 Immune-related adverse events of special interest
Immune-related adverse events of special interest
Pneumonitis (report as AESI if an irAE is ≥Grade 2)
∀Acute interstitial pneumonitis
∀Interstitial lung disease
∀Pneumonitis
Colitis (report as AESI if an irAE is ≥Grade 2 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)
∀Intestinal obstruction
∀Colitis
∀Colitis microscopic
∀Enterocolitis
∀Enterocolitis haemorrhagic
∀Gastrointestinal perforation
∀Necrotising colitis
∀Diarrhea
Endocrine (report as AESI if an irAE is ≥Grade 3 or ≥Grade 2 and resulting in dose 
modification or use of systemic steroids to treat the AE)


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Immune-related adverse events of special interest
∀Adrenal insufficiency
∀Hyperthyroidism
∀Hypophysitis
∀Hypopituitarism
∀Hypothyroidism
∀Thyroid disorder
∀Thyroiditis
∀Hyperglycaemia, if ≥ Grade 3 and associated with ketosis or metabolic acidosis
Endocrine (report as AESI for any grade)
∀Type 1 diabetes mellitus (if new onset)
Haematologic (report as AESI if an irAE is ≥Grade 3 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)
∀Autoimmune haemolytic anaemia
∀Aplastic anaemia
∀Thrombotic thrombocytopenic purpura
∀Idiopathic (or immune) thrombocytopenia purpura
∀Disseminated intravascular coagulation
∀Haemolytic-uraemic syndrome
∀Any Grade 4 anaemia regardless of underlying mechanism
Hepatic (report as AESI if an irAE is ≥Grade 2, or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)
∀Hepatitis
∀Autoimmune hepatitis
∀Transaminase elevations (ALT and/or AST)
Infusion Reactions (report as AESI for any grade)
∀Allergic reaction
∀Anaphylaxis
∀Cytokine release syndrome
∀Serum sickness
∀Infusion reactions
∀Infusion-like reactions
Neurologic (report as AESI for any grade)
∀Autoimmune neuropathy
∀Guillain-Barre syndrome
∀Demyelinating polyneuropathy
∀Myasthenic syndrome


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


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10.4
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Date of amendment
21 January 2022
EudraCT number
EU number
Not applicable
BI Trial number
1502-0001
BI Investigational Medicinal 
Product(s)
Ezabenlimab 
BI 765063
Title of protocol
A Phase I open label study to assess safety, 
feasibility, efficacy, and biological activity of 
single administration of Ezabenlimab in 
combination with BI 765063 and Pembrolizumab 
in combination with BI 765063 as neoadjuvant 
treatments in patients with newly diagnosed 
surgically-resectable, locoregional colorectal 
cancer
Global Amendment
X
Section to be changed
Lay Title


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Description of change
Old Lay Title –
A study to test the safety and activity of one dose 
of ezabenlimab or pembrolizumab in combination 
with BI 765063 in people with newly diagnosed 
colorectal cancer who are scheduled for surgery.
New Lay Title –
A study in people with colorectal cancer to test 
whether ezabenlimab or pembrolizumab in 
combination with BI 765063 lead to side effects or 
delays in surgery.
Rationale for change
The lay title was updated
Section to be changed
Flowchart
Description of change
Line “Optional BioBanking from blood” removed
Reference deleted from bottom of flowchart:
Rationale for change
The study will not collect blood for Biobanking
Section to be changed
Grammar, typographical errors, and grammar was 
corrected throughout the document.
Description of change
Grammar, typographical errors, and grammar was 
corrected throughout the document.
Rationale for change
The corrections were made throughout the 
document to ensure that grammar and all errors in 
tense were corrected.
Section to be changed
Section 3.3.3.- Exclusion Criteria
Description of change
The following exclusion criteria was added:
1. Patients who are deemed to be high risk for 
colonic obstruction and/or perforation per 
investigator assessment
2. Patients eligible for neoadjuvant therapy 
(chemotherapy, radiotherapy, 
chemoradiotherapy) as standard of care.


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Rationale for change
Clarification of eligibility criteria following FDA 
comments from 15th and 16th of December 2021
Section to be changed
Section 4.1.1:1 Ezabenlimab (BI 754091)
Description of change
Language “concentrate for solution” was changed 
to read “solution for infusion”
Rationale for change
The previous language was incorrect per our 
Clinical Trial Supply Unit (CTSU).  It has been 
corrected to read properly
Section to be changed
4.2.2 Prohibited Concomitat Medications
Description of change
The following information was added:
Any standard of care therapy is allowed in the 
adjuvant (post-operative setting) that is deemed 
clinically indicated by the treating physician.
Rationale for change
Clarification of the description of other therapies 
to be allowed in the study by the treating 
physician.
Section to be changed
5.5 Biobanking
Description of change
Additional language added to section 5.5:  Also, 
Option for blood biobanking has been removed 
from the protocol.
Rationale for change
Due to the low number of patients to be enrolled 
in the study the decision was made to delete the 
option for blood biobanking
Section to be changed
6.2.2 Treatment period(s); Visit 1 (V01)
Description of change
Pregnancy testing 
-
(urine or serum) was added
Rationale for change
Urine or serum was added to give the site a choice 
for either test to capture pregnancy testing at Visit 
1
Section to be changed
Section 10.2 – 10.2


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Description of change
Table was deleted.  The time schedule is found on 
the flowchart on page 9 
Rationale for change
The table was redundant and did not provide any 
additional information.

SAP_001.pdf: 
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TRIAL STATISTICAL ANALYSIS PLAN
 
Document No.:
c44070053
BI Trial No.:
1502-0001
Title:
A Phase I open label study to assess safety, feasibility, efficacy, 
and biological activity of single administration of Ezabenlimab in 
combination with BI 765063 and Pembrolizumab in combination 
with BI 765063 as neoadjuvant treatments in patients with newly 
diagnosed surgically-resectable, locoregional colorectal cancer
Investigational
Product(s):
Ezabenlimab 
BI 765063
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
23 FEB 2024
Version:
1.0
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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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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................3
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................5
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................6
5.
ENDPOINTS(S).....................................................................................................6
5.1
PRIMARY ENDPOINT(S)...................................................................................6
5.2
SECONDARY ENDPOINT(S).............................................................................6
5.2.1
Key secondary endpoint(s) ...................................................................................6
5.2.2
Secondary endpoint(s)...........................................................................................6
6.
GENERAL ANALYSIS DEFINITIONS.............................................................7
6.1
TREATMENT(S) ..................................................................................................7
6.2
IMPORTANT PROTOCOL DEVIATIONS......................................................7
6.3
INTERCURRENT EVENTS................................................................................7
6.4
SUBJECT SETS ANALYSED .............................................................................7
6.6
HANDLING OF MISSING DATA AND OUTLIERS ......................................7
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS......................7
7.
PLANNED ANALYSIS ........................................................................................8
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...........8
7.2
CONCOMITANT DISEASES AND MEDICATION........................................8
7.3
TREATMENT COMPLIANCE ..........................................................................8
7.4
PRIMARY OBJECTIVE ANALYSIS ................................................................8
7.4.1
Main analysis .........................................................................................................8
7.4.4
Supplementary analysis ........................................................................................8
7.5
SECONDARY OBJECTIVE ANALYSIS ..........................................................8
7.5.1
Key secondary objective analysis.........................................................................8
7.5.2
Secondary objective analysis................................................................................9
7.6
FURTHER OBJECTIVE ANALYSIS................................................................9
7.7
EXTENT OF EXPOSURE ...................................................................................9
7.8
SAFETY ANALYSIS............................................................................................9
7.8.1
Adverse Events ......................................................................................................9
7.8.2
Laboratory data.....................................................................................................9
7.8.3
Vital signs...............................................................................................................9
7.8.4
ECG ........................................................................................................................9
7.9
OTHER ANALYSIS .............................................................................................9


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7.9.1
Biomarker analyses...............................................................................................9
7.9.2
PK / PD analyses....................................................................................................9
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............10
9.
REFERENCES ....................................................................................................11
11.
HISTORY TABLE..............................................................................................13
LIST OF TABLES
Table 11: 1
History table .....................................................................................................13


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
BI
Boehringer Ingelheim
CTP
Clinical Trial Protocol
ECG
Electrocardiogram
ICH
International Conference On Harmonisation
CTR
Clinical Trial Report
PD
Pharmacodynamics
PK
Pharmacokinetics
SAS®
Statistical Analysis System
TSAP
Trial Statistical Analysis Plan


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3. INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP). The TSAP readers 
may consult the CTP for more background information on the study, e.g., on study objectives, 
study design, population, treatments, definition of measurements and variables, planning of 
sample size, and randomization.
Due to the early discontinuation of the study following a slow enrolment of only two patients, 
this TSAP will specify a very limited analysis with data output consisting of a patient profile 
listing containing data collected for these individual patients.
SAS® Version 9.4 will be used to create the patient profile listing.


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pat
4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Due to the early discontinuation of the study following the enrolment of only two patients, 
this TSAP will provide only a patient profile listing containing data collected for these 
individual patients rather than the statistical outputs and analyses described in the trial 
protocol (including amendments). 
The rationale behind creating patient profiles lies in the absence of statistical summary 
outputs. With a population size of 2, utilizing patient profiles rather than statistical summary 
outputs will facilitate a more straightforward presentation of the minimal data regarding 
patient disease background and patient safety details.
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoints are defined in Section 2.1.2 of CTP. However, due to the early 
discontinuation of the study following the enrolment of only two patients, only the patient 
profile listing will be provided in this TSAP.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
No key secondary endpoint has been specified for this study.
5.2.2
Secondary endpoint(s)
The secondary endpoints are defined in Section 2.1.2 of CTP. However, due to the early 
discontinuation of the study, only the patient profile listing will be provided in this TSAP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on investigational products, assignment of treatment, and 
selection of doses, please see CTP, Sections 3 and 4.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Due to the very early discontinuation of the study, any assessed protocol deviations will be 
provided in the patient profile listing.
6.3
INTERCURRENT EVENTS
It is not applicable for this TSAP due to the very early discontinuation of the study.
6.4
SUBJECT SETS ANALYSED
Only the treated two patients will be included in the patient profile listing.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards.
6.7 BASELINE, TIME WINDOWS AND CALCULATED VISITS
It is not applicable for this TSAP due to the very early discontinuation of the study.


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7.
PLANNED ANALYSIS
Due to the early discontinuation of the study following a slow enrolment of only two patients, 
this TSAP will provide a patient profile listing containing data collected for these individual 
patients rather than the statistical analyses and outputs described in the trial protocol.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
No descriptive statistics are planned for this section of the report, but the patient profile listing 
will include the demographics and baseline characteristics data.
7.2
CONCOMITANT DISEASES AND MEDICATION
No descriptive statistics are planned for this section of the report, but the patient profile listing 
will include the concomitant disease and medication data.
7.3
TREATMENT COMPLIANCE
This is not applicable for this TSAP due to the very early discontinuation of the study 
following a slow enrolment of only two patients.
7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
Due to the early discontinuation of the study following a slow enrolment of only two patients, 
this TSAP will provide a patient profile listing containing data collected for these individual 
patients rather than the statistical analyses and outputs described in the trial protocol.
7.4.4
Supplementary analysis
No supplementary analysis is planned.
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
No key secondary endpoint has been specified for this study.


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7.5.2
Secondary objective analysis
The secondary objective analysis will not be performed for this study due to its early 
discontinuation. This TSAP will provide a patient profile listing containing data collected for 
these individual patients rather than the statistical methods described in the trial protocol.
7.6
FURTHER OBJECTIVE ANALYSIS
Further objective analysis will not be performed for this study due to the early discontinuation 
of the study. This TSAP will provide a patient profile listing containing data collected for 
these individual patients compared to the statistical methods described in the trial protocol.
7.7
EXTENT OF EXPOSURE
It is not applicable for this TSAP due to the very early discontinuation of the study.
7.8
SAFETY ANALYSIS
All safety data will be presented in the patient profile listing for two treated patients.
7.8.1 Adverse Events
All the adverse events data will be presented in the patient profile listing for two treated 
patients.
7.8.2
Laboratory data
All the laboratory data will be presented in the patient profile listing for two treated patients.
7.8.3
Vital signs
The patient profile listing for two treated patients will present the vital signs data.
7.8.4
ECG
The patient profile listing will present the ECG data for two treated patients.
7.9
OTHER ANALYSIS
No other analyses are planned.
7.9.1 Biomarker analyses
It is not applicable for this TSAP due to the very early discontinuation of the study.
7.9.2 PK / PD analyses
It is not applicable for this TSAP due to the very early discontinuation of the study.


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8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
As this is an open label study, the treatment information for each patient was loaded into the 
trial database at trial initiation.


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9.
REFERENCES
9.1
BI-VQD-23790-S-G_50-415_AD-02: “Project Analysis Dataset (PADS) Template 
(template)”, current version, group / owning department “Med Biostatistics & 
Data Sciences”, DMS for controlled documents.
9.2
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
9.3
BI-VQD-12682-S-G_50-415_AD-03: “Clinical Trial Analysis Decision Log 
(template)”, current version, group / owning department “Med Biostatistics & 
Data Sciences”, DMS for controlled documents.
9.4
BI-VQD-12177_40-106_AD-03: “Clinical Trial Protocol general template for 
Phase I-IV”, current version, group / owning department “Med Clinical 
Development & Operations”, DMS for controlled documents.
9.5
001-MCS-80-606: “Management of Non-Compliances, Audit and Inspection 
Responses”, current version, group / owning department “Med Quality Medicine”, 
DMS for controlled documents.
9.6
BI-VQD-12045_40-413: “Identify and Manage Important Protocol Deviations 
(iPD)”, current version, group / owning department “Med Clinical Development & 
Operations”, DMS for controlled documents.
9.7
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND 
OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for 
human use, and repealing Directive 2001/20/EC, European Commission webpage.
9.8
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical 
Study Reports, current version, EMA webpage.
9.9
001-MCS-30-475_RD-01: “Biomarker: Intended Use & Implementation Statement 
(IUIS) (template)”, current version, group / owning department “Med 
Translational Medicine Clinical Pharmacology”, DMS for controlled documents.


Boehringer Ingelheim
Page 12 of 13
TRIAL STATISTICAL ANALYSIS PLAN
1502-0001
c44070053
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies.
Date: 23 FEB 2024, Version 1.0
BI-VQD-12681-S-G_50-415_AD-01 (5.0)


Boehringer Ingelheim
Page 13 of 13
TRIAL STATISTICAL ANALYSIS PLAN
1502-0001
c44070053
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies.
Date: 23 FEB 2024, Version 1.0
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
11. HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1.0
22-FEB-24
None
This is the final TSAP.