Clinical trial NCT04147234
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2020-08-03; Completion date: 2024-03-21
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in adults with advanced cancer (solid tumours) in whom previous treatment was not successful. The study tests 2 medicines called BI 1387446 and BI 754091. Both medicines may help the immune system fight cancer. In this study, BI 1387446 is given to humans for the first time.

The purpose of this study is to find out the highest dose of BI 1387446 alone and in combination with BI 754091 the participants can tolerate. BI 1387446 is injected directly into the tumour.

Participants get BI 1387446 injections every week at the beginning and then every 3 weeks.

Some participants get BI 754091 in addition to BI 1387446. BI 754091 is given as an infusion into a vein every 3 weeks.

As long as they benefit from treatment and can tolerate it, participants can stay in the study for up to 2 years and 8 months. During this time, they visit the study site regularly. At these visit, doctors record any unwanted effects. The doctors also regularly check participants' health.

Detailed description:

Arms: arm 1: Participants were administered 50 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. The injection volume depended on tumor diameter. arm 2: Participants were administered 100 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. The injection volume depended on tumor diameter. arm 3: Participants were administered 200 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. The injection volume depended on tumor diameter. arm 4: Participants were administered 400 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. The injection volume depended on tumor diameter. arm 5: Participants were administered 50 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. BI 754091 (ezabenlimab) was administered intravenously at the recommended phase II dose of 240 mg once every 3 weeks. The maximum duration of ezabenlimab treatment was 34 cycles. BI 1387446 injections were preferably performed after completing the ezabenlimab infusion. arm 6: Participants were administered 100 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. BI 754091 (ezabenlimab) was administered intravenously at the recommended phase II dose of 240 mg once every 3 weeks. The maximum duration of ezabenlimab treatment was 34 cycles. BI 1387446 injections were preferably performed after completing the ezabenlimab infusion. arm 7: Participants were administered 200 μg of BI 1387446 intratumorally under visual inspection for visible skin tumors or under imaging guidance. BI 754091 (ezabenlimab) was administered intravenously at the recommended phase II dose of 240 mg once every 3 weeks. The maximum duration of ezabenlimab treatment was 34 cycles. BI 1387446 injections were preferably performed after completing the ezabenlimab infusion.
Interventions: intervention 1: BI 1387446 50 μg intervention 2: BI 754091 intervention 3: BI 1387446 100 μg intervention 4: BI 1387446 200 μg intervention 5: BI 1387446 400 μg
Intervention descriptions: intervention 1: Participants received 50 μg BI 1387446 intratumorally based on tumor diameter, on Day 1 of a 21-day cycle. Injections were administered under visual inspection for skin tumors or imaging guidance. intervention 2: Participants received BI 754091 (ezabenlimab) intravenously at a dose of 240 mg once every 21-day cycle. intervention 3: Participants received 100 μg BI 1387446 intratumorally based on tumor diameter, on Day 1 of a 21-day cycle. Injections were administered under visual inspection for skin tumors or imaging guidance. intervention 4: Participants received 200 μg BI 1387446 intratumorally based on tumor diameter, on Day 1 of a 21-day cycle. Injections were administered under visual inspection for skin tumors or imaging guidance. intervention 5: Participants received 400 μg BI 1387446 intratumorally based on tumor diameter, on Day 1 of a 21-day cycle. Injections were administered under visual inspection for skin tumors or imaging guidance.

Protocol documents:
Prot_000.pdf: 




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Time frame for all secondary endpoints: From start of treatment 
until the earliest of progression, death or end of trial 
(approximately 1 year).
Trial design
Open label trial with a dose finding phase 
Total number of patients 
entered
Approximately 78 patients
Number of patients on 
each treatment
Approximately 78 patients

monotherapy superficial lesions: approximately 34 patients

combination therapy superficial lesions: approximately 44
patients
Diagnosis
Various malignant solid tumours
Main in- and exclusion 
criteria
Main inclusion criteria:

Adult male or female patients with diagnosis of an advanced, 
unresectable and/or metastatic malignant solid tumour and 
indication for treatment.  

Patient must have exhausted established treatment options 
known to prolong survival for the malignant disease, or is not 
eligible for established treatment options.

Arms A, B: At least one tumour lesion which is suitable for 
injection, appropriate for the allocated treatment arm, and 
measurable. At least 1 discrete lesion, in addition to the 
lesion proposed for injection, which is amenable to biopsy.

ECOG 0 or 1
Main exclusion criteria:

Any investigational or antitumour treatment within 4 weeks 
or 5 half-life periods prior to the first treatment whichever is 
shorter

Persistent toxicity from previous treatments (including 
irAEs) that has not resolved to ≤ Grade 1, except for 
alopecia, xerostomia, and immunotherapy related 
endocrinopathies 

History or evidence of active, non-treatment related 
autoimmune disease, except for endocrinopathies

History of pneumonitis related to prior immunotherapy

Presence of other active invasive cancers other than the one 
treated in this trial within 5 years prior to screening

Presence or history of uncontrolled or symptomatic brain or 
subdural metastases unless local therapy completed and 
metastases considered stable

Known history of HIV infection

Active infection requiring systemic therapy at the start of 
treatment in the trial

Immunosuppressive corticosteroid doses (>10 mg prednisone 
daily or equivalent) within 2 weeks prior to the first 
treatment.


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Test product(s)
BI 1387446 
Ezabenlimab (BI 754091)
dose
BI 1387446: 
per day of administration
Ezabenlimab (BI 754091): 240 mg every 3 weeks
mode of 
administration
BI 1387446: intratumoural injection (i.tu.)
Ezabenlimab (BI 754091): intravenous infusion (i.v.)
Duration of treatment
Administration will continue until progressive disease (PD),
unacceptable toxicity, other withdrawal criteria, or a maximum 
treatment duration of 34 cycles, whichever occurs first.
Statistical methods
Descriptive statistics will be used for all analyses. 
Dose escalation will be guided by a Bayesian logistic regression 
model (BLRM) with overdose control that will be fitted to binary 
toxicity outcomes using a hierarchical modelling approach to jointly 
model escalation arms A and B. The estimates of the model 
parameters will be updated as data are accumulating using the 
BLRM. At the end of the dose escalation the toxicity probability at 
each dose level in each arm will be calculated to determine an 
estimate of the MTD in each arm.






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1.
All cycles are 3 weeks 
in duration. Patients will continue treatment with the study drugs until progressive disease (PD) by RECIST, withdrawal of patient 
consent, an unacceptable toxicity occurs, or the maximum number of cycles of treatment are reached, whichever occurs first. The maximum duration of treatment 
with BI 1387446 (Arms A and B) is 18 cycles, unless the patient has a partial response according to itRECIST, in which case treatment may continue for cycles 19-
34 after consultation with the sponsor. BI 1387446 has to be paused if there is no lesion suitable for injection any more, but may be re-started in the absence of PD if 
any lesion becomes suitable for injection again. The maximum duration of treatment with ezabenlimab (BI 754091) (Arm B only) is 34 cycles. Patients will be 
allowed to stay on treatment in the case of initial radiological PD (iUPD by itRECIST), if the Investigator judges that it is in the patient’s best interest and the patient 
has signed an informed consent describing this circumstance. Day 1 of Cycle 1 is defined as the day when BI 1387446 is first administered. 
2.
Applicable only to patients who did not experience PD on treatment. After the 90dFU, patients will have follow-up visits (in person or by telephone) for tumour
progression and to monitor safety by collecting AEs/SAEs/AESIs every 3 months until PD, introduction of new anti-cancer treatment, death, loss to follow-up, 
withdrawal of consent or for a maximum of 6 months after EoT.
3.
EoT visit: When a decision is taken to discontinue all treatment drugs, the EoT visit should be done instead of the scheduled visit. 30dFU visit: To be performed in 
person 30 days after the EoT visit. At this visit, all AEs/SAEs/AESIs and other required information must be collected as specified in the Flow Chart. 90dFU visit:
To be performed by telephone (or in person if the investigator deems necessary) 90 days after the EoT visit. Only AEs/SAEs/AESIs and concomitant therapy need to 
be collected at the 90dFU visit.
4.
At Cycle 2 Day 1, an overnight stay is recommended if logistically possible due to sampling planned at the visit. 
5.
The informed consent for trial participation should be signed prior to any trial procedure. Re-consenting may become necessary when new relevant information 
becomes available and should be conducted according to the sponsor’s instructions. A separate informed consent should be signed for biobanking if agreed by the 
patient. Per Section 4.1.2.3, a patient will be allowed to stay on treatment in the case of initial radiological PD (corresponding to iUPD by itRECIST/, if the 
Investigator judges that it is in the patient’s best interest and the patient has signed a separate informed consent describing the circumstance.
6.
The screening medical history and demographics, physical examination and Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, 
electrocardiogram (ECG), echocardiography (or MUGA scan), safety laboratory, and screening pregnancy test (serum) should be done ≤28 days prior to initiation of 
treatment. If these assessments are performed within 72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 Day 1 with the exception of the 
ECOG performance status, an abbreviated physical examination, and vital signs (pre- and post-infusion) prior to first trial dose. 
7.
Measurements of vital signs should precede blood sampling. 
8.
Safety laboratory assessments including haematology, serum biochemistry, and urinalysis will be performed locally. The parameters to be assessed at each visit is 
listed in Section 5.2.3.
9.
Focused/ limited parameters will be measured, refer to Section 5.2.3.
10. Triplicate 12-lead electrocardiograms (ECGs) will be obtained only at the timepoints outlined in Blood Sample Flow Chart for Arm A and Flow Chart for Arm B. At 
all other timepoints indicated in the Flow Chart and whenever the Investigator deems it necessary, single ECGs will be done prior to drug administration. ECG at 
screening must be done before blood work or other procedures after at least 5 minutes in resting position. ECG recording will be sent to a vendor for central 
evaluation.
11. A single ECG will be obtained as clinically indicated prior to drug administration, at least every two to three cycles (i.e. on Day 1 in Cycle 7, 9, 11, 13, 16, 19, 23,




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26. AEs which were ongoing at the 30dFU will be followed.
27. Consecutive biopsies should be taken always from the same lesion if clinically feasible.
28. Biopsies are taken from the projected injected and one distinct non-injected lesion if not indicated differently in the Flow Chart. Mandatory timepoints are baseline 
and C2D1. At optional timepoints only, patients with lesions suitable for diagnostic biopsy associated with limited procedural risks should be included (refer to 
Section 5.4 for details). 
29. Sampling for ADA only in Cycles 6, 9, 12, 18, 24, 30 and 34.
30. Abbreviated physical examination (focused on the specific disease, at the Investigator’s discretion).
31. After Cycle 5, every other cycle (i.e. Cycle 7, 9, 11…33).
32. Safety laboratory does not need to be repeated if the result is available within 24h prior to the drug administration.
33. No need to perform tumour assessment if it has been done within the 3 weeks prior to EoT.
34. Echocardiography will be obtained prior to administration of trial drugs (if drug administration is applicable) on Day 1 in Cycle 4, C7, C11, C15, and at EOT (a time 
window of -7 days is acceptable). For Cycle 2 Day 1, echocardiography may be performed within 72 hours prior to drug administration. 
35. If the patient stops trial treatment prior to completion of maximum number of cycles for a reason other than PD, the tumour assessment according to RECIST will be 
performed according to standard of care until the last follow-up needed according to protocol.
36. A slit-lamp examination will be performed by an ophthalmologist at screening, at the 30-day safety follow-up, and at any time during the treatment period, if 
clinically indicated. Opacities as seen on clinical slit-lamp examination will be graded according to LOCS III.
37. Although echocardiography is the preferred method, MUGA scans are permitted to quantify LVEF. The same method should be used in a single patient throughout 
the trial.


















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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART: OVERVIEW-ARM A AND ARM B ........................................................5
BLOOD SAMPLE FLOW CHART: ARM A.....................................................................10
BLOOD SAMPLE FLOW CHART: ARM B .....................................................................13
TABLE OF CONTENTS ......................................................................................................18
ABBREVIATIONS................................................................................................................23
1.
INTRODUCTION...............................................................................................28
1.1
MEDICAL BACKGROUND.............................................................................28
1.2
DRUG PROFILE................................................................................................28
1.2.1
BI 1387446 ...........................................................................................................28
1.2.2
Ezabenlimab (BI 754091) ...................................................................................30
1.2.3
Combination of BI 1387446 and ezabenlimab (BI 754091).............................31
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................31
1.4
BENEFIT - RISK ASSESSMENT.....................................................................32
1.4.1
Benefits.................................................................................................................32
1.4.2
Risks .....................................................................................................................32
1.4.3
Discussion.............................................................................................................36
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................36
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........36
2.1.1
Main objectives....................................................................................................36
2.1.2
Primary endpoint(s)............................................................................................36
2.1.3
Secondary endpoint(s) ........................................................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................37
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................37
3.1.1
Sequence of treatment arms and cohorts..........................................................39
3.1.2
Method of assigning patients to individual treatment cohorts .......................40
3.1.3
Definition of superficial lesions..........................................................................41
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................42
3.3
SELECTION OF TRIAL POPULATION .......................................................43
3.3.1
Main diagnosis for trial entry ............................................................................43
3.3.2
Inclusion criteria .................................................................................................43
3.3.3
Exclusion criteria ................................................................................................44
3.3.4
Withdrawal of patients from treatment or assessments..................................46
3.3.4.1
Discontinuation of trial treatment .........................................................................46


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3.3.4.2
Withdrawal of consent to trial participation .........................................................47
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................47
3.3.4.4
Replacement of patients........................................................................................48
3.3.5
Discontinuation of trial enrolment by the sponsor ..........................................48
4.
TREATMENTS...................................................................................................48
4.1
INVESTIGATIONAL TREATMENTS ...........................................................48
4.1.1
Identity of the Investigational Medicinal Products..........................................48
4.1.2
Selection of doses in the trial and dose modifications......................................50
4.1.2.1
BI 1387446............................................................................................................50
4.1.2.1.1
Dose escalation scheme ........................................................................................50
4.1.2.1.2
Determination of injection volume for BI 1387446..............................................51
4.1.2.2
Ezabenlimab (BI 754091).....................................................................................51
4.1.2.3
Treatment schedule ...............................................................................................52
4.1.3
Method of assigning patients to treatment groups...........................................53
4.1.4
Drug assignment and administration of doses for each patient......................53
4.1.4.1
Lesion selection – BI 1387446..............................................................................54
4.1.4.2
Restrictions for lesion selection – BI 1387446 .....................................................55
4.1.4.3
Dose reductions and dose delays ..........................................................................55
4.1.4.4
Dose limiting toxicity............................................................................................56
4.1.4.5
Precautions and surveillance for procedural risks from intratumoural application
...............................................................................................................................59
4.1.4.6
Cytokine release syndrome...................................................................................59
4.1.4.7
Management of immune-related AEs ...................................................................61
4.1.5
Blinding and procedures for unblinding...........................................................61
4.1.5.1
Blinding.................................................................................................................61
4.1.5.2
Unblinding and breaking the code ........................................................................61
4.1.6
Packaging, labelling, and re-supply...................................................................61
4.1.7
Storage conditions...............................................................................................61
4.1.8
Drug accountability.............................................................................................61
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................62
4.2.1
Other treatments and emergency procedures..................................................62
4.2.2
Restrictions ..........................................................................................................62
4.2.2.1
Restrictions regarding concomitant treatment ......................................................62
4.2.2.2
Restrictions on diet and life style..........................................................................64
4.2.2.3
Contraception requirements..................................................................................64
4.3
TREATMENT COMPLIANCE........................................................................65
5.
ASSESSMENTS..................................................................................................65
5.1
ASSESSMENT OF EFFICACY........................................................................65
5.2
ASSESSMENT OF SAFETY.............................................................................66
5.2.1
Physical examination ..........................................................................................66
5.2.2
Vital signs.............................................................................................................67
5.2.3
Safety laboratory parameters ............................................................................67
5.2.4
Electrocardiogram ..............................................................................................70


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5.2.5
Echocardiography / MUGA scan.......................................................................71
5.2.6
Other safety parameters.....................................................................................72
5.2.7
Assessment of adverse events.............................................................................72
5.2.7.1
Definitions of AEs ................................................................................................72
5.2.7.1.1
Adverse event........................................................................................................72
5.2.7.1.2
Serious adverse event............................................................................................73
5.2.7.1.3
AEs considered “Always Serious”........................................................................73
5.2.7.1.4
Adverse events of special interest.........................................................................73
5.2.7.1.5
Intensity (severity) of AEs....................................................................................76
5.2.7.1.6
Causal relationship of AEs....................................................................................76
5.2.7.2
Adverse event collection and reporting ................................................................77
5.2.7.2.1
AE Collection........................................................................................................77
5.2.7.2.2
AE reporting to the sponsor and timelines............................................................77
5.2.7.2.3
Pregnancy..............................................................................................................77
5.2.7.2.4
Exemptions to AE/SAE reporting.........................................................................78
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................79
5.3.1
Assessment of pharmacokinetics .......................................................................79
5.3.2
Plasma sampling for metabolism analysis ........................................................79
5.3.3
Methods of sample collection .............................................................................80
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................81
5.4.1
Methods of sample collection .............................................................................81
5.5
BIOBANKING ....................................................................................................84
5.5.1
Methods and timing of sample collection..........................................................84
5.6
OTHER ASSESSMENTS...................................................................................84
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................85
6.
INVESTIGATIONAL PLAN.............................................................................85
6.1
VISIT SCHEDULE.............................................................................................85
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................86
6.2.1
Screening and run-in period(s)..........................................................................86
6.2.2
Treatment period(s)............................................................................................87
6.2.3
Follow-up period and trial completion..............................................................87
6.2.3.1
30-day and 90-day safety follow-up visits............................................................88
6.2.3.2
Follow-up visit......................................................................................................88
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................88
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................94
7.2
PLANNED ANALYSES.....................................................................................94
7.2.1
General considerations .......................................................................................94


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7.2.2
Primary endpoint analyses.................................................................................94
7.2.3
Secondary endpoint analyses .............................................................................95
7.2.5
Safety analyses.....................................................................................................96
7.2.6
Other analyses .....................................................................................................96
7.2.7
Interim Analyses .................................................................................................97
7.3
HANDLING OF MISSING DATA ...................................................................97
7.4
RANDOMISATION ...........................................................................................98
7.5
DETERMINATION OF SAMPLE SIZE .........................................................98
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........98
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................98
8.2
DATA QUALITY ASSURANCE ......................................................................99
8.3
RECORDS...........................................................................................................99
8.3.1
Source documents .............................................................................................100
8.3.2
Direct access to source data and documents...................................................101
8.3.3
Storage period of records .................................................................................101
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................101
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......101
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................102
8.6
TRIAL MILESTONES.....................................................................................102
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................103
9.
REFERENCES..................................................................................................104
9.1
PUBLISHED REFERENCES..........................................................................104
9.2
UNPUBLISHED REFERENCES....................................................................107
10.
APPENDICES...................................................................................................108
10.1
IMMUNE-RELATED ADVERSE EVENTS .................................................108
10.1.1
Immune related adverse events of special interest.........................................108
10.1.2
Management of immune-related adverse events............................................110
10.2
MANAGEMENT OF CRS...............................................................................119
10.3
TUMOUR ASSESSMENTS.............................................................................121
10.3.1
Injected lesions ..................................................................................................123
10.3.2
Non-injected lesions ..........................................................................................124
10.3.2.1
Target non-injected (T-NI) lesions .....................................................................124
10.3.2.2
Non-target non-injected (NT-NI) lesions............................................................125
10.3.2.3
Confirmation of response....................................................................................125
10.4
PHARMACOKINETIC METHODS AND ANALYSES..............................125
10.5
STATISTICAL APPENDIX............................................................................126
11
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................146
11.1
GLOBAL AMENDMENT 1 ...........................................................................146
11.2
GLOBAL AMENDMENT 2 ...........................................................................156


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11.3
GLOBAL AMENDMENT 3 ...........................................................................162
11.4
GLOBAL AMENDMENT 4 ...........................................................................169
11.5
GLOBAL AMENDMENT 5 ...........................................................................175


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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original and Accurate
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
activated Partial Thromboplastin Time
ASBMT
American Society for Blood and Marrow Transplantation
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point Area under the 
Curve
BHM
Bayesian Hierarchical Model
BI
Boehringer Ingelheim
BiPAP
Bilevel Positive Airway Pressure
BLQ
Below the Limit of Quantification
BLRM
Bayesian Logistic Regression Model
CA
Competent Authority
CDN
Cyclic dinucleotide
CI
Checkpoint inhibitor
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology
Cmax
Maximum measured concentration of the analyte in plasma
CPAP
Continuous Positive Airway Pressure
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRS
Cytokine Release Syndrome
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events


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CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DHEA
Dehydroepiandrosterone
DILI
Drug Induced Liver Injury
DLT
Dose limiting Toxicity
DMARD
Disease modifying anti-rheumatic drugs
DNA
Deoxyribonucleic Acid
LV dp/dtmax
Decrease in contractility
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoT
End of Treatment
EoTrial
End of Trial
EudraCT
European Clinical Trials Database
EWOC
Escalation With Overdose Control
FC
Flow Chart
FFPE
Formalin-Fixed Paraffin-Embedded
FIH
First in Human
FUP
Follow-up
GCP
Good Clinical Practice
GEP
Gene Expression Profiling
GMP
Good Manufacturing Practice
HA
Health Authority
HCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HCO3
Bicarbonate
i.v.
intravenous


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IB
Investigator’s Brochure
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IFN
Interferon
IgG4
Immunoglobulin G4
IHC
Immunohistochemistry
IL-6
Interleukin-6
IL6R
Interleukin 6 Receptor
IL-8
Interleukin-8
INR
International Normalized Ratio
irAE
Immune-related Adverse Event
IRB
Institutional Review Board
iRECIST
Immunotherapy Response Evaluation Criteria in Solid Tumours
IRR
Infusion related reactions
IRT
Interactive Response Technology
ISF
Investigator Site File
itRECIST
Response Criteria for Intratumoural Immunotherapy in Solid Tumours
i.tu.
Intratumoural
LDH
LOCS III
Lactate Dehydrogenase
Lens Opacities Classification System III
LPLT
Last Patient Last Treatment
LPLV
Last Patient Last Visit
mAb
Monoclonal Antibodies
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum tolerated dose
MUGA
Multigated Acquisition
NC
Not Calculated
NOA
Not Analysed
NOR
No Valid Result
NOS
No Sample Available


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NYHA
New York Heart Association
OD
Over Dose
OPU
Operative Unit
OR
Objective Response
ORR
Objective Response Rate
PD
Progressive Disease
PD-1
Programmed Cell Death-1
PD-L1
programmed Death-Ligand 1
PET
Positron emission tomography
p.o.
per os (oral)
PK
Pharmacokinetics
PT
Prothrombin time
PLT
Platelet
RA
Regulatory Authority
RBC
Red Blood Cell
RD-P2
Recommended Dose Part 2
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RNA  
Ribonucleic Acid
RT
Radiotherapy
SAE
Serious Adverse Event
SC
Steering Committee
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
STING
Stimulator of Interferon Genes
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Target Dose
TIL
Tumour-infiltrating Lymphocyte
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TMB
Tumour Mutational Burden
TMF
Trial Master File
TNM
Tumour, (lymph) Node, and Metastasis


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TSAP
Trial Statistical Analysis Plan
TSH
Thyroid Stimulating Hormone
UD
Under Dose
ULN
Upper Level of Normal
WBC
White Blood Cell
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Despite the recent advancements in cancer treatment, cancer remains a leading cause of death 
globally. In the United States (US), approximately 1,762,450 new cancer cases were expected 
to be diagnosed in 2019. The American Cancer Society estimated that there would be 
approximately 606,880 deaths due to cancer in the US during 2019 [R19-0312]. In particular 
if the disease is diagnosed in late, advanced stages, or after disease progression on available 
treatments, the prognosis of patients is poor and the vast majority succumb to their disease. 
Therefore, there is a substantial need for novel therapeutic agents and treatment strategies to 
improve the treatment outcome for cancer patients. 
The STING pathway has been identified as a key innate immune sensing pathway to detect 
the presence of cytosolic cyclic dinucleotides derived from microbial invasion and self-DNA 
leakage. Mice deficient in the STING pathway show blunted type I IFN production, reduced 
anti-tumour T cell priming, and fail rejection of immunogenic tumours [R19-0315].
STING is an intracellular pattern recognition receptor expressed in various endothelial and 
epithelial cell types, as well as in hematopoietic cells such as T cells, macrophages and 
dendritic cells, including plasmacytoid dendritic cells. It stimulates the transcription of 
numerous genes involved in immune response, such as the type I interferons [R19-0314] and 
other proinflammatory cytokines, and through cross-priming by antigen presenting cells may 
lead to an adaptive antitumour immune response against tumour antigens, a concept which 
has previously been described as 'in-situ vaccination' [R19-0317].
The STING pathway plays a key role in spontaneous or treatment induced cancer immune 
response, and activation of this pathway is considered to induce or augment an anti-tumour
immune response [R19-0506, R19-0674]. Intratumoural administration of STING agonists 
has resulted in remarkable therapeutic activity in animal models [R19-0316].
Activity of STING agonists was also observed in patients when used as single agent, and 
more pronounced when used in combination with a PD1-antibody [R19-0608, R19-0623].
1.2
DRUG PROFILE
1.2.1
BI 1387446
Mode of action
STING is a pattern recognition receptor that detects cytosolic nucleic acids and transmits 
signals that activate type I interferon (IFN) responses. It is localized in the endoplasmic 
reticulum. Double stranded DNA derived from either dying tumour cells or pathogens binds 
and activates the enzyme cyclic GMP-AMP Synthase (cGAS) which then generates cyclic di-
nucleotides (CDNs) which bind to and activate STING. The naturally occurring CDN 
cGAMP and the synthetic CDN BI 1387446 induce a conformational change in STING 
homo-dimers that allows the binding and activation of the interaction partner tank binding 




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release profile for BI 1387446 in combination with tocilizumab was assessed in Cynomolgus 
monkeys. A marked increase in plasma levels of cytokines was observed when tocilizumab 
was administered 24 hours prior to BI 1387446 compared to BI 1387446 monotherapy, while 
no relevant effect was observed when animals were treated with tocilizumab 6h post BI 
1387446.  For details, refer to the Investigator’s Brochure.
Data from clinical studies
This is the first trial in human and therefore no clinical data is available.
For a more detailed description of the BI 1387446 profile, refer to the current Investigator’s 
Brochure (IB) [c26065921].
1.2.2
Ezabenlimab (BI 754091)
Mode of action
Ezabenlimab (BI 754091) is a humanised IgG4Pro isotype anti PD 1 mAb being developed as 
an i.v. infusion for the treatment of cancer. Ezabenlimab (BI 754091) has highly human 
frameworks and a low predicted immunogenicity score. The ezabenlimab (BI 754091)
molecule has a molecular weight of approximately 148 kilodaltons. 
Ezabenlimab (BI 754091) shows strong anti-tumour effects in several mouse tumour models. 
Single and repeat dosing studies showed that ezabenlimab (BI 754091) was well tolerated (as 
judged by body weight changes and clinical signs) and resulted in significant tumour growth 
inhibition (≥83%).
REP of ezabenlimab (BI 754091) is 30 days. 
Data from clinical studies
Ezabenlimab (BI 754091) is currently being tested in patients in several BI-sponsored clinical 
trials, e.g. 1381-0001, 1381-0002. The dose of 240 mg ezabenlimab (BI 754091) once every 
3 weeks was taken forward into the expansion portion of the Trial 1381-0001 trial and is 
considered the recommended phase II dose for ezabenlimab (BI 754091).
A total of 139 patients have been dosed with ezabenlimab (BI 754091) in clinical trials, 56 
patients with monotherapy ezabenlimab (BI 754091), and 83 patients with ezabenlimab (BI 
754091) plus BI 754111. At the data cut-off, there were no DLTs or Grade 5 AEs 
experienced by any patient on monotherapy treatment. The overall most common AEs for 
patients treated with monotherapy ezabenlimab (BI 754091) were fatigue, nausea, and 
decreased appetite. Thirteen of the 56 patients on monotherapy ezabenlimab (BI 754091)
experienced immune related adverse events (irAEs) of rash, maculo-papular rash, colitis, 
diarrhoea, hypothyroidism, increased ALT, increased AST, arthralgia, pneumonitis, and 
pruritus. There were one ≥ Grade 3 irAE (Grade 3 increased AST) experienced by patients in 
the monotherapy population.
For a more detailed description of the ezabenlimab (BI 754091) profile, refer to the current 
IB [c07895879].




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In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (refer to Section 5.5). If the patient agrees, banked samples 
may be used for future biomarker research and drug development projects, e.g. to identify 
patients that are more likely to benefit from a treatment or experience an adverse event (AE), 
or to gain a mechanistic or genetic understanding of drug effects and thereby better match 
patients with therapies. Banking will be limited to samples left over after primary analysis. 
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Most patients with metastatic or recurrent malignancies will succumb to their disease. Thus, 
there is a substantial need for novel therapeutic strategies to improve the outcome for patients 
with advanced or metastatic malignancies.
BI 1387446 in preclinical studies has led to shrinkage and complete disappearance of injected 
tumours in mice, durable antitumour memory, and growth inhibitory effects on non-injected 
tumours. Intratumoural activation of the STING pathway is considered to induce a de novo
anti-tumour immune response, leading to improved priming and activation of tumour-specific 
cytotoxic CD8+ T cells and increased CD8+ T cell infiltration into the tumour. Thus, STING 
agonists may be effective to treat tumours which are primarily non-responsive to checkpoint 
inhibitors as well as tumours with acquired resistance to checkpoint inhibitors.
Combination with an anti-PD1 antibody is considered indicated in relation to the mode of 
action, i.e. to counteract IFN-mediated PD-L1 expression and maintain CD8+T-cell 
activation.
1.4.2
Risks
BI 1387446 is a CDN targeting the STING receptor, which has not been tested in humans 
before. The risks of treatment have been evaluated based on the expected effects of 
 intratumoural STING pathway activation, the nonclinical in vivo and toxicology 
data, and available clinical data on other compounds targeting the STING pathway.
Based on the mode of action and available non-clinical data for BI 1387446, and considering 
the route of administration, the main potential risks associated with this drug are presumed to 
be:
•
cytokine release syndrome
•
procedural risks from intratumoural application
•
immune-related adverse events
•
decrease in cardiac contractility
Based on non-clinical data, a potential risk is supposed to be: 

eye lens toxicity 
Published clinical data indicate that STING agonists are well tolerated when injected 
intratumourally into superficial lesions. MK-1454 demonstrated a manageable toxicity profile 
in patients with advanced malignant tumours as monotherapy and combination with 


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pembrolizumab. The most common treatment-related AEs in ≥10% of patients included 
pyrexia, chills, fatigue, and injection site pain, which in most patients were grade 1 and 2 
severity [R19-0609, R19-0623]. For ADU-S100 monotherapy, the most common AEs in 
≥10% of patients were injection site pain, headache and pyrexia [R19-0608].
General safety measures for this FIH trial include:
•
sequential enrolment of patients into a single cohort (Section 3.1.1)
•
sequential start of cohorts at the same dose of BI 1387446 (Section 3.1.1)
•
sequential start of backfill enrollment (Section 3.1.1)
•
mandatory surveillance of patients (Sections 4.1.4.5 and 4.1.4.6)
The trial will be monitored by a Safety Monitoring Committee (SMC). The SMC will be 
chaired by an Investigator with experience in early clinical trials, and will be composed of 
Investigators/delegates from participating investigational sites and the sponsor. For details 
refer to the SMC charter and Section 8.7.
Cytokine release syndrome
Following intratumoural injection of BI 1387446 in animal models, a type I interferon 
response was elicited in the injected tumour and a transient increase in cytokines was 
detectable in plasma, with peak values around 
 post injection. The half life in plasma 
 In ongoing clinical trials with other STING agonists, fever was detected as a 
cytokine mediated symptom and may be classified as cytokine release syndrome (CRS) grade 
1, but no CRS of higher grade with hypotension or hypoxia was reported. Risk mitigation 
measures include recommendations for prevention, early detection and treatment of CRS, e.g.
•
guidance to avoid injection into lesions with high risk for accidental intravascular 
administration, e.g. lesions encasing or infiltrating major blood vessels, or 
subcapsular liver lesions (Section 4.1.4.2)
•
mandatory patient surveillance (Section 4.1.4.5)
•
recommendations for management of CRS (Section 4.1.4.6)
•
assessment of adverse events, PK and blood cytokine data in regular intervals by 
the SMC
Immune-related adverse events
Immune-related AEs as defined in Appendix 10.1 will be captured as AESI and reviewed by 
the SMC in regular intervals throughout the trial. Recommendations for management are 
included in Appendix 10.1.2.
Procedural risks associated with intratumoural application and tumour biopsy
Injection of a drug using a needle is always associated with procedural risks. These include 
and are not limited to:
•
infection
•
bleeding
•
injury to tissues in the needle track, e.g. nerves, vessels, organs
•
reactions to local anesthesia if used, e.g. allergy, arrhythmia
•
other events (e.g. possible ulcerations (scarring after biopsy) or compression due 
to swelling)


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Risk mitigation measures to address procedural risks are:
•
selection of investigational sites with interventional radiology expertise and/or 
Investigators experienced in diagnostic biopsies and injection of drugs into tumour
lesions
•
risk adapted patient surveillance after intratumoural injection for early recognition 
of complications (Section 4.1.4.5)
•
exclusion of patients in whom the designated lesion for injection has a high risk 
for local complications, e.g. bleeding related to encasement/infiltration of major 
blood vessels or contact with liver capsule, compression of vital structures in case 
of swelling of injected lesion (Section 4.1.4.2)
Decrease in cardiac contractility
In a telemetry study in Cynomolgus monkeys, a decline in contractility measured as LV 
dp/dtmax was observed at doses from 
The decline in contractility was not 
associated with a decline in blood pressure or an increase in heart rate. 
Risk mitigation measures include
•
exclusion of patients with cardiac insufficiency NYHA grade III or IV or a left 
ventricular ejection fraction of < 50 % from the trial (Section 3.3.3).
•
detailed instructions for monitoring of vital signs (heart rate, blood pressure, 
Sections 4.1.4.5 and 4.1.4.6).
•
assessment of cardiac biomarkers (e.g. troponin, natriuretic peptide, Section 5.2.3) 
•
assessment of cardiac function by left ventricular ejection fraction (Section 5.2.4)
Eye lens toxicity
In a repeated dose toxicity study in C57Bl/6 mice, increased incidences of diffuse 
subcapsular opacities in the anterior lens region were observed in males at 
 
cycle and in females at 
 cycle at the end of treatment. Due to the 
absence of any histopathological findings in the lenses of all treated animals, the fact that 
spontaneous ocular pathologies are well known for C57Bl/6 mice (R19-0517), and taking 
into account that cytokines may be secondarily elevated in various inflammatory ocular 
diseases, but have not been reported to induce direct lenticular changes, these lens opacities 
are not considered to be unequivocally test item-related.
Risk mitigation measures include

Exclusion of patients with absolute contraindications for cataract surgery

Assessment of lens opacity using slit-lamp by an ophthalmologist at screening, at the 30-
day safety follow-up, and at any time during the treatment period, if clinically indicated
(refer to Section 5.2.6).
BI 1387446 in combination with ezabenlimab (BI 754091)
Combination of ezabenlimab (BI 754091) and BI 1387446 may lead to an increased rate and 
severity of irAEs compared to either drug alone, as is documented for combination of 
checkpoint inhibitors. 
Preclinical data suggest that ezabenlimab (BI 754091) does not potentiate BI 1387446 
mediated cytokine release. CRS to BI 1387446 and IRRs to ezabenlimab (BI 754091) may be 




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1.4.3
Discussion
A number of safety measures to mitigate possible risks are implemented in this trial. Patients 
with advanced and/or metastatic malignancies may possibly benefit from treatment with 
BI 1387446, and possibly even more from the combination of BI 1387446 and ezabenlimab 
(BI 754091). Possible benefit of trial treatments is expected to outweigh the risks in patients 
with advanced solid tumours who have exhausted treatment options.
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
Characterize the safety and determine the maximum tolerated dose (MTD) for BI 1387446 as 
single agent and for BI 1387446 in combination with ezabenlimab (BI 754091). Obtain a 
preliminary efficacy signal.
2.1.2
Primary endpoint(s)
•
MTD based on number of Dose-limiting toxicities (DLTs) (for definition of MTD 
refer to Section 7)
•
Number of patients with DLT in the MTD evaluation period
Time frame: Arms A, B From start of treatment until end of cycle 1 (3 weeks, MTD 
evaluation period)
2.1.3
Secondary endpoint(s)
•
Objective response based on Response Criteria for Intratumoural Immunotherapy
in Solid Tumours (itRECIST)
•
Best percentage change from baseline in size of injected target lesions
•
Best percentage change from baseline in size of non-injected target lesions
Time frame for all secondary endpoints: From start of treatment until the earliest of 
progression, death or end of trial (approximately 1 year).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This study will consist of 3 arms, which will recruit patients in parallel with a clear 
predefined hierarchy for slot allocation (Section 3.1.2).
•
Arm A: Dose escalation of BI 1387446 as single agent administered 
intratumourally into superficial lesions
•
Arm B: Dose escalation of BI 1387446 administered intratumourally into 
superficial lesions, in combination with ezabenlimab (BI 754091) intravenously
Trial overview is shown in below Figure 3.1: 1.
Figure 3.1: 1 Trial overview
This study will determine the MTD as well as the safety, PK, and pharmacodynamics of BI 
1387446 as monotherapy and in combination with ezabenlimab (BI 754091). 


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Arm A will determine the MTD for BI 1387446 intratumourally into superficial lesions as 
single agent. Patients with progressive disease may cross over to Arm B after completion of 
cycle 1, provided that Arm B is open for recruitment. 
Arm B will determine the MTD for BI 1387446 intratumourally into superficial lesions in 
combination with ezabenlimab (BI 754091). 
Arms A and B will investigate the safety, PK, and pharmacodynamics of BI 1387446 
monotherapy (Arm A) or BI 1387446 in combination with ezabenlimab (BI 754091) (Arm 
B).
Arms A and B will start in a staggered manner (refer to Section 3.1.1).
To acquire additional data to more fully inform dose selection, additional patients may be 
enrolled to backfill cohorts at dose levels that have been previously cleared (refer to Section 
3.1.1).
Dose escalation will be guided by Bayesian logistic regression modelling with overdose 
control: In Arm A and B, dose escalation will be guided by a BLRM using a hierarchical 
modelling approach to jointly model both arms. The data obtained from both arms will 
determine the MTD estimate per arm based on a BLRM employing an escalation with 
overdose control (EWOC) principle [R13-4803].  
The BLRM estimates the MTD by updating estimates of the probability of observing a DLT 
in the MTD evaluation period (first treatment cycle including echocardiographic/MUGA scan 
measurements acquired on Day 1 of Cycle 2 and related findings) for each dose level in the 
trial as patient information becomes available. At any time in the trial, it will not be permitted 
to escalate to a dose which does not fulfil the EWOC criterion (refer to Section 7).
The trial will be monitored by a SMC which will convene for each dose escalation decision. 
The SMC will assess for each dose cohort if dose escalation to the next dose level is possible 
based on DLTs in the MTD evaluation period, AEs, and safety laboratory data. DLTs and 
AEs reported in later cycles of patients enrolled in previous dose cohorts will be considered 
in addition. After the patients in a dose cohort have either experienced a DLT or have been 
observed for at least the MTD evaluation period without experiencing a DLT, the BLRM will 
be updated with the newly accumulated data. In particular, during dose escalation, the BLRM 
will be evaluated after the occurrence of each DLT before enrolling any further patients.
The SMC may recommend stopping the dose escalation after the criterion for MTD (refer to 
Section 7) is fulfilled. The RP2D will not exceed the MTD and will not exceed the highest 
dose investigated during dose escalation.


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3.1.1
Sequence of treatment arms and cohorts
A dose level of BI 1387446 will always be explored as single agent first. Only once 
determined to be safe as single agent, this dose of BI 1387446 will be used in combination 
with ezabenlimab (BI 754091), always lagging at least one dose level behind when 
administered in combination with BI 754091.
Figure 3.1.1: 1
Sequence of cohorts. BI446: BI 1387446, PD1: ezabenlimab (BI 754091).
Patients with progressive disease on BI 1387446 monotherapy (Arm A) may cross over to the 
combination (Arm B) after completion of cycle 1 and will be treated at the highest dose level 
declared to be safe by the SMC at this time. These patients will continue treatment in 
combination by re-starting treatment at Cycle 1 Day 1 in Arm B. These patients will be 
analysed in Arm A as long as treated with monotherapy. Instead of completing the REP after 
monotherapy, patients may cross over to Arm B without repetition of all screening 
procedures, but will have to undergo a limited set of assessments as specified in Section 
6.2.1. A minimum interval of 7 days must have elapsed between last dose of BI 1387446 in 
Arm A and first dose of ezabenlimab (BI 754091) or BI 1387446 in Arm B. Cross-over 
patients will be included together with other ‘backfill patients’ (patients enrolled to backfill 
cohorts at dose levels that do not exceed the MTD, see Section 3.1.2 for details) in the safety 
and efficacy assessment in Arm B, but will not be considered for the main analysis of the 
MTD. For the main analysis of the MTD, cross-over patients will only be included while 
being treated with BI 1387446 monotherapy in Arm A. However, cross-over patients will be 
included in the sensitivity analyses of the MTD and thus be considered in addition (refer to
Section 7 for details).
Arm B will open at the starting dose level once the starting dose level in Arm A is considered 
safe by the SMC. 




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Treatment start of individual patients within the same cohort
For all patients enrolled into a cohort required for DLT assessment, a minimum time period 
has to be elapsed between first treatment days of subsequent patients. In the first dose level in 
each arm, the second patient can receive the first dose of trial drug the earliest 7 days after the 
first patient has been dosed. For the second and all subsequent dose levels in a single 
treatment arm, a minimum of 3 days is required between the first dose to the first and second 
patient. For all subsequent patients prior to dose escalation in this arm, a 2 day interval is 
required. Only once a dose level has been determined safe by the SMC, subsequent patients 
(‘backfill’) may be dosed at the same day on this dose level in the respective treatment arm.
In case of the occurrence of DLTs, the SMC may decide about intervals between enrollment 
of patients, if applicable.
Table 3.1.2: 1
Minimum intervals between first dose of trial drug given to 
subsequent patients within the same cohort.
Dose
Patient 2
subsequent pts (prior 
to SMC/cohort safe)
subsequent pts 
(‘backfill’, post 
SMC/cohort safe)
Level 1
+7 days
+2 days
any time
Level ≥2
+3 days
+2 days
any time
3.1.3
Definition of superficial lesions
During screening, a projected lesion for injection needs to be selected. 


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Table 3.1.3: 1 
Definition of superficial lesions
Definition
injected lesion outside of a body 
cavity
Location
skin
subcutaneous
intramuscular
chest wall (without infiltration of 
visceral pleura)
abdominal wall (without 
infiltration of intraabdominal 
structures)
Location
superficial lymph nodes 
(cervical, supra-/infraclavicular, 
axillary/pectoral, epitrochlear/ 
brachial, inguinal, femoral, 
popliteal)
superficial organs (salivary 
glands, thyroid, parathyroid, 
breast)
Dose 
escalation arm
A, B
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Ezabenlimab (BI 754091) is expected to be required for efficacy due to the upregulation of 
PD-L1 following STING activation. This expectation is supported by internal and published 
preclinical data as well as clinical data on MK-1454 as monotherapy and in combination with 
pembrolizumab. Preclinical data for ADU-S100 indicate that the dose response relationship 
may be non-linear, possibly resulting in a decline in efficacy on non-injected lesions at higher 
doses. Thus, early combination with ezabenlimab (BI 754091) during dose finding is 
considered important for selection of a recommended dose for further development of BI 
1387446.
In addition, a flexible enlargement of cohorts which have been confirmed to be safe by the 
SMC, the so called ‘backfill’ concept will be used to generate sufficient data at lower dose 
levels which appear relevant for dose selection and may only be identified during trial 
conduct.
BI 1387446 by its mode of action will increase cytokines, and thus has a potential risk to lead 
to cytokine release syndrome. Although there has been no increase of cytokines in preclinical 


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models for combination of BI 1387446 and ezabenlimab (BI 754091) compared to BI 
1387446 alone, the trial design will ensure that a dose of BI 1387446 can only be tested in 
combination with ezabenlimab (BI 754091) if the same or a higher dose has been confirmed 
safe as monotherapy.
Dose escalation and cohort size will be determined based on the recommendation of the 
SMC, guided by a BLRM with overdose control. An escalation with overdose control design 
will increase the chance of treating patients at efficacious doses while reducing the risk of 
overdosing. This design is based on practical experience and is an efficient method due to its 
ability to identify the dose with a desired toxicity rate and its allocation of a greater 
proportion of patients to doses at, or close to, that desired dose [R13-4802, R13-4804, R13-
4805]. The use of Bayesian models for Phase I studies has also been advocated by the EMA 
guideline on small populations [R07-4856] and by the FDA [R13-4881].
3.3
SELECTION OF TRIAL POPULATION
A total of approximately 78 patients may be treated in this trial, which will be conducted at 
about 6 sites in Europe, the United Kingdom, and the United States. Each site is expected to 
enrol on average approximately 10-20 patients.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is determined eligible in error (does not meet all inclusion criteria or meets one or 
more exclusion criteria on the day of enrolment), the sponsor should be contacted 
immediately.
3.3.1
Main diagnosis for trial entry
Patients with malignant solid tumours will be eligible for this trial.
Refer to Section 8.3.1 for the documentation requirements pertaining to the in- and exclusion 
criteria.
3.3.2
Inclusion criteria
1. At least 18 years of age at the time of consent or over the legal age of consent in countries 
where that is greater than 18 years.
2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
If a patient declines to participate in the voluntary pharmacogenetics component of the 
trial, he/she will not be excluded from other aspects of the trial.
3. Male or female patients. Women of childbearing potential (WOCBP) [defined as a 
woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 


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methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause]  and men able 
to father a child 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, during trial participation and for at least 6 months after the last 
administration of trial medication. A list of contraception methods meeting these criteria 
is provided in Section 4.2.2.3.
4. Eastern Cooperative Oncology Group score of 0 or 1 [R01-0787].
5. Life expectancy of at least 12 weeks after the start of the treatment according to the 
Investigator’s judgement.
6. Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or 
metastatic malignant solid tumour and indication for treatment
7. Patient must have exhausted established treatment options known to prolong survival for 
the malignant disease, or is not eligible for established treatment options.
8. Medically fit and willing to undergo all mandatory trial procedures.
9. At least one tumour lesion which is suitable for injection (Section 4.1.4.1, 
Screening/initial administration), appropriate for the allocated treatment arm (Section 
3.1.3), and measurable as defined in Section 10.3.
10. At least 1 discrete lesion, in addition to the lesion proposed for injection, which is 
amenable to biopsy and is not located in the brain, mediastinum or pancreas.
11. Adequate organ function or bone marrow reserve as demonstrated at screening by the 
following laboratory values:
a.
absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1.5 x 103/µL, ≥ 1,500/mm3)
b. platelet count ≥ 100 x 109/L (≥ 100 x 103/µL, ≥ 100 x 103/mm3)
c.
haemoglobin ≥ 90 g/L (≥9.0 g/dL, ≥5.6 mmol/L)
d. total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except for patients with 
Gilbert’s syndrome: total bilirubin ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN.
e.
alanine aminotransferase (ALT)/Aspartate aminotransferase (AST): 
-
patients without liver metastases: ALT/AST ≤2.5 x ULN  
-
patients with liver metastases with planned injection into liver lesion: 
ALT/AST ≤2.5 x ULN
-
patients with liver metastases without planned injection into liver lesions: 
ALT/AST ≤ 5 x ULN
f.
Creatinine ≤ 1.5 x ULN. If creatinine is > 1.5 x ULN, patient is eligible if concurrent 
creatinine clearance ≥45 ml/min (≥ 0.045 L/min) (measured or calculated by CKD-
EPI formula).    1
g. prothrombin time (PT) ≤ 1.5 x ULN
h. activated partial thromboplastin time (aPTT) ≤1.5 x ULN
3.3.3
Exclusion criteria
1. Any investigational or antitumour treatment (including antibodies targeting PD1- or PD-
L1) within 4 weeks or 5 half-life periods (whichever is shorter) prior to the initial 
administration of BI 1387446 or ezabenlimab (BI 754091).


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2. Persistent toxicity from previous treatments (including irAEs) that has not resolved to ≤ 
Grade 1, except for alopecia, xerostomia, and immunotherapy related endocrinopathies 
which may be included if clinically stable on hormone supplements or antidiabetic drugs
as per Investigator judgement
3. History or evidence of active, non-treatment related autoimmune disease, except for 
endocrinopathies which may be included if clinically stable on hormone supplements or 
antidiabetic drugs. 
4. History or evidence of pneumonitis related to prior immunotherapy
5. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 
2 weeks prior to the first dose of BI 1387446 or ezabenlimab (BI 754091).
6. The tumour at the projected injection site has a high risk for local complications, e.g.
bleeding related to encasement/infiltration of major blood vessels or contact with liver 
capsule, compression of vital structures in case of swelling of injected lesion, in the 
opinion of the Investigator (see Section 4.1.4.2).
7. Presence or history of uncontrolled or symptomatic brain or subdural metastases, unless 
local therapy was completed and metastases considered stable by the Investigator
8. Presence of other active invasive cancers other than the one treated in this trial within 5 
years prior to screening, with the exception of appropriately treated basal-cell carcinoma 
of the skin, in situ carcinoma of the uterine cervix, or other local tumours considered 
cured by local treatment.
9. Known history of human immunodeficiency virus (HIV) infection.
10. Active infection requiring systemic therapy at the start of treatment in the trial, including 
active viral hepatitis infection or active tuberculosis infection.
11. Has received a live vaccine within 30 days prior to first dose of BI 1387446.
12. Cardiac insufficiency NYHA III or IV
13. Left ventricular ejection fraction < 50% measured by echocardiography or MUGA scan 
14. Significant resting ECG abnormalities defined as ventricular tachyarrhythmias, presence 
of unstable atrial fibrillation (defined as ventricular response >100 bpm), significant 
bradycardia (defined as a heart rate of <50 bpm), complete left bundle branch block, right 
bundle branch block and left anterior hemiblock, third degree AV block, or a mean 
resting corrected QT interval (QTc) >470 msec
15. History of severe hypersensitivity reactions to mAbs
16. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial in the 
opinion of the Investigators.
17. a. Arm C: Patients on therapeutic doses of anticoagulants (see section 4.2.2.1). This 
criterion was effective through Clinical Trial Protocol Version 3.0 (26-May-2021) only.
b. For Arm C, radiation therapy of the lesion proposed for injection within 6 months of 
initial administration of BI 1387446. This criterion is effective starting with Protocol 
Amendment, Clinical Trial Protocol Version 4.0.
c.
Starting with this Protocol Amendment, Clinical Trial Protocol Version 5.0, Arm C 
has been removed and this criterion is no longer applicable.
18. Chronic alcohol or drug abuse
19. Major surgery (major according to the Investigator’s assessment) performed within 4 
weeks prior to first trial treatment.


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20. Any pre-existing or concurrent disease or condition that, in the Investigator’s opinion, 
would compromise patient safety, poses an undue risk to the patient, makes him/her an 
unreliable trial subject, unlikely to complete the trial, or unable to comply with the 
protocol procedures.
21. Women who are pregnant, nursing, or who plan to become pregnant or nurse during the 
trial or within 6 months after the last dose of study treatment.
22. Presence of any absolute contraindications to cataract surgery
23. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
including congenital long QT syndrome, family history of sudden unexpected death from 
cardiac related causes, myocardial infarction or major cardiac surgery within 3 months 
prior to enrollment, history or presence of uncontrolled hypertension (>150 mmHg 
systolic or >100 mmHg diastolic bp)
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; refer to Sections 3.3.4.1 and 
3.3.4.2.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (refer to Sections 5.2.7.2.1 and 
5.2.7.2.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the Investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment (Refer to Section 4.2.2.1).

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). Recurring radiologic disease progression
(Refer to Section 4.1.2.3). 


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
Adverse events requiring a permanent discontinuation of trial drugs, e.g.Cytokine release 
syndrome Grade ≥3Infusion-related reaction to ezabenlimab (BI 754091) Grade ≥3Drug-
related AE not recovering to G1/baseline within 12 weeks
o
More than 2 dose reductions of BI 1387446 would be required for management of 
AEs
o
Immune-related AEs requiring permanent treatment discontinuation as per Section 
10.1.2.

If the patient experiences an infection with SARS-CoV-2 (as confirmed in accordance 
with local practice/accepted guidelines, see Section 5.2.3), the patient may resume trial 
treatment following recovery from SARS-CoV-2 infection if the patient is expected to 
derive clinical benefit, as agreed between the investigator and sponsor.
Patients in a dose cohort needed to make a dose escalation decision will be replaced in case 
they discontinued early during Cycle 1 for non-safety related reasons (e.g. unable to attend 
the protocol defined visits for to personal reason, refer to Section 3.3.4.4 below), or trial 
disruption e.g., measures to control the spreading of COVID-19. These patients will be 
replaced until the minimum number of patients required for evaluation is reached.
In case of a temporary reason for trial disruption, trial treatment should be restarted if 
medically justified, refer to see Section 4.1.4.3.
Even if the trial treatment is discontinued, the patient without disease progression remains in 
the trial and, given his/her agreement, will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in the Flow Chart and Section 6.2.3.
If a patient should become pregnant during the trial, the treatment with BI 1387446 and 
ezabenlimab (BI 754091) (where applicable) must immediately be stopped. The patient will 
be followed up until delivery or termination of pregnancy (see Section 5.2.7.2.3 for 
information on pregnancy forms). The data of the patient will be collected and reported in the 
eCRF until the last patient’s last visit and any events occurring thereafter will be reported in 
the BI drug safety database.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the Investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, refer to see Section 3.3.4.1.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.


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2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. 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).
3.3.4.4
Replacement of patients
In Arms A and B, patients withdrawn during the MTD evaluation period for a reason other 
than having a DLT, or who miss any dose of study medication during the MTD evaluation 
period, or who miss the echocardiography/MUGA scan measurements acquired on Day 1 of 
Cycle 2 ), are not evaluable for the MTD determination. These patients will be replaced if not 
decided otherwise by the SMC (e.g. because the number of evaluable patients for the current 
dose cohort is considered high enough for a dose escalation decision). Patients who
experience a DLT will not be replaced.
3.3.5
Discontinuation of trial enrolment by the sponsor
Boehringer Ingelheim reserves the right to discontinue enrolment of new patients in the trial 
at any time if the development of the compound is terminated. All patients that have signed 
the ICF by the time of development termination will continue with the treatment plan as 
originally specified in the clinical trial protocol.
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristic of test products are given in below.




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Table 4.1.1:3
Ezabenlimab (BI 754091)
Substance:
Ezabenlimab (BI 754091)
Pharmaceutical formulation:
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
Administration of the assigned doses on specific 
treatment days within treatment cycles of 
 
duration (see Section 4.1.2.3 for details)
Mode of administration:
intravenous infusion (i.v.)
4.1.2
Selection of doses in the trial and dose modifications
4.1.2.1
BI 1387446
BI 1387446 will be administered intratumourally under visual inspection for visible skin 
tumours, or under imaging guidance, e.g. ultrasound, CT.
Starting dose
Based on toxicology studies, a starting dose of 
 day has been chosen for 
Arms A and B. For details, refer to the IB [c26065921]. 
Maximum dose
The maximum dose for BI 1387446 being tested in this trial will be 
4.1.2.1.1
Dose escalation scheme
The starting dose for BI 1387446 in Arms A and B is 
Dose escalation steps will be 
guided by a BLRM. Dose increments between subsequent dose levels in a dose escalation 
arm will not exceed 100%.
The provisionally planned dose levels to be assigned to separate cohorts of patients are listed 
in Table 4.1.2.1.1: 1. Intermediate or lower dose levels, depending on the number of DLTs 
observed in the trial may be investigated as long as they fulfil the EWOC criterion if agreed 
upon by the SMC.




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4.1.2.3
Treatment schedule 
Patients will receive either BI 1387446 as single agent (Arm A) or BI 1387446 in 
combination with BI 754091 (Arms B and C) as described in Table 4.1.2.3: 1 for Arm A, 
Table 4.1.2.3: 2 for Arm B.
All treatments will be administered in cycles of 
duration. 
Patients will continue treatment with the study drugs until progressive disease (PD) by 
RECIST, withdrawal of patient consent, an unacceptable toxicity occurs, or the maximum 
number of cycles of treatment are reached, whichever occurs first.
PD assessment will be based on itRECIST and refers to the overall response assessment 
including all injected and non-injected lesions. Overall PD assessment after initial 
progression is comparable to iUPD with iRECIST (the possibility of iTPD will not be 
considered in this study).
Treatment beyond initial radiological progression can only be administered if there is 

objective evidence of clinical benefit, 

absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease, 

absence of decline in ECOG performance status that can be attributed to disease 
progression, 

absence of tumour progression at critical anatomical sites (e.g., leptomeningeal 
disease) requiring urgent alternative medical intervention, and 

absence of significant, unacceptable or irreversible toxicities related to study 
treatment.
The maximum duration of treatment with BI 1387446 is 18 cycles, unless the patient has a 
partial response, in which case treatment may continue for cycles 19-34 after consultation 
with the sponsor. BI 1387446 has to be paused if there is no lesion suitable for injection any 
more, but may be re-started in the absence of PD if any lesion becomes suitable for injection 
again.
The maximum duration of treatment with ezabenlimab (BI 754091) (arm B only) is 34 
cycles.
Patients will be allowed to stay on treatment in the case of initial radiological PD, if the 
Investigator judges that it is in the patient’s best interest and the patient has signed an 
informed consent describing this circumstance. 






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The longest diameter of the proposed tumour lesion for injection (including lymph nodes) for 
a superficial lesion has to be ≥1 cm.
Repeat administration
Upon repeat administration, BI 1387446 should be administered preferably into the same 
lesion, as long as the lesion is suitable for injection (independent of size). In case other 
lesions than the primarily projected or selected lesion appear more suitable for injection than 
the previously selected lesion, BI 1387446 may be injected into a different lesion, as long as 
the new lesion is in line with the criteria as outlined above for screening/initial 
administration. 
If no lesion is suitable for injection, BI 1387446 may be paused and restarted as considered 
indicated if a lesion suitable for injection becomes available in the absence of progression. As 
long as patients continue receiving ezabenlimab (BI 754091), BI 1387446 may be re-started 
independent of the duration of the interruption. In case both trial drugs need to be paused, the 
treatment may only be resumed if the treatment interruption is ≤12 weeks. 
Initial and repeat administration
If more than one lesion qualify for injection, the lesion which is safest to inject should be 
selected first. In case two or more lesions are considered equally safe by the Investigator, the 
largest lesion should be selected for injection first. Lesions considered high risk for local 
complications should not be selected for injection (Section 4.1.4.2).
A single dose should preferably be injected into one lesion. The injection volume (Section 
4.1.2.1.2) should be distributed across the tumour volume as much as possible by moving the 
needle within the tumour. In case the smallest possible volume as per Table 4.1.2.1.2: 1
cannot be injected into a single lesion and a second lesion qualifying for injection in the 
respective treatment arm is available, the dose may be distributed into up to two lesions.
4.1.4.2
Restrictions for lesion selection – BI 1387446
Lesions considered high risk for local complications should not be selected for injection. This 
includes tumours with 

encasement or suspected infiltration of major blood vessels, 

lesions located adjacent to vital structures which would be functionally impaired by 
swelling of injected lesion, e.g. trachea, carotid artery
4.1.4.3
Dose reductions and dose delays
As a general rule, any SAEs/AEs of ≥ Grade 3 will result in a pause of treatment with 
BI 1387446 and/or ezabenlimab (BI 754091) until resolution to baseline or Grade 1. 
In combination treatment arms, both drugs (BI 1387446 and ezabenlimab (BI 754091)) will 
be stopped, paused, or re-exposed together unless an AE can be attributed to either BI 
1387446 or ezabenlimab (BI 754091). Only if a causal relationship to one trial drug can be 
unequivocally established, the other trial drug may be continued.


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BI 1387446
Up to 2 dose reductions of BI 1387446 are allowed if the treatment pause due to an AE is ≤12 
weeks and the re exposure is considered clinically indicated by the Investigator.
Dose reductions will be only permitted to doses previously explored in lower dose levels. In 
case of re-occurrence or worsening of the same AE upon re-start of BI 1387446 at a lower 
dose, a second dose reduction of BI 1387446 is not permitted and BI 1387446 has to be 
permanently discontinued. Re-escalation to higher doses is not permitted. In case a third dose 
reduction would be required, treatment of that patient should be permanently discontinued. 
Treatment interruptions >12 weeks are only permitted for AEs not considered drug related 
and may be agreed on a case by case basis with the Sponsor.
Ezabenlimab (BI 754091)
Dose reductions or escalations of ezabenlimab (BI 754091) are not permitted. In case of 
adverse events, administration of ezabenlimab (BI 754091) should be delayed for up to 12 
weeks to permit recovery from adverse events. Treatment interruptions >12 weeks are only 
permitted for AEs not considered drug related and may be agreed on a case by case basis with 
the Sponsor.
Infusion-related reactions
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of ezabenlimab (BI 
754091) may be decreased by 50% or interrupted until resolution of the event and re-initiated 
at 50% of the initial rate until completion of the infusion. In patients experiencing infusion-
related reactions ≤ Grade 2, subsequent infusions may be administered at 50% of the initial 
rate. If an infusion-related reaction is Grade 3 or higher in severity at any point during the 
study, treatment with ezabenlimab (BI 754091) has to be permanently discontinued.
4.1.4.4
Dose limiting toxicity
DLTs will be recorded throughout the trial. Only DLTs starting in the first cycle of 
monotherapy (Arm A), or during the first cycle of BI 1387446 in combination with 
ezabenlimab (BI 754091) (Arm B) are required for dose-escalation decisions made by the 
SMC. DLT information from later cycles will be taken into consideration if applicable.
Any of the following AEs will be classified as DLTs unless unequivocally due to underlying 
malignancy or an extraneous cause:
A) Hematologic toxicity
1) any grade 5 toxicity
2) neutropenia grade 4 lasting for >5 days
3) neutropenia grade ≥3 with documented infection
4) febrile neutropenia
5) thrombocytopenia grade 4 
6) thrombocytopenia grade 3 with concomitant bleeding grade ≥2 (i.e. bleeding 
requiring intervention)


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B) Grade 4 anaemia


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C) Non-haematological toxicity
1) AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without 
initial findings of cholestasis (e.g. findings consistent with Hy's law or the FDA 
definition of potential DILI)
2) AST or ALT elevation grade ≥ 4
3) CRS grade ≥3
4) Any other ≥Grade 3 non-haematologic toxicity with the following exceptions:
a.
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with 
immunosuppressive therapy within 2 weeks
b. Grade 3 fatigue that persists <7 days
c.
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
d. Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated 
with clinical or radiographic evidence of pancreatitis
e.
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
intervention
f.
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤ Grade 1 
either spontaneously or with conventional medical intervention
g. Alopecia
h. Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) 
that are managed with or without systemic corticosteroid therapy and/or 
hormone replacement therapy, and the patient is asymptomatic.
i.
Grade 3 tumour flare syndrome
5) Pneumonitis Grade 2
6) Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 2 weeks or 
requires systemic treatment
7) Any Grade ≥2 toxicity that persists and results in a delay of >14 days of Cycle 2 
Day 1.
The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays, will be analysed to determine if a 
given toxicity not listed above should be considered a DLT for dose escalation purposes.
Late DLTs are AEs that meet the DLT criteria but occur on treatment after the completion of 
the initial MTD evaluation period (Arm A and B: Cycle 1, including 
echocardiographic/MUGA scan measurements acquired on Day 1 of Cycle 2 and related 
findings). If any late DLT is reported during dose escalation, the BLRM will be rerun using 
all DLTs, and updated results will be reviewed in the SMC meeting to recommend the next 
dose level and cohort size.


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4.1.4.5
Precautions and surveillance for procedural risks from intratumoural application
Needle insertion into a tumour lesion is associated with procedural risks known from 
diagnostic biopsy, e.g. infection, bleeding, injury to tissues in the needle track (e.g. nerves, 
vessels, organs), adverse reactions to local anesthesia if used.
BI 1387446 may only be administered by a physician who is experienced in diagnostic 
biopsy or intratumoural injection of immunotherapy drugs (physician, 
radiologist/interventional radiologist, or surgeon).
In case patient develops symptoms potentially indicating local complications, adequate 
surveillance and additional diagnostic measures need to be implemented as medically 
appropriate. A decline in Hgb by ≥2.0 g/dL (≥ 20 g/L, ≥ 1.24 mmol/L) must result in 
prolongation of surveillance by at least 4h including repetition of all assessments as per Table 
4.1.4.5: 1. Imaging should be performed as medically indicated for diagnosis of a bleed.
Table 4.1.4.5: 1
Duration of in-hospital patient surveillance needs to be adapted for 
procedural risks
Lesion location
Minimum 
duration of 
surveillance
Mandatory assessments
Superficial lesion
30 minutes
vital signs (depending on surveillance period, at 
least at 30 +/- 15 mins or 60 +/- 15 mins)
visual inspection of injection site
In case longer surveillance is mandated on selected visits for other reasons, e.g. risk 
mitigation of cytokine release syndrome (Section 4.1.4.6), the longest duration as defined per 
protocol at a given timepoint will apply.
4.1.4.6
Cytokine release syndrome
Patients will be closely monitored for CRS and, in case of suspected or confirmed CRS, have 
to receive appropriate and immediate treatment. All trial sites will have emergency 
resuscitation services and access to intensive care available.
Mandatory surveillance for CRS

Patients will remain under surveillance for 24 hours after the first administration of BI 
1387446 (STING agonist) on Cycle 1 Day 1.

Patients will remain under surveillance for at least 8 hours after the second and third 
administration of BI 1387446 on Cycle 1 

Patients will remain under surveillance for at least 8 hours on Cycle 2 Day 1.

Patient will remain under surveillance for at least 8 hours in Cycle 5 Day 1 of Arms A
and B.


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
Patient surveillance may be shortened on subsequent administrations as medically 
appropriate, considering the minimum duration as defined in Section 4.1.4.5, provided 
that no cytokine release syndrome was observed in the previous administration. 

In case a patient suffered from cytokine related symptoms at the previous BI 1387446 
injection, the surveillance at the subsequent administration needs to be prolonged to at 
least 8 hours.

Patients requiring steroids as premedication or requiring medication for symptoms of 
any kind (including any signs/symptoms concerning CRS) for any reason during the 
CRS surveillance periods will stay for observation and continue to be monitored for 
CRS for at least 24 hours after administration of BI 1387446
Monitoring of asymptomatic patients will include measurement of body temperature, heart 
rate, and blood pressure, at least every 2 hours. Parameters have to be captured in CRF. 
Those parameters will not only be used to capture the symptoms of CRS, but also be 
evaluated for signs of cardiac insufficiency. If more frequent assessments are chosen due to 
clinical symptoms, a representative selection of these additional assessments need to be 
captured in the CRF as well. Patients will be assessed for signs or symptoms of CRS (e.g.
fever, hypotension, tachycardia, hypoxia, nausea, fatigue, headache, myalgias, and malaise).
Patients will be informed about possible signs and symptoms of CRS, and the need to 
immediately contact or present to the investigational site if symptoms occur after discharge, 
or in case of urgency to another, closer hospital.
CRS grading should be performed according to American Society for Blood and Marrow 
Transplantation (ASBMT) consensus grading [R19-0309], organ toxicities in the context of 
CRS should be reported according to Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0. AEs of CRS Grade ≥2 are defined as AESIs. 
Treatment of CRS should be based on published recommendations and guidelines [R19-0310, 
R19-0311], the recommendations for treatment of CRS in Appendix 10.2 should be 
considered by the investigator as guidance. In general, in case more than symptomatic 
treatment is required, corticosteroids should be administered first. IL-6 targeting drugs should 
be used only once appropriate doses of corticosteroids did not result in adequate 
improvement or resolution. Pre-emptive administration of anti-IL6-therapy, e.g. use of 
tocilizumab or siltuximab prior to BI 1387446 injection or immediately thereafter without 
presence of clinical symptoms of CRS, is not permitted.
In patients with clinically manifested CRS, it is recommended to measure cytokines in the
local laboratory at onset of symptoms, approximately 24 hours, and 48 hours thereafter or 
upon discharge from hospitalization (whichever occurs earlier).
A patient with CRS grade 1 or 2 may be re-exposed to BI 1387446 and ezabenlimab (BI 
754091) at the subsequent planned administration timepoint provided that all symptoms have 
completely resolved for at least 48 hours.
Following a CRS grade 3 or 4, patients must not be re-exposed to the drug which is 
considered associated with the event. In case of uncertain causality assessment, both trial 


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drugs must be permanently discontinued. For details on management of trial drugs refer to
Appendix 10.2.
4.1.4.7
Management of immune-related AEs
Immune related AEs are expected with the use of ezabenlimab (BI 754091) and/or BI 
1387446, and need to be documented and managed according to Appendix 10.1 and 
published guidelines [P19-00269]. 
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This trial will be conducted as an open-label fashion.
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 Trial 
Manager (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The Investigator or designee will receive the investigational drugs delivered by the sponsor
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 and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority (CA),

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,


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
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. 
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 specified doses and reconcile all investigational medicinal 
products received from the sponsor. Unused and partially used trial drug will be destroyed on 
site according to local site procedure after relevant reconciliations have been completed.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Anticancer therapy
No other investigational therapy or anticancer agent should be given to patients. If such 
agents are required for a patient, then the patient must first be withdrawn from the trial.
Immunosuppressive medications
Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumour necrosis factor-alpha blockers are prohibited. Use of immunosuppressive medications 
for the management of investigational product-related AEs or in patients with contrast 
allergies is acceptable, and does not necessarily warrant immediate treatment discontinuation. 
In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injections (e.g.
intra-articular injection) is permitted. Temporary uses of corticosteroids for concurrent 
illnesses (e.g. food allergies, computed tomography (CT) scan contrast hypersensitivity) are 
acceptable upon discussion with the Sponsor.
For the treatment of CRS, supportive therapy including steroids, interleukin 6 receptor (IL6R) 
antagonists and IL6 antagonists may be used as clinically indicated.


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Vaccines
In Arm A, live attenuated vaccines are prohibited during the trial through 30 days after the 
last dose of BI 1387446. In Arm B, the use of live attenuated viruses has to be delayed until 
70 days after the last dose of ezabenlimab (BI 754091) or 30 days after the last dose of BI 
1387446, whichever comes later.
The decision on COVID-19 vaccination of a BI study patient must be taken based on an 
individual Benefit-Risk Assessment by the investigator after thorough discussion with the 
patient. This assessment should consider the approved labels of the respective vaccine as well 
as the provisions given in the Clinical Trial Protocol. Furthermore, there should be a time 
window of at least 3 days between administration of the vaccine and study medication. 
COVID-19 vaccination or BI 1387446 may be postponed considering the patients individual 
risk. COVID-19 vaccination should be considered as concomitant medication and reported as 
such in the CRF.
Considering the mechanism of action of activation of the STING pathway and PD-1 receptor 
blockade, attenuation of vaccine-induced protective immunity by BI 1387446 and/or BI 
754091, respectively, is not assumed. 
The package insert for approved COVID-19 vaccinations should be carefully reviewed for 
local guidance considering acute moderate/severe febrile illness, and the risk of an 
anaphylactic reaction to the vaccine. A diminished response to the vaccine needs to be 
considered for immunocompromised conditions which may be observed in patients with 
advanced or metastatic solid tumour after prior anti-cancer therapies.
It is important to encourage a patient to continue taking precautions such as wearing a mask, 
maintaining social distancing and washing hands frequently, even after a patient receives a 
COVID-19 vaccine. These precautions will be necessary until public health experts advise 
otherwise.
Herbal medications
Herbal preparations/medications are not allowed throughout the trial unless agreed to by the 
Principal Investigator. These herbal medications include, but are not limited to: St.
John’s wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. If instructed by the Principal Investigator, patients 
should stop using these herbal medications 7 days prior to first dose of study treatment.
Palliative radiotherapy
For symptom control, palliative radiotherapy of a single lesion is permitted in the dose 
escalation part of the trial, except during the first cycle as it could interfere with the DLT 
evaluation for MTD determination. Palliative radiotherapy is allowed only for lesions which 
are not previously injected with BI 1387446, provided that the reason for radiotherapy does 
not reflect PD and does not interfere with response assessment. Lesions that have been 
exposed to radiotherapy are no longer evaluable, and may not be included in the imaging 
based response assessment of target/ non-target lesions and the overall assessment. The 


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Sponsor should be informed prior to the administration of palliative radiotherapy, except for 
emergency situations.
IL-6 antagonists
In case tocilizumab or other IL-6 antagonists are required for management of severe adverse 
events, BI 1387446 and ezabenlimab (BI 754091) have to be permanently discontinued. 
4.2.2.2
Restrictions on diet and life style
The usual restrictions on diet and life style that were already applicable for a given patient 
before entry into the trial, according to his/her medical condition, have to be continued.
4.2.2.3
Contraception requirements
Due to the advanced stage of disease of Phase I trial patient populations and the high medical 
need, females of childbearing potential can be included in this trial provided that they agree 
to use a highly-effective contraception method. 
Females not of childbearing potential must have evidence of such by fulfilling one of the 
following criteria at screening:

Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy

Post-menopausal: defined as more than 50 years-of-age and amenorrhoeic for at 
least 12 months following cessation of all exogenous hormonal treatments

Women under 50 years-of-age would be considered postmenopausal if they have 
been amenorrhoeic for at least 12 months following the cessation of exogenous 
hormonal treatments, and have serum follicle-stimulating hormone and luteinizing 
hormone levels in the postmenopausal range for the institution.
WOCBP (trial participant or partner of a trial participant) 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.
These methods include:

Total sexual abstinence when this is in line with the preferred and usual lifestyle 
of the study participant (periodic abstinence such as calendar, ovulation, 
symptothermal, post-ovulation methods and withdrawal are not acceptable 
methods of contraception), or

Bilateral tubal ligation, or

vasectomised partner (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate and provided that partner is the sole sexual 
partner of the female clinical trial participant), or

Intrauterine device or intrauterine hormone-releasing system.
Women of childbearing potential must follow these methods during the trial and for at least 6 
months after the end of the trial treatment.


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Note: although hormonal contraception is considered a highly effective method of birth 
control, women of childbearing potential using a contraceptive pill must use an additional 
barrier method.
Men (trial participant or partner of a trial participant) must agree to use a condom, unless
vasectomised with documented absence of sperm, and ensure that their female partner of 
childbearing potential is using an additional highly-effective method of birth control, during 
the trial and until at least 6 months after the end of the trial treatment.
Details of contraception methods may be adapted according to local requirements and are
described in the patient information in the ICF.
4.3
TREATMENT COMPLIANCE
BI 1387446 and ezabenlimab (BI 754091) will be administered at the sites by the Investigator
and/or trained site personnel, and dosing will be recorded in the eCRF. Therefore, actual 
dosing is expected to precisely follow the prescribed drug regimen. Missed or interrupted 
doses will be recorded in the eCRF with the associated reasons. The method of collecting 
dosing information assures that total exposure can be calculated programmatically taking into 
account any missing doses.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The tumour response will be evaluated according to Response Criteria for Intratumoural 
Immunotherapy in Solid Tumours (itRECIST) (R20-2734). itRECIST criteria have been 
introduced recently and are tailored for solid tumours and intratumoural therapy trials. 
itRECIST criteria incorporate features of RECIST 1.1 (R09-0262) and iRECIST (R17-0923)
with the intent to capture both systemic and local effects of intratumoural therapy. Thus, 
injected lesions remain evaluable for overall response assessment as long as these are integral 
to the intratumoural treatment regimen. As with RECIST 1.1, the classification algorithm 
follows the quantitative and qualitative assessment of tumour burden and defines the maximal 
number of target lesion (TL) tumours using the same measuring criteria as with RECIST 1.1. 
Importantly, the new criteria further categorize the target and nontarget tumour categories 
into injected and noninjected tumours (i.e., target injected (T-I), target noninjected (T-NI), 
nontarget injected (NT-I), and nontarget noninjected (NT-NI)). For details please refer to 
Section 10.3 and the recently published paper by Goldmacher et al (R20-2734).
The assessment by the Investigator and/or the local radiologist will be the basis for 
continuation or discontinuation of the trial in an individual patient (in addition to safety). The 
baseline imaging must have been performed within 4 weeks prior to treatment with the trial 
medication and the Investigator will record the target and non-target lesions in the eCRF.
Target lesions will be classified as target injected (T-I) or target non-injected (T-NI). The 
same method of assessment and the same technique must be used to characterise each 


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reported lesion at baseline and during treatment. Lesions in previously irradiated areas may 
not be considered measurable at baseline unless the lesions appeared after irradiation. 
Tumour assessments will be performed as indicated in the Flow Chart

at screening (as close as possible to the treatment start and no more than 28 days 
before the start of BI 1387446 in Arms A and B).

before treatment administration at Cycle 2 Day 1 (a time window of -5 days is 
acceptable) in all treatment arms. 

before treatment administration (a time window of -7 days is acceptable) in C4, C6, 
C8, C10, C13, C16, C19, C23, C27, C31 and at EOT.
Copies of the scans will be collected by the sponsor or designee.
Additional imaging may be obtained at the discretion of the Investigator.
If the patient stops trial treatment prior to completion of maximum number administrations 
for a reason other than PD, the tumour assessment according to itRECIST will be performed 
according to standard of care until the last follow-up needed according to protocol.
All tumour imaging data acquired in this trial will be centrally collected by a CRO and 
centrally assessed by a designated core lab. Based on the centrally collected imaging data 
further integrated assessments of treatment-induced changes in imaging metrics, e.g. in 
tumour volume(s), shape(s), texture(s), will be performed. This so-called radiomics analysis 
is exploratory and will be performed by a service provider (CRO or academic) nominated by 
the Sponsor. Furthermore, centrally collected imaging data may be evaluated on an 
exploratory basis by a designated core lab to explore the impact of itRECIST on assessing 
efficacy outcomes over iRECIST/RECIST 1.1. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
Physical examinations will be performed at screening, prior to trial medication administration 
on Day 1 of each cycle, at the EOT visit, and at the 30-day safety follow-up visit. However, 
patients will have an additional abbreviated physical examination (focused on the specific
disease, at the Investigator’s discretion) as indicated in the Flow Chart.
The physical examination will include measurement of height (screening only) and of body 
weight, and the evaluation of the ECOG performance score. Weight will be measured during 
screening and at each full physical examination (not during abbreviated physical 
examinations).
The ECOG score will be assessed at screening, on Day 1 of Cycles 1, 2 and 3, on Day 1 of 
every other cycle beginning with Cycle 5 prior to trial medication intake, at the EOT visit, 
and at the 30-day safety follow-up visit.
The results must be included in the source documents available at the site. 


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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.
Vital signs will be monitored after drug administration as specified in Section 4.1.4.5 and 
Section 4.1.4.6.
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.


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Table 5.2.3: 1 
Safety laboratory tests
Category
Parameters 
Screen.
CxD1
EOT
other
Haematology
white blood cell count (WBC), 
haemoglobin, platelet count 
(PLT)
x
x
x
haematocrit, red blood cell count 
(RBC), white blood cell 
differentiation preferably 
expressed in absolute values 
(neutrophils, bands, 
lymphocytes, monocytes, 
eosinophils, basophils, other if 
applicable)
x
x
Coagulation
International Normalized Ratio 
(INR), activated Partial 
Thromboplastin Time (aPTT), 
Prothrombin Time (PT)
x
x
x
Biochemistry
Glucose, sodium, potassium, 
creatinine, AST, ALT, alkaline 
phosphatase, lactate 
dehydrogenase (LDH), creatine 
kinase (CK), total bilirubin. 
If total bilirubin is elevated: 
direct bilirubin.
If CK is elevated: CK-MB 
(cardiac), Troponin I and 
myoglobin.
x
x
x
calcium, phosphate, magnesium, 
chloride, bicarbonate (HCO3), 
urea, total protein, albumin, C-
reactive protein
x
x
Troponin I or Troponin T1
x
C4
N-terminal pro BNP (brain 
natriuretic peptide)2
x
C2
C4
C7
Cholesterol, triglycerides, c-
peptide
x
x3


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Table 5.2.3: 1 
Safety laboratory tests (cont.)
Category
Parameters 
Screen.
CxD1
EOT
other
Creatinine clearance if creatinine 
is >1.5xULN
x
Hormones
TSH, free T4
x
Immunoglobulins
Serum immunoglobulin levels 
(IgG, IgM, IgA, IgE).
x
x4
Urinalysis
Dipstick analysis of pH, protein, 
glucose, blood, leucocytes,
nitrite.
In case of pathological findings 
further evaluation should be 
performed and results
documented 
x
x
Pregnancy test
β-HCG testing in serum in 
females of childbearing potential
x
x
1.
One test to be selected per investigational site and patient and to be reported throughout
2.
If Nt proBNP not available, it may be replaced with a decline in preference by mid-regional pro-ANP, total BNP 
or ANP. One test to be selected per investigational site and patient and to be reported throughout.
3.
If clinically indicated
4.
Obtained at all timepoints where lymphocyte typing is done (refer to the assessment of immune cell subsets (via 
FACS) in Section 5.4.2 and in the Flow Chart)
Cardiac markers (Troponin I or Troponin T, NTproBNP or listed substitutes) have to be 
obtained at screening, in the respective treatment cycle indicated in Table 5.2.3:1, and as 
clinically indicated in other cycles. In case the patient develops clinical symptoms of cardiac 
insufficiency, cardiac markers should be obtained as appropriate in addition to the mandatory 
timepoints. The same markers as listed for mandatory timepoints should be obtained.
Unequivocal clinical symptoms of cardiac insufficiency should always trigger an 
unscheduled echocardiography. In the absence of unequivocal clinical symptoms, the 
following cut-offs for cardiac markers should be considered as guidance to trigger further 
diagnostic workup including assessment of left ventricular ejection fraction (Section 5.2.5):

Troponin T: increase to more than 3x baseline/ULN or absolute value > 100 ng/L (> 
0.1 ng/mL, > 0.10 µg/L)

NTproBNP: increase to more than 2 x baseline/ULN or absolute value >600 pg/mL (> 
600 ng/L)
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Screening laboratory assessments performed within 72 hours of the first trial treatment 
administration are not required to be repeated on Cycle 1 Day 1. Other safety laboratory 
should be performed within 24 hours of the visits.


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Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (refer to Section 5.2.7).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (refer to Section 5.2.7.1.4 and the DILI Checklist provided in the eDC system). 
The amount of blood taken from the patient concerned will be increased due to this additional
sampling.
5.2.4
Electrocardiogram
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting electrocardiograms (ECGs) will 
be digitally recorded at various time points throughout the trial. The Flow Chart outlines
which visits will require ECGs, and Blood sampling Flow Chart outlines which time points 
require triplicate ECGs to be done along with certain PK samples (Arm A and B).
All ECGs will be obtained after the patient has been resting supine for at least 5 minutes prior 
to the indicated times. All ECGs should be recorded with the patient in the same physical 
position.
Electrocardiogram machines will be provided for the trial to facilitate central readings. 
Before study start, the study sites will be trained for the proper use of the equipment and 
transfer of the electronic data to the vendor. All ECGs will be transmitted to the central 
vendor for analysis. 
ECGs may be repeated for quality reasons and the repeated recording will be used for 
analysis. If necessary, additional ECGs may be recorded for safety reasons. 
The ECG recordings must also be analysed and checked for abnormality by the Investigator 
(or designated physician) who will also calculate the QTcF value for each time point as the 
mean of the 3 ECGs.  Particular attention must be paid to T wave inversions. It is not 
mandatory to wait for central evaluation of ECGs to make clinical decisions. Clinically 
relevant abnormal findings will be reported either as baseline condition (if identified at the 
screening visit) or otherwise as adverse events and will be followed up and/or treated as 
medically appropriate. CTCAE Version 5 will be used for the grading of prolonged QTcF 
intervals.
In case of related ECG changes and whenever the Investigator deems necessary, additional 
ECG monitoring will be performed in the respective and later courses of treatment. The 
ECGs will be recorded using dedicated equipment provided by a vendor. The ECGs will be 
sent for evaluation by a central vendor. Data from this central review will be taken for 
retrospective data analysis. To allow for a heart rate correction of QT intervals the QT 


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intervals will be matched to the preceding RR intervals using at least QTcF (Fridericia’s 
formula QTcF = QT/RR-1/3) and QTcB (Bazett’s formula QTcB = QT/RR-1/2).
In case of QTcF prolongation to >500 ms (mean of 3 ECGs) AFTER receiving therapy, the 
Investigator will initiate further ECG monitoring and diagnostics (e.g. check electrolytes and 
check concomitant therapy that may be contributing to QTcF prolongation) and if required 
provide adequate treatment according to medical standards. The patient will be discharged 
from the investigational site only after resolution of ECG findings as assessed by the 
Investigator.
In case of occurrence of symptoms suggestive of arrhythmia related to QTcF prolongation, a 
cardiologic evaluation will be performed, and treatment will be provided according to 
medical standards at the discretion of the Investigator.
At timepoints when ECG and blood sampling for PK are planned at the same time, ECG 
should be performed prior to PK sampling. Triplicate ECGs should be performed within a 
maximum period of 5 minutes prior to blood sampling.  
The centralised ECG evaluation will include the semi-automatic determination of the RR, PR 
interval, QRS complexes, and QT intervals.
All interval measurements in one patient will be performed on the same lead. The intervals 
will be measured from four cardiac cycles (beats) in lead II. If lead II shows a flat T wave or 
is not measurable for any reason, lead V5 will be used, or if that lead is not measurable, then 
lead I will be used for assessment of all ECGs.
Central morphological analyses of the ECGs (cardiologic assessments) will be performed by 
a board-certified cardiologist or equivalent. In case additional (unscheduled) ECGs due to 
safety reasons are recorded at the study site, all ECGs of this time point including the 
additional ECGs will undergo interpretation. The ECG interpretation will include an overall 
assessment (normal, abnormal, not assessable) as well as assessments concerning rhythm, 
conduction, presence of myocardial infarction, ST segment deviations, T wave morphology, 
and U wave morphology findings.
Abnormalities detected during centralised ECG evaluation will not necessarily qualify as 
AEs. In case of clinically relevant abnormalities (e.g. heart blocks or large changes in interval 
duration) the ECG core laboratory may contact the Investigator and vice versa.
Centrally assessed ECGs will comply with the ICH E14 guidance document and supplements 
[R05-2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital 
ECGs [R09-4830].
5.2.5
Echocardiography / MUGA scan
Echocardiography to assess left ventricular (LV) function needs to be performed at screening 
and in regular intervals as indicated in the Flow Chart. In case trial drugs are administered at 
the respective visit, echocardiography should be obtained prior to trial drug administration.


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LV ejection fraction (LVEF) has to be measured and reported in the eCRF, additional 
relevant abnormal findings may be reported as baseline conditions/adverse events.
Although echocardiography is the preferred method, MUGA scans are permitted to quantify 
LVEF. The same method should be used in a single patient throughout the trial.
In case the patient develops clinical symptoms of cardiac insufficiency, unscheduled 
echocardiography should be obtained as soon as possible to quantify LV ejection fraction and
additional parameters as clinically indicated.
A clinically relevant decline in LVEF, defined as an absolute decrease by at least 10
percentage points, should be confirmed by a subsequent assessment after 1-2 weeks. A
confirmed LVEF decline should be reported as adverse event. Upon detection of a clinically 
relevant decline in LVEF, BI 1387446 should be paused until LVEF returns to baseline, and 
should only be resumed at a reduced dose. In case of a recurrent decline upon re-exposure at 
a reduced dose of BI 1387446, treatment should be permanently discontinued.
In case a clinically relevant decline in LVEF is observed, patients should be closely followed 
for signs of cardiac disease throughout the trial. Results from additional imaging studies 
should be captured in the eCRF.
5.2.6
Other safety parameters
Assessment of lens opacity
Ocular history as part of the medical history will be reviewed at screening. Examination of 
patients for the presence and extent of lens opacities using slit-lamp examination will be 
performed by an ophthalmologist at screening, at the 30-day safety follow and at any time 
during the treatment period, if clinically indicated. Lens opacities as seen on clinical slit-lamp 
examination will be graded and documented according to the Lens Opacities Classification 
System III (LOCS III) (R99-2093).
5.2.7
Assessment of adverse events
5.2.7.1
Definitions of AEs 
5.2.7.1.1
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 or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening pre-existing conditions, excluding disease progression.


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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.
5.2.7.1.2
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
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.7.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the 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 above.
5.2.7.1.4
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 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see
Section 5.2.7.2.2.


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The following are considered as AESIs:
Dose limiting Toxicities (DLTs)
All DLTs are considered to be AESIs, and must be reported as such. The definition of DLT is
presented in Section 4.1.4.4.
Hepatic injury and drug-induced liver injury (DILI)
During the course of the trial the Investigator will remain vigilant for increases in liver
biochemistry. The Investigator is responsible for determining whether a patient meets the
hepatic injury definition or potential Hy´s law criteria at any point during the trial.
The Investigator participates, together with the Medical Monitor and clinical project 
representatives, in review and assessment of cases meeting potential hepatic injury and Hy´s 
law criteria. Hy´s law criteria are met if there is no alternative explanation for the elevations 
in liver biochemistry other than a DILI caused by the investigational product.
The Investigator is responsible for recoding data pertaining to these cases and for reporting 
them as AEs and/or SAE according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Hepatic injury definition:
A hepatic injury is defined by the following alterations of hepatic laboratory parameters in 
patients with normal liver parameters at baseline (ALT, AST, and bilirubin within normal 
limits): 

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, or in samples drawn 
within 30 days of each other, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
For patients with abnormal aminotransaminase levels between >1 and <3 x ULN at baseline:

An elevation of AST and / or ALT ≥3-fold the baseline value combined with an
elevation of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is
elevated at baseline), measured in the same blood sample, or in samples drawn within 
30 days of each other; or;

Aminotransferase elevations ≥5-fold the baseline value.
For patients with abnormal aminotransaminase levels between ≥3 x ULN and <5 x ULN at 
baseline:

An elevation of AST and / or ALT ≥2-fold the baseline value combined with an
elevation of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is
elevated at baseline); measured in the same blood sample or in samples drawn within
30 days if each other; or;

Aminotransferase elevations ≥3-fold the baseline value.


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Hy’s Law cases have the following 3 components:

The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST

Among trial subjects showing such aminotransferase elevations, often with elevations 
much greater than 3 times ULN, one or more also show elevation of serum total bilirubin 
to >2 times ULN, without initial findings of cholestasis (elevated serum ALP)

No other reason can be found to explain the combination of increased aminotransferase 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury.
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 eDC 
system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Lab values meeting the hepatic injury definition will need to be reported as AESI. Please 
follow the flowchart below for reporting hepatic injury / potential DILI cases
Figure 5.2.7.1.4: 1
Processing Potential DILI Cases in Oncology


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Immune related adverse events (irAE)
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. All immune-relate events are to be reported as AEs. Some irAEs also 
need to be reported as AESIs as defined by the sponsor in Table 10.1.1: 1. If an Investigator
determines a grade 3 event (not on the list) to be immune-related, the Investigator should also 
report that event as an AESI.
Recommendations for the management of irAEs are presented in Appendix 10.2.
5.2.7.1.5
Intensity (severity) of AEs
The severity of adverse events should be classified and recorded in the CRF according to the 
CTCAE v5.0.
5.2.7.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).


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Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.7.2
Adverse event collection and reporting
5.2.7.2.1
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
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 treatment related SAEs and trial treatment 
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 5.2.7.2.2), but not on the CRF.
5.2.7.2.2
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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send 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.
5.2.7.2.3
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.


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Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner; in
the event that consent cannot be obtained, information will be collected and reported in 
accordance with regulatory requirements. The ISF will contain the trial specific information 
and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.7.2.4
Exemptions to AE/SAE reporting
The occurrence of disease progression is recorded as part of the assessment of trial endpoints
for the analysis of efficacy. The following rules will be followed for reporting disease 
progression and associated signs and symptoms for the analysis of safety;

If the disease progression, or any associated signs and symptoms, meet standard 
seriousness criteria (see Section 5.2.7.1.2), ‘disease progression’ must be reported as 
an SAE.

If the disease progression and any associated signs and symptoms do not meet 
standard seriousness criteria, ‘disease progression’ is not reported as an AE.

Clinical signs and symptoms of disease progression which do not meet standard 
seriousness criteria will be recorded on the AE page of the eCRF. If a sign or 
symptom is on the ‘Always Serious AE’ list, it will also be reported as an SAE. If 
signs and symptoms are attributable to a diagnosis (other than ‘disease progression’), 
reporting the diagnostic term is preferable e.g. pulmonary embolism rather than 
dyspnoea, intestinal obstruction rather than abdominal pain.

If there is evidence suggesting a causal relationship between the investigational 
drug(s) and the progression of the underlying malignancy, the event must be reported 
as an SAE.

Lab values meeting the potential severe DILI definition in Section 5.2.7.1.4 must 
always be reported as AESI, even if the most likely cause is disease progression. No 
exemption to AE reporting applies.
Exempted events are reviewed at appropriate intervals by the Sponsor and the SMC.




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(see Blood sampling Flow Charts). At each of these times, 4.9 mL blood will be needed for 
metabolite analysis. The blood samples will be processed in the same way as the PK samples 
(see Section 5.3.3). However, the plasma obtained (approximately 2 mL) will be transferred 
into polypropylene tubes (each containing approximately 1 mL, labelled MIST1 and MIST2).
Samples will be stored at approximately -20°C or below until transfer to the metabolism 
laboratory. At a minimum, the sample tube labels should list BI trial number, subject number,
visit, planned sampling time and ‘MetID’.
Plasma samples dedicated to metabolism investigation are transferred to:
Only data related to the parent compound and its metabolites will be acquired. Evaluation of
drug metabolism will be reported separately and will not be included in the Clinical Trial 
Report (CTR). The study samples will be discarded after completion of the experiments but 
not later than 5 years after the CTR has been archived.
5.3.3
Methods of sample collection
Blood samples should not be obtained from the arm used for ezabenlimab (BI 754091)
infusion.  In case a central venous access is used for infusion, the blood sample can be 
collected from either forearm or central line.  Blood sampling for BI 1387446 should be 
performed in anatomical distance from the injection site, e.g. if the right arm is the injection 
site for the tumour, the left arm should be used for PK blood sampling. The actual sampling 
date and time (24-hour time clock) for each sample has to be recorded accurately.
For quantification of analyte concentrations, blood will be drawn for BI 1387446 and 
ezabenlimab (BI 754091) at the time points specified in the PK time schedule in Blood 
sample Flow Charts.
Samples may be used for further methodological investigations, however only data related to 
this trial, the analyte or bioanalytical assay will be generated by these additional 
investigations (e.g. using the sample for ADA or biomarker for PK if sample volume allows).  
The trial samples will be discarded after completion of the additional investigations but not 
later than 5 years after the final trial report has been signed.
Details on sample collection for BI 1387446 and ezabenlimab (BI 754091) characteristics, 
processing, handling and shipment are provided in the Laboratory Manual.


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5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. 
The study of biomarkers will be hypothesis-generating and will substantially contribute to the 
understanding of the BI 1387446 mode of action. Where possible biomarkers will be used to 
retrospectively identify patient subgroups with differential prognoses and/or responses to 
treatment. The following exploratory biomarkers may be examined in this trial:

Immunohistochemical analysis of immune-oncology –related markers on tumour cells 
and Immune cell infiltrates

Peripheral cytokine secretion

Flow analysis of different immune cell subsets in blood 

Gene expression analysis of immune-oncology-related panel of genes in blood and 
tissue.

Genomic profiling to determine tumour mutational burden (TMB) and microsatellite 
status.

Germline STING variants. 
Should other tissue/blood biomarkers 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 literature or early analyses.
In the case of premature trial discontinuation due to the reasons specified under section 3.3.4
or 3.3.5, the sponsor reserves the right to discontinue selected analyses. Respective samples 
may be used for further investigations as described in 5.4.1, or if  a separate informed consent 
has been given, samples may be used for biobanking (section 5.5).
5.4.1
Methods of sample collection
Fresh pre- and on-treatment tumour biopsy collections for biomarker analyses will be 
mandatory from all patients (according to the Flow Chart). All samples must be adequately 
labelled by the trial site personnel. For fresh biopsies always use the equivalent of no less 
than two core needle biopsies (18 gauge or greater).
If available additional archival tumour tissue from the most recent time point before study 
entry will be collected during screening (see Flow Chart) for all patients. Archival tumour
tissue sample should be provided as FFPE-preserved tissue, preferably as an embedded block 
and less preferably as mounted tissue sections (at least 8 up to 20 sections of 5 μm thickness) 
prepared under RNase free conditions.


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Details about tumour tissue and blood sample collection, plasma/serum preparation, required 
tubes, labelling of tubes, storage and shipment (frequency and addresses) will be provided in 
the ISF and the respective lab manual.
Samples may be used for further methodological investigations, however only data related to 
this trial, the analyte or an analytical assay will be generated by these additional 
investigations. If the patient has not consented to optional biobanking (see Section 5.5) trial 
samples left over after primary analysis will be discarded after completion of these additional 
investigations but not later than 5 years after the final trial report has been signed.


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements. Banked samples may be used for 
further unspecified explorative investigations.
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 timepoints see Flow Chart.
Banking will be limited to samples left over after primary analysis as specified in Section 5.4.
The following samples may be banked:
•
Plasma samples
•
FFPE tissue 
•
DNA and RNA
5.6
OTHER ASSESSMENTS
Assessment of anti-drug antibodies (ADAs)
For ADA assessments (ezabenlimab (BI 754091)), the specified blood volume will be drawn 
into blood-drawing tubes at the time points listed in Blood sampling Flow Charts.
Details on sample characteristics, processing, handling, and shipment are provided in the 
Laboratory Manual.
Samples may be used for further methodological investigations, however only data related to 
this trial, the analyte or bioanalytical assay will be generated by these additional 
investigations (i.e. using the sample for ADA or biomarker for PK if sample volume allows).  




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In addition to the scheduled assessments, unscheduled assessments for safety reasons may be 
performed at any time according to clinical need.
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and 
assessments, and home healthcare nurse visits. The implementation of these measures will 
depend on patient’s consent, operational feasibility, local law and regulations. If alternative 
methodology is implemented, the deviations from the original plan will be precisely 
documented.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
Screening Period
Following informed consent, the patient will undergo screening assessments as indicated in 
the Flow Chart. 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. If more than one screening assessment is 
available, the latest assessment prior to the start of treatment must be used to assess 
eligibility.
Re-screening of patients who have previously failed screening will be permitted. In this 
situation patients will be allocated a new patient number.
Patients who cross over from Arm A to Arm B do not have to repeat all screening procedures, 
but a limited set of assessments should be available, i.e.
-
Imaging for response assessment (unless available between last dose of BI 1387446 in 
Arm A and first dose of ezabenlimab (BI 754091) or BI 1387446 in Arm B, and not 
older than 28 days).
-
Biopsy from injected and non-injected lesion (unless performed in Arm A and no 
subsequent treatment with trial drugs in Arm A following the biopsy) 
-
Echocardiography, unless performed within the last 4 weeks
These patients will start treatment in Arm B at Cycle 1 Day 1.
Baseline Conditions
Demographics (sex, year of birth, race, and ethnicity where allowed), information on tobacco 
and alcohol use, and baseline conditions will be collected during the screening visit.
If the patient meets the eligibility criteria during screening, the first treatment visit should be 
scheduled. Baseline conditions which are present at the Screening visit should be reported in 
the eCRF.
Medical History:
Medical history of cancer:


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History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumour site will 
be reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumour, (lymph) 
node, and metastasis (TNM) classification (TNM Classification of Malignant Tumours) will 
be provided as obtained at diagnosis and at trial screening. Previous surgeries will be 
reported. The patient’s reason(s) for not being eligible for established treatment options
should be documented in the patient record and will be recorded in the eCRF.
Previously administered chemotherapy, tyrosine kinase inhibitor treatment, vaccine therapy, 
antibodies therapy, immune therapy, and hormone therapy will be reported, including start 
and end dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
lines of treatment will be recorded, if known.
Other medical history:
Past diseases and/or diagnoses relevant to patient's safety/ trial assessments during the trial as 
judged by the Investigator will be recorded in eCRF.
Molecular characteristics of the tumour: 
Microsatellite status, Tumour mutational burden (TMB), Expression levels of PD-L1, ER, 
PR, HER2, HPV status and any available information on tumour mutations will be recorded 
in the eCRF.
Concomitant medication:
Relevant concomitant diagnoses and/or therapies present in the past, at trial entry and/or 
during screening and relevant to the patient’s safety during the trial as judged by the 
Investigator will be recorded in the eCRF (see Section 4.2.2 for details on concomitant 
medications). Post-trial therapy for advanced or metastatic disease will also be documented.
6.2.2
Treatment period(s)
Refer to the Flow Chart for a detailed presentation of each visit during the treatment period.
6.2.3
Follow-up period and trial completion
The EOT visit will be performed as soon as possible but no later than 7 days after permanent 
discontinuation of the trial medications (BI 1387446 and/or ezabenlimab (BI 754091)) for 
any reason or e.g. when the Investigator decided with the patient to permanently discontinue 
the trial medications or became aware that the trial medications had been terminated.
The assessments of the EOT visit will then be performed instead of at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of EOT, unless it has been done within the past 3 weeks.


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6.2.3.1
30-day and 90-day safety follow-up visits
The 30-day safety follow-up visit is performed in person 30 (+7) days after the EOT visit. At 
this visit, all AEs/SAEs/AESIs and other required information must be collected as specified 
in the Arm A/B Flow Chart. The 90-day safety follow-up visit is performed by telephone (or 
in person if the investigator deems necessary) 90 (+14) days after the EOT visit. At this visit, 
only AEs/SAEs/AESIs and concomitant therapy need to be collected. 
A patient will be considered as having completed the trial if he/she discontinues because of 
PD and has performed the safety follow-up visit 90 days after EOT, or was lost to follow up, 
or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for any 
other reason, he/she will be considered as withdrawn.
6.2.3.2
Follow-up visit
Additional follow-up visits after the 90-day safety follow-up visit will only be performed for 
patients who did not progress on treatment to monitor tumour progression and safety. These 
will be performed once every 12 weeks at least (by telephone or in person) until PD, 
introduction of a new anti-cancer treatment, death, loss to follow-up, withdrawal of consent, 
or for a maximum of 6 months after EoT.
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This trial will be performed as an open-label trial. The primary objectives of this trial are to 
determine the MTD and/or the RD-P2 of BI 1387446 as monotherapy in superficial lesions
(Arm A) and to determine the MTD and/or the RD-P2 of BI 1387446 in combination with 
ezabenlimab (BI 754091) in superficial lesions (Arm B). To determine the MTDs, patients 
are entered sequentially into escalating dose cohorts (see Section 3). 
The dose escalation will be guided by a Bayesian 5-parameter logistic regression model with 
overdose control [R15-4233] using a hierarchical modelling approach to jointly model both
arms and taking into account data available for ezabenlimab (BI 754091) from the ongoing 
trial 1381-0001. Trial 1381-0001 is also an oncology dose finding trial which comprises a 
similarly heterogeneous population of patients with solid tumours. A comparison between 
trial 1426-0001 and 1381-0001 regarding study population, DLT definition and treatment 
schedule is presented in Appendix Table 10. 5: 3. A visualisation of the joint-modelling 
approach is given in Figure 7: 1.


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Figure 7: 1
Joint BLRM modelling approach for Arms A and B
The logistic regression model for Arm A and B is defined as follows. Let π1,d1 be the 
probability of having a DLT when giving dose d1 of BI 1387446 as monotherapy, and π2,d2 the 
probability of having a DLT when giving dose d2 of the combination partner ezabenlimab (BI 
754091) as monotherapy, respectively. A logistic regression is used to model the dose-
toxicity relationship for each of these drugs individually:
BI 1387446:
logit(π1,d1) =log(α1) + β1log(d1/d1*)
Ezabenlimab (BI 754091):
logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses 
and d2* = 240 mg represent the reference doses for BI 1387446
and ezabenlimab (BI 754091), respectively.
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination dose d1, d2 is obtained as 
π012,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds 
odds(π012,d1,d2)= π012,d1,d2 /(1- π012,d1,d2)
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 
between BI 1387446 and ezabenlimab (BI 754091), a dose-dependent interaction term -∞<
η<∞ is introduced in the model by the following definition:
odds(π12,d1,d2) = odds(π012,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)


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where rd1,d2 denotes the random variable describing the observed number of DLTs in nd1,d2
patients at the dose combination d1,d2.
The joint analysis of the dose escalation Arms A and B of this trial and the information 
available from trial 1381-0001 follows a normal-normal hierarchical model with 3 parameter 
models:
1) A multi-variate normal distribution for BI 1387446 as single agent: 
, = 	log	, , log	,~ 	(, ), Ψ,  = 1, … ,3
2) A multi-variate normal distribution for ezabenlimab (BI 754091) as single 
agent:, = 	log	, , log	,~ 	(, ), Ψ,  = 1, … ,3
3) A normal distribution for the interaction parameters ηj:
~	 , ! 
,  = 1, …,3
The parameters ,, ,, and  are the corresponding trial-specific parameters of each trial-
specific BLRM (for trials j=1,2,3). The covariance matrices Ψ" (i=1,2) are assumed to be of 
the form
Ψ" = #
!$

%"!$!$
%"!$!$
!$

&
For this hierarchical model, the monotherapy dose-finding in Arm A and the double 
combination therapy dose-finding in Arm B, and trial 1381-0001 are assumed to be separate 
trials, with different inter-study random effects !, !, !, !, ! for the involved 
parameters. The parameters log	", and log	", (i=1,2; j=1,2,3) are assumed to be 
potentially correlated with correlation coefficients %", i=1, 2, while the remaining parameters 
are assumed to be uncorrelated. Refer to [R18-3210] for details. 
Since a Bayesian approach is applied, prior distributions f for each of the parameters 
, , , ,  , !, !, !, !, ! and for %, and % need to be specified. Weakly 
informative prior distributions were chosen for the µ- and ρ-parameters, prior distributions 
for the τ-parameters are chosen to represent a small to moderate between-trial heterogeneity
(see Table 7: 1).


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Table 7: 1
Prior parameters of the joint model for Arms A and B
Parameter
Prior distribution

N(log(0.5),2)

N(0,1)

N(log(0.5),2)

N(0,1)
 
N(0,1)
!
logN(log(0.25),log(2)/1.96)
!
logN(log(0.125),log(2)/1.96)
!
logN(log(0.25),log(2)/1.96)
!
logN(log(0.125),log(2)/1.96)
! 
logN(log(0.125),log(2)/1.96)
%
U(-1,1)
%
U(-1,1)
The toxicity probabilities π1,d1, and π12,d1,d2, of a DLT at each dose/dose combination will be 
calculated directly from the posterior samples regarding the arm-specific parameters, i.e. 
including the respective arm-specific random effects per parameter. They will be summarized 
per arm using the following intervals:
Under toxicity: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Overtoxicity: [0.33, 1.00]
Prior probabilities of DLTs at different dose levels/dose combinations, as well as the 
corresponding probability of under-, targeted and overtoxicity, are shown in Table 7: 2 and
Table 7: 3 for the initial weakly informative priors of the joint model for Arms A and B. As 
can be seen from these tables, the prior medians of the DLT probabilities represent 
reasonable assumptions on toxicity, and the uncertainty around the medians is large, showing 
the low amount of information this prior provides.
Prior probabilities in Arm A show that 
fulfils the EWOC criterion and is therefore a 
suitable starting dose for the monotherapy dose finding in superficial lesions. Prior 
probabilities for Arm B do not allow to start combination dose finding at 
 
without additional data. However, from the data scenarios provided in Section 10.5 and from 






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
At least 12 patients have been treated in the specific arm.
And at least one of the following criteria is fulfilled:

The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.50, OR

At least 6 patients have been treated at the MTD.
A detailed evaluation of the model using hypothetical data scenarios and operating 
characteristics is provided in the statistical appendix (Section 10.5).
The dose finding part of the trial will be analysed once using the hierarchical model described 
above. A sensitivity analysis of the dose finding part will consist of separate analyses of each 
dose finding arm using weakly informative priors for each arm. 
7.1
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory testing is performed and hence no null and alternative hypotheses are 
defined. A justification of the sample size is provided in Section 7.5.
7.2
PLANNED ANALYSES
7.2.1
General considerations
For the determination of the MTD, only MTD evaluable patients will be considered. For the 
analysis of all other endpoints, all patients in the treated set (i.e. patients treated with at least 
one dose of trial medication) will be included in the analysis. Analyses will in general be 
performed by initial treatment, with the exception of patients who cross over from Arm A to 
Arm B. These patients will be analysed as part of Arm A as long as they are treated with 
monotherapy and as part of Arm B when they are treated with combination therapy.
More details and all other patient analysis sets will be defined in the Trial Statistical Analysis 
Plan (TSAP). 
No per protocol set will be used in the analysis. However, important protocol deviations will 
be summarized. 
7.2.2
Primary endpoint analyses
In order to identify the MTD, the number of evaluable patients with DLTs during the MTD 
evaluation period at each dose level in each arm must be presented. Replaced patients will be 
excluded from the determination of MTD. 
For Arm A and B, the main analysis of the MTD will use the joint 5-parameter BLRM model 
described above using DLT data from the MTD evaluation period. For this analysis, cross-
over patients will only be included while being treated with BI 1387446 monotherapy in Arm 
A. 


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The following sensitivity analyses for the analysis of the MTD will be performed to support 
the determination of the RD-P2:
-
Separate BLRMs will be used for each escalation arm using all DLT data, not only 
DLT data from the MTD evaluation period
-
The joint BRLM will be evaluated using all DLT data, not only DLT data from the 
MTD evaluation period
The sensitivity analyses will include all treated patients, including ‘backfill’ patients and 
cross-over patients. More details on sensitivity analyses will be specified in the TSAP.
7.2.3
Secondary endpoint analyses
The OR based on itRECIST criteria (i.e. including injected and non-injected lesions) will be 
analysed descriptively in terms of OR rate, defined as the proportion of patients with best 
overall response of CR or PR. Best percentage change from baseline in size of non-injected 
target lesions and Best percentage change from baseline in size of injected target lesions will 
be analysed using descriptive statistics as well as waterfall plots. 
The secondary endpoints will be displayed for each escalation arm separately.






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7.4
RANDOMISATION
No randomisation will be performed in this trial. Patients will be assigned to escalation arms 
as described in Section 3.1.1. 
7.5
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine the sample size were performed for this 
trial. 
For the dose escalation part, in Arm A and B, approximately 78 patients are expected to be 
enrolled based on the number of dose levels that are planned to be tested. That is, the planned 
number of patients for the individual treatment arms is approximately: 34 patients for Arm A
and 44 patients for Arm B.
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalisation of the 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 


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(IEC and 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 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 documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.


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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.
Copies of tumour assessment scans will be collected by the sponsor for later Radiomics 
assessment. This could include CT/MRI scans of the chest and abdomen and/or imaging of 
any other known or suspected sites of disease (e.g. pelvis, brain) using an appropriate 
method. 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 before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 


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conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.

Technical information collected on PK sampling days (e.g. PK sampling times, repeated 
vital signs linked with PK) may be collected on specific paper PK logs, which will be 
considered as source data for related entries in eCRF and are considered Part of the ISF.
8.3.2
Direct access to source data and documents
The Investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see Section 6), site access may be restricted thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralized 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
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.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:


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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.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
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 visit primary endpoint” (LPLVPE) date is defined as the date on 
which the last patient finalised the first cycle and underwent echocardiogram/MUGA scan on 
Day 1 of Cycle 2 for MTD assessment in Arm A or Arm B.
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual Investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial
milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate Investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
Safety Monitoring Committee
The Safety Monitoring Committee (SMC) will be composed of Investigators from 
participating investigational sites and representatives from the Sponsor:

BI Clinical Program Lead

BI Clinical Trial Lead

BI Statistician

BI Pharmacovigilance Representative

All Investigators participating in the clinical trial

Guests may be invited as appropriate, e.g. interventional radiologists from participating 
investigational sites
The SMC will convene for all dose escalation decisions. For decision making during dose 
escalation, the following members need to attend the meeting:
-
BI CPL or appropriately qualified delegate
-
Investigators or appropriately qualified delegate involved in the treatment of patients 
in the respective dose cohort
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The Investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CT 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), Clinical Research Associates (CRAs), and Investigators of participating 
countries.


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The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
Vendors for IRT and central ECG will be used in this trial. Details will be provided in the 
IRT Manual and ECG manual, available in the ISF.
External laboratory services will be used in this trial. Details will be provided in the 
Laboratory Manuals, available in the ISF.
9.
REFERENCES
9.1
PUBLISHED REFERENCES
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): 1714-1768.
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et 
al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982. 5: 649-55.
R05-2311
CH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs. Current Step 4 
version dated 12 May 2005.
R07-4856
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on clinical trials in small populations. 
London, 27 July 2006: doc. ref. CHMP/EWP/83561/2005.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009. 45: 228-47.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide. March 21, 2005.
R13-0801
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs: 
questions and answers (R1). ICH. October 2012.


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R13-4095
Committee for Medicinal Products for Human Use (CHMP): ICH guideline 
E14 - questions and answers: step 5. EMA/CHMP/ICH/310133/2008. May 
2012.
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol. 2013. 71: 1107-
14.
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med. 2008. 27: 2420-39.
R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol. 2007. 
25(31): 4982-6.
R13-4805
Le Tourneau C, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted 
agents. Plos One. 2012. 7(12): e51039.
R13-4881
"FDA's critical path initiative. U.S. Food and Drug Administration; 2012
R15-4233
Zhao W, Yang H, editors. Statistical methods in drug combination studies. 
(CRC Biostatistics Series) Boca Raton: CRC Press. 2015.
R17-0923
Seymour L, Bogaerts J, Perone A, Ford R, Schwartz LH, Mandrekar S, et 
al. RECIST Working Group iRECIST: guidelines for response criteria for 
use in trials testing immunotherapeutics. Lancet Oncol. 2017. 18(3): e143-
e152.
R18-3210
Neuenschwander B, Roychoudhury S, Schmidli H. On the use of co-data in 
clinical trials. Stat Biopharm Res. 2016. 8(3): 345-354.
R18-3850
Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T 
et al. Starting the fight in the tumour: expert recommendations for the 
development of human intratumoural immunotherapy (HIT-IT). Ann Oncol. 
2018. 11: 2163-74.


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R19-0309
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et 
al. ASBMT consensus grading for cytokine release syndrome and 
neurological toxicity associated with immune effector cells. Biology of 
Blood and Marrow Transplantation, Accepted Manuscript, Published 
online: December 25, 2018, doi: 10.1016/j.bbmt.2018.12.758; 2018.
R19-0310
Mahadeo KM, Khazal SJ, Abdel-Azim H, Fitzgerald JC, Taraseviciute A, 
Bollard CM, et al, Pediatric Acute Lung Injury and Sepsis Investigators 
(PALISI) Network. Management guidelines for paediatric patients 
receiving chimeric antigen receptor T cell therapy. Nat Rev Clin Oncol. 
2019. 16: 45-63.
R19-0311
Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et 
al. Chimeric antigen receptor T-cell therapy - assessment and management 
of toxicities. Nat Rev Clin Oncol. 2018. 15: 47-62.
R19-0312
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 
2019. 69(1): 7-34.
R19-0313
Eggermont AMM, Kroemer G, Zitvogel L. Immunotherapy and the concept 
of a clinical cure. Eur J Cancer. 2013. 49: 2965-2967.
R19-0314
Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 
2015. 15: 760-770.
R19-0315
Corrales L, and Gajewski, TF. Endogenous and pharmacologic targeting of 
the STING pathway in cancer immunotherapy. Cytokine. 2016. 77: 245-
247.
R19-0316
Corrales L, McWhirter SM, Dubensky TW, Gajewski TF. The host STING 
pathway at the interface of cancer and immunity. J Clin Invest. 2016. 
126(7): 2404-2411.
R19-0317
Hammerich L, Bhardwaj N, Kohrt HE, Brody JD. In situ vaccination for the 
treatment of cancer. Immunotherapy. 2016. 8(3): 315-330.
R19-0318
Andrews MC, Wargo JA. Immunotherapy resistance: the answers lie ahead 
- not in front - of us. J Immunother Cancer. 2017. 5: 10.
R19-0506
Sivick KE, Desbien AL, Glickman LH, Reiner GL, Corrales L, Surh NH, et 
al. Magnitude of therapeutic STING activation determines CD8+ T cell-
mediated anti-tumour immunity. Cell Rep. 2018. 25: 3074-3085.
R19-0517
Moore BA, Roux MJ, Sebbag L, Cooper A, Edwards SG, Leonard BC, et 
al. A population study of common ocular abnormalities in C57BL/6N rd8 
mice. Invest Ophthalmol Vis Sci 59 (6), 2252 - 2261 (2018)
R19-0608
Meric-Bernstam F, Werner TL, Hodi FS, Messersmith W, Lewis N, Talluto 
C, et al. Phase I dose-finding study of MIW815 (ADU-S100), an 
intratumoural STING agonist, in patients with advanced solid tumours or 
lymphomas. 33rd Ann Mtg and Pre-Conf Programs of the Society for 
Immunotherapy of Cancer (SITC), Washington, November 7 - 11 Nov 2018 
(Poster). 2018.


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R19-0609
Harrington KJ, Brody J, Ingham M, Strauss J, Cemerski S, Wang M, et al. 
Preliminary results of the first-in-human (FIH) study of MK-1454, an 
agonist of stimulator of interferon genes (STING), as monotherapy or in 
combination with pembrolizumab (pembro) in patients with advanced solid 
tumours or lymphomas. 43rd Ann Cong of the European Society for 
Medical Oncology (ESMO), Munich, 19 - 23 Oct 2018. Ann Oncol 2018; 
29(Suppl 8): VIII712.
R19-0623
Harrington K, Brody J, Ingham M, Strauss J, Cemerski S, Wang M, et al. 
Preliminary results of the first-in-human study of MK-1454, an agonist of 
stimulator of interferon genes (STING), as monotherapy and in 
combination with pembrolizumab in patients with advanced solid tumours 
or lymphomas. 43rd Ann Cong of the European Society for Medical 
Oncology (ESMO), Munich, 19 - 23 Oct 2018 (Poster). 2018.
R19-0674
Vatner RE, Janssen EM. STING, DCs and the link between innate and 
adaptive tumour immunity. Molecular Immunology, Article In Press, 
Available online 20 December 2017, doi: 10.1016/j.molimm.2017.12.001; 
2017.
R20-2734
Goldmacher GV, Khilnani AD, Andtbacka RHI, et al. Response Criteria for 
Intratumoural Immunotherapy in Solid Tumours: itRECIST. J Clin Oncol. 
2020;38(23):2667-2676. doi:10.1200/JCO.19.02985.
R20-2735
Moore JB, June CH. Cytokine release syndrome in severe COVID-19: 
lessons from arthritis and cell therapy in cancer patients point to therapy for 
severe disease. Science. 2020; 368 (6490): 473-474. 
R21-3791
Hoffmann DH, Andrew G.  The No-U-Turn Sampler: Adaptively Setting 
Path Lengths in Hamiltonian Monte Carlo. Journal of Machine Learning 
Research 2014; 15: 1351-1381.
R99-2093
Chylack LT, Wolfe JK, Singer DM, Leske MC, Bullimore MA, Bailey IL, 
et al. Longitudinal Study of Cataract Study Group . The lens opacities 
classification system III. Arch Ophthalmol (Chicago) 111, 831 - 836 (1993)
9.2
UNPUBLISHED REFERENCES
c07895879
Investigator’s Brochure BI 754091 (Ezabenlimab)
c26065921
Investigator’s Brochure BI 1387446


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10.
APPENDICES
10.1
IMMUNE-RELATED ADVERSE EVENTS
10.1.1
Immune related adverse events of special interest
Table 10.1.1: 1
Immune-related adverse events of special interest
Immune-related adverse events of special interest
Pneumonitis (reported as an AESI if ≥Grade 2)

Acute interstitial pneumonitis

Interstitial lung disease

Pneumonitis
Colitis (reported as an AESI if ≥Grade 2 or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)

Intestinal obstruction

Colitis

Colitis microscopic

Enterocolitis

Enterocolitis haemorrhagic

Gastrointestinal perforation

Necrotizing colitis

Diarrhoea
Endocrine (reported as an AESI if ≥Grade 3 or ≥Grade 2 and resulting in dose modification 
or use of systemic steroids to treat the AE)

Adrenal insufficiency

Hyperthyroidism

Hypophysitis

Hypopituitarism

Hypothyroidism

Thyroid disorder

Thyroiditis

Hyperglycaemia, if ≥ Grade 3 and associated with ketosis or metabolic acidosis
Endocrine (reported as an AESI)

Type 1 diabetes mellitus (if new onset)


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Table 10.1.1: 1
Immune-related adverse events of special interest (cont.)
Immune-related adverse events of special interest
Hematologic (reported as an AESI if ≥Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)

Autoimmune haemolytic anaemia

Aplastic anaemia

Thrombotic thrombocytopenic purpura

Idiopathic (or immune) thrombocytopenia purpura

Disseminated intravascular coagulation

Haemolytic-uraemic syndrome

Any Grade 4 anaemia regardless of underlying mechanism
Hepatic (reported as an AESI if ≥Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)

Hepatitis

Autoimmune hepatitis

Transaminase elevations (ALT and/or AST)
Cytokine Release Syndrome (reported as an AESI if ≥Grade 2)
Infusion Reactions (reported as an AESI for any grade)

Allergic reaction

Anaphylaxis

Serum sickness

Infusion reactions

Infusion-like reactions
Neurologic (reported as an AESI for any grade)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as an AESI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE)

Uveitis

Iritis


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Table 10.1.1: 1
Immune-related adverse events of special interest (cont.)
Immune-related adverse events of special interest
Renal (reported as an AESI if ≥ Grade 2)

Nephritis

Nephritis autoimmune

Renal failure

Renal failure acute

Creatinine elevations (report as an AESI if ≥Grade 3 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)
Skin (reported as an AESI for any grade)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (reported as an AESI if ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (reported as an AESI for any grade)

Myocarditis

Pancreatitis

Pericarditis

Any other Grade 3 event that is considered immune-related by the physician
10.1.2
Management of immune-related adverse events
Regarding management of immune-related adverse events, grading and treatment, up-to-date 
published guidelines should be considered [e.g. P19-00269]. Only limited guidance on 
management of specific irAEs can be given here.
Please refer to published guidelines (e.g. ASCO guideline, Brahmer [P19-00269]) for details. 
In general, 
-
For irAEs listed below, the guidance from Section 4.1.4.3 is not considered applicable 
stating that only if a causal relationship to one trial drug can be unequivocally 
established, the other trial drug may be continued. On combination treatment both 


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drugs (BI 1387446 and ezabenlimab (BI 754091)) will be stopped, paused, or re-
exposed together.
-
Ezabenlimab (BI 754091) and BI 1387446 should be continued with close monitoring 
in case of grade 1 irAEs, with the exception of irAEs that may rapidly evolve into 
severe or fatal conditions (encephalitis of any grade, myocarditis of any grade, 
pneumonitis that is grade 1 but shows radiographic evidence of worsening – see 
detailed guidance below). A dose reduction of BI 1387446 may be considered, but is 
not required for the first occurrence of an irAE grade 1.
-
For most Grade 2 irAEs, ezabenlimab (BI 754091) and BI 1387446 should be 
withheld and treatment with corticosteroids is commonly warranted, usually with an 
initial dose of 0.5 to 1 mg/kg prednisone / prednisone equivalent daily. Restart of 
therapy is commonly possible once symptoms and/or laboratory values have resolved 
to grade 1 or less, and on ≤ 10 mg prednisone / prednisone equivalent per day. A dose 
reduction of BI 1387446 should be considered, but is not required for the first 
occurrence of an irAE, but is mandatory if the same irAE recurs upon rechallenge 
with BI 1387446.
-
For Grade 3 irAEs, ezabenlimab (BI 754091) and BI 1387446 has to be withheld, and 
treatment with high-dose corticosteroids (1-2mg/kg/d prednisone / prednisone 
equivalent) is usually warranted. Upon improvement, steroids should be tapered 
slowly over 4-6 weeks. Non-steroidal immunosuppressives (e.g. infliximab, 
mycophonlate mofetil) should be considered if no improvement or worsening occurs 
within the initial 48 to 72 hours. Upon recovery to grade 1 or less, and on ≤ 10 mg 
prednisone / prednisone equivalent per day, restarting ezabenlimab (BI 754091) and 
BI 1387446 may be considered for selected irAEs, but caution is advised, in particular 
in patients with early-onset irAEs. Expert consultancy and agreement with medical 
monitor is recommended prior to restart of therapy. BI 1387446 should be 
administered at a reduced dose.
-
Most Grade 4 irAEs warrant permanent discontinuation of ezabenlimab (BI 754091)
and BI 1387446. 
-
Restart of therapy is commonly possible for endocrine irAEs regardless of grade once 
stable hormone replacement has been instituted and symptoms have recovered. In 
case of multiple hormone deficiencies, corticosteroid replacement has to precede 
thyroid hormone replacement therapy by several days in order to avoid adrenal crisis. 
A dose reduction of BI 1387446 may be considered, but is not required for the first 
occurrence of an endocrine irAE.
In case of prolonged steroid therapy or treatment with immunosuppressives consider the 
possibility of opportunistic infections and tuberculosis reactivation. Careful monitoring and
consideration of administration of prophylactic antibiotics where appropriate are warranted. 
Commonly, referral to experts in the management of organ-specific conditions is highly 
recommended, especially for irAEs grade 3 or grade 4, or irAEs where management is 
complex. 
Ezabenlimab (BI 754091) and BI 1387446 should be permanently discontinued for immune 
related


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
encephalitis, aseptic meningitis, transverse myelitis, or Guillain-Barre syndrome of 
any grade 

acquired thrombotic thrombocytopenic purpura of any grade

myocarditis of any grade

myasthenia gravis, peripheral neuropathy or autonomic neuropathy of grade ≥3

myositis grade 2 with objective findings (see below), any myositis grade ≥3   

hepatitis grade ≥3  (transaminase >5 times ULN [or >10x ULN if baseline was >2.5-
5x ULN] or total bilirubin >3x ULN [or >5x ULN if baseline was >1.5-3x ULN), 
recurrent hepatitis grade ≥2

nephritis grade ≥3, persisting grade 2 nephritis unresponsive to initial steroid therapy 
or worsening, and recurrent nephritis grade ≥2 

pneumonitis grade ≥3, 

rash, bullous dermatoses, severe cutaneous adverse reaction, Stevens Johnson 
Syndrome, toxic epidermal necrolysis of grade 4, and recurrent rash grade ≥3 

colitis grade 4, and recurrent colitis of any grade 

uveitis, iritis, episcleritis of grade ≥3

autoimmune-haemolytic anaemia grade ≥2

haemolytic uremic syndrome grade ≥3

immune thrombocytopenia grade 4

any recurrent irAE grade ≥3, 

inability to taper steroids to 10 mg or less prednisone or equivalent within 12 weeks, 
or

persistent Grade 2-3 AEs that do not recover to Grade 1 or less within 12 weeks. 
For BI 1387446, up to 2 dose reductions are allowed if the treatment pause due to an AE is 
≤12 weeks and the re exposure is considered clinically indicated by the Investigator. Dose 
adjustment of ezabenlimab (BI 754091) besides interrupting or permanently discontinuing 
ezabenlimab (BI 754091) are not allowed (see Section 4.1.4.3). 
In rare situations when benefit and risk assessment is considered positive for a patient to 
continue ezabenlimab (BI 754091) and/or BI 1387446 treatment despite guidance to 
permanently discontinue (e.g. in case no alternative anti-cancer therapy is available), it 
should be discussed with the sponsor.  
Pneumonitis:

For Grade 1 pneumonitis with radiographic evidence of worsening, withhold ezabenlimab 
(BI 754091) and BI 1387446 until improvement or resolution; ezabenlimab (BI 754091)
and BI 1387446 may be reintroduced upon radiographic improvement. In the absence of 
radiographic improvement within 3-4 weeks, follow guidance as for grade 2 event. 

For Grade 2 pneumonitis, hold ezabenlimab (BI 754091) and BI 1387446 until resolution 
to at least grade 1. If not already started, initiate therapy for the event as per available 
guidelines. Follow guidance as for grade 3 pneumonitis if no clinical improvement after 
48 -72 hr of starting therapy. 

For Grade 3-4 pneumonitis, permanently discontinue ezabenlimab (BI 754091) and BI 
1387446 and immediately initiate treatment according to available guidelines. 


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Diarrhoea/Colitis:

For Grade 1 diarrhoea/colitis, consider interruption of ezabenlimab (BI 754091) and BI 
1387446 therapy.  

For Grade 2 diarrhoea/colitis, withhold ezabenlimab (BI 754091) and BI 1387446 until 
patient’s symptoms recovered to grade 1 or less. Consider initiating treatment with 
steroids. 

For Grade 3 diarrhoea/colitis, withhold ezabenlimab (BI 754091) and BI 1387446 and 
immediately start treatment (steroids, non-steroidal immunosuppressants) as per available 
guidelines. 

For Grade 4 diarrhoea/colitis, permanently discontinue ezabenlimab (BI 754091) and BI 
1387446 and immediately commence adequate therapy (e.g. i.v. corticosteroids).   

For Grade 1-3 colitis, restart of ezabenlimab (BI 754091) and BI 1387446 may be 
considered once symptoms improve to Grade 1 or less without need for continued 
steroids. After careful benefit risk assessment, ezabenlimab (BI 754091) and BI 1387446 
may also be restarted after recovery to grade 1 or less, and on corticosteroid ≤ 10 mg per 
day  

Ezabenlimab (BI 754091) and BI 1387446 should be permanently discontinued for 
recurrent diarrhoea/colitis of any grade.  
Diabetes

Consider withholding ezabenlimab (BI 754091) and BI 1387446 in case of grade 2 
hyperglycemia. Check for ketonuria. In case of new onset of diabetes or unexpected 
worsening of pre-existing diabetes, check for new manifestation of type 1 diabetes. 

For new onset Type 1 diabetes mellitus, or Grade 3-4 hyperglycaemia associated with 
ketosis (ketonuria or metabolic acidosis)
-
Initiate insulin therapy 
-
Evaluate subjects as appropriate per available guidelines regarding presence of type 1 
diabetes
-
Ezabenlimab (BI 754091) and BI 1387446 should be withheld until glucose level is 
controlled with insulin with no sign of ketoacidosis.  

Ezabenlimab (BI 754091) and BI 1387446 may be restarted once insulin therapy has 
established stable glycemic control 
Thyroid disorders:
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at screening and in regular intervals during treatment as indicated in Flow 
Chart and Section 5.2.3, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders. For diagnosed thyroid disorders, thyroid hormone 
supplementation and monitoring should occur as per available guidelines

Primary hypothyroidism:
-
For Grade 1 hypothyroidism, ezabenlimab (BI 754091) and BI 1387446 may be 
continued, with regular monitoring of thyroid values. 
-
For Grade 2 hypothyroidism, consider withholding ezabenlimab (BI 754091) and BI 
1387446
-
For Grade 3-4 hypothyroidism, withhold ezabenlimab (BI 754091) and BI 1387446, 
consider admission and IV therapy, especially in case of myxedema 


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-
Ezabenlimab (BI 754091) and BI 1387446 may be restarted once symptoms resolve to 
baseline with appropriate thyroid hormone supplementation

Primary hyperthyroidism
-
For Grade 1 hyperthyroidism, ezabenlimab (BI 754091) and BI 1387446 may be 
continued, with regular monitoring of thyroid values. 
-
For Grade 2 hyperthyroidism, consider withholding ezabenlimab (BI 754091) and BI 
1387446, initiate therapy as per available guidelines. 
-
For Grade 3-4 hyperthyroidism, withhold ezabenlimab (BI 754091) and BI 1387446. 
Consider hospitalization, especially in case of thyrotoxicosis. 
-
Ezabenlimab (BI 754091) and BI 1387446 may be restarted once symptoms resolve to 
baseline.
Note: in case of concomitant adrenal dysfunction, this must be corrected first, prior to thyroid 
hormone replacement (reduced stress tolerance) 
Adrenal insufficiency

Interruption of ezabenlimab (BI 754091) and BI 1387446 therapy should be considered 
for adrenal insufficiency grade 1 or 2, and is warranted for grade 3 and grade 4 adrenal 
insufficiency, until patient is stabilized on hormone replacement therapy. 

Therapy with ezabenlimab (BI 754091) and BI 1387446 may be restarted once stable 
replacement therapy has been achieved.

Note: in case of concomitant hypothyroidism, steroid replacement therapy should precede 
thyroid hormone substitution to avoid adrenal crisis.
Hypophysitis:

Diagnostic workup for hypophysitis should be considered e.g. for patients with multiple 
endocrinopathies, unexplained fatigue, new severe headaches or vision changes. 

Patients should be appropriately advised regarding potentially reduced stress tolerance 
and increased substitution demands e.g. in case of infections, and to wear a medical alert 
bracelet to inform medical personnel about potentially increased hormone demands in 
situations of stress, in case of emergencies.

Interruption of ezabenlimab (BI 754091) and BI 1387446 therapy should be considered 
for Grade 1 or 2 hypophysitis, and is warranted for Grade 3 and higher hypophysitis, until 
patient is stabilized on hormone replacement therapy. 
Hepatitis:

Work-up for other causes of elevated liver enzymes, see also section on potential DILI
(Section 5.2.7.1.4).

For Grade 1 hepatitis (elevated AST/ALT < 3x ULN and/or total bilirubin <1.5x ULN), 
ezabenlimab (BI 754091) and BI 1387446 may be continued, close monitoring of liver 
values is warranted.  

For Grade 2 hepatitis (AST/ALT 3–5x ULN and/or total bilirubin >1.5 to ≤ 3x ULN), 
ezabenlimab (BI 754091) and BI 1387446 should be suspended. Monitoring of liver 
values every 3 days is recommended. Initiate treatment according to available guidelines. 
Restarting of ezabenlimab (BI 754091) and BI 1387446 may be considered upon recovery 
to grade 1 or less, and on corticosteroid ≤ 10 mg per day.


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
For Grade 3 or higher hepatitis, ezabenlimab (BI 754091) and BI 1387446 have to be 
permanently discontinued. 
For eligible patients with elevated screening/baseline AST/ALT (>2.5-5x ULN or bilirubin 
>1.5-3x ULN): 

Carefully monitor patients for signs of autoimmune hepatitis. 

In case of increased levels of AST/ALT >2x baseline to ≤10x ULN and/or bilirubin >2x 
baseline to ≤5x ULN, ezabenlimab (BI 754091) and BI 1387446 should be suspended. 
Monitoring of liver values every 3 days or more frequently, if clinically indicated, is 
recommended. Restarting of ezabenlimab (BI 754091) and BI 1387446 may be 
considered upon recovery to baseline or less, and on corticosteroid ≤10 mg per day.

In case of increased AST/ALT >10x ULN and/or bilirubin >5x ULN, ezabenlimab (BI 
754091) and BI 1387446 have to be permanently discontinued. Initiate treatment as per 
guidelines
Nephritis:

For Grade 1 nephritis, consider temporarily withholding ezabenlimab (BI 754091) and BI 
1387446.

For Grade 2 nephritis, withhold ezabenlimab (BI 754091) and BI 1387446. Consult 
nephrology. Initiate treatment according to guidelines. In case of no improvement or 
worsening, permanently discontinue ezabenlimab (BI 754091) and BI 1387446.
Ezabenlimab (BI 754091) and BI 1387446 may only be re-started upon recovery to grade 
1 or less, and on corticosteroid ≤ 10 mg per day.

For Grade 3 or higher nephritis, permanently discontinue ezabenlimab (BI 754091) and 
BI 1387446. Consult nephrology. Treat with steroids 1-2 mg/kg prednisone or equivalent. 
If improved to grade 1 or less, taper corticosteroids over no less than 4-6 weeks.

Ezabenlimab (BI 754091) and BI 1387446should also be permanently discontinued for 
recurrent nephritis grade 2 or higher.
Rash

For Grade 1 rash, continue ezabenlimab (BI 754091) and BI 1387446. Initiate topical 
treatment.  

For Grade 2 rash, ezabenlimab (BI 754091) and BI 1387446may be continued, in case of 
no improvement upon weekly monitoring, consider interruption of ezabenlimab (BI 
754091) and BI 1387446 therapy. Treat topically, add systemic corticosteroid therapies as 
clinically appropriate. 

For Grade 3 rash, withhold ezabenlimab (BI 754091) and BI 1387446. Initiate topical and 
systemic therapy as per available guidelines. Upon improvement of event to grade 1 or 
less, and on corticosteroid ≤ 10 mg per day, consult with dermatology whether therapy 
with ezabenlimab (BI 754091) and BI 1387446 might be restarted, especially in case no 
alternative anti-neoplastic therapy is available. 

For Grade 4 rash, ezabenlimab (BI 754091) and BI 1387446 should be permanently 
discontinued.


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
Ezabenlimab (BI 754091) and BI 1387446 should also be discontinued for recurrent rash 
grade 3 or higher.
Bullous dermatosis

For Grade 1 bullous dermatosis, use local wound care and observation. Ezabenlimab (BI 
754091) and BI 1387446 can be continued. 

For Grade 2 bullous dermatosis, withhold ezabenlimab (BI 754091) and BI 1387446. 
Administer topical therapy, add systemic therapy as clinically adequate. 

For Grade 3 bullous dermatosis, withhold ezabenlimab (BI 754091) and BI 1387446, 
initiate topical and systemic therapy as per available guidelines. Upon recovery to grade 
1 or less, and on corticosteroid ≤ 10 mg per day, restarting of ezabenlimab (BI 754091)
and BI 1387446 may be considered after dermatology consultation. 

For Grade 4 bullous dermatosis, permanently discontinue ezabenlimab (BI 754091) and 
BI 1387446.
Severe cutaneous adverse reaction (SCAR), Stevens Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN)

For Grade 2 events, withhold ezabenlimab (BI 754091) and BI 1387446, initiate 
treatment as per available guidelines. Closely monitor for improvement or worsening. 

For Grade 3 events, withhold ezabenlimab (BI 754091) and BI 1387446. Initiate 
treatment as per available guidelines. In case mucous membranes are affected, involve 
appropriate disciplines in management to prevent sequelae from scarring (e.g. 
ophthalmology). 

For Grade 4 events, permanently discontinue ezabenlimab (BI 754091) and BI 1387446, 
immediately administer adequate therapy. Immediate admission to burn center or 
intensive care with dermatology and wound care is recommended, involve appropriate 
other disciplines as needed in management of mucosal involvement. 
In case of Grade 2 or Grade 3 events, ezabenlimab (BI 754091) and BI 1387446 may only be 
re-started upon event recovered to Grade 1 or less, on corticosteroid ≤ 10 mg per day, and 
after consultation with dermatology. 
Encephalitis/Aseptic meningitis

Ezabenlimab (BI 754091) and BI 1387446 should be permanently discontinued for any 
grade.
  
Myasthenia gravis

For Grade 2 myasthenia gravis, withhold ezabenlimab (BI 754091) and BI 1387446, 

For Grade 3 or 4 myasthenia gravis, permanently discontinue ezabenlimab (BI 754091)
and BI 1387446
Guillain Barré Syndrome (GBS)

Discontinue ezabenlimab (BI 754091) and BI 1387446permanently for any grade GBS. 


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Transverse Myelitis

Discontinue ezabenlimab (BI 754091) and BI 1387446 permanently for any grade 
transverse myelitis. 
Peripheral neuropathy, autonomic neuropathy

For Grade 1 events, may continue ezabenlimab (BI 754091) and BI 1387446, but with 
low threshold to discontinue while monitoring closely for worsening. 

For Grade 2 events, withhold ezabenlimab (BI 754091) and BI 1387446 until resolution 
to grade 1 or less, and on corticosteroid ≤ 10 mg per day. Initiate therapy as appropriate 
per available guidelines. 

For Grade 3 or grade 4 events, permanently discontinue ezabenlimab (BI 754091) and BI 
1387446. 
Inflammatory Arthritis

For Grade 1 arthritis, ezabenlimab (BI 754091) and BI 1387446 can be continued. 
Administer analgetic treatment (acetaminophen, NSAID). 

For Grade 2-4 arthritis, withhold ezabenlimab (BI 754091) and BI 1387446. Initiate 
treatment as per available guidelines, cave regarding reactivation of 
tuberculosis/opportunistic infections in case of prolonged immunosuppressive/disease 
modifying anti-rheumatic drugs (DMARD) therapy. 
Ezabenlimab (BI 754091) and BI 1387446 may be restarted after consultancy with 
rheumatology once recovery to grade 1 or less, and on corticosteroid ≤ 10 mg per day. 
Myositis
Diagnostic workup should consider the need to also evaluate myocardial involvement.   

For Grade 1 myositis, ezabenlimab (BI 754091) and BI 1387446 may be continued. 
Initiate adequate therapy as clinically warranted. In case of elevated CK or muscle 
weakness, treat as grade 2. 

For Grade 2 myositis, withhold ezabenlimab (BI 754091) and BI 1387446, discontinue 
permanently in patients with objective findings (elevated enzymes, abnormal EMG, 
abnormal muscle MRI or biopsy). Initiate therapy as per available guidelines. Resuming 
ezabenlimab (BI 754091) and BI 1387446 may be considered in patients without 
objective findings, symptoms have resolved to grade 1 or less without any 
immunosuppressive therapy, and after consultation with rheumatology/neurology. 

For Grade 3 or 4 myositis, permanently discontinue ezabenlimab (BI 754091) and BI 
1387446. 

Ezabenlimab (BI 754091) and BI 1387446 should be permanently discontinued if there is 
any evidence of myocardial involvement.
Polymyalgia-like syndrome

For Grade 1 event, ezabenlimab (BI 754091) and BI 1387446 can be continued.   

For Grade 2 event, withhold ezabenlimab (BI 754091) and BI 1387446 and promptly 
initiate adequate therapy. If no improvement, treat as grade 3.

For Grade 3 or G4 event, withhold ezabenlimab (BI 754091) and BI 1387446, promptly 
initiate adequate therapy Rheumatology consultancy is highly recommended.


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Ezabenlimab (BI 754091) and BI 1387446 may be resumed after careful assessment of 
risks and benefits, rheumatology consultancy highly recommended prior to reinitiation. 
Ezabenlimab (BI 754091) and BI 1387446 may only be re-started upon recovery to 
grade 1 or less and on corticosteroid ≤ 10 mg per day. 
Myocarditis

Discontinue ezabenlimab (BI 754091) and BI 1387446 permanently for any grade of 
myocarditis. 
Uveitis/Iritis, Episcleritis

For Grade 1 events, treatment with ezabenlimab (BI 754091) and BI 1387446 can 
continue. Treat topically as needed.

For Grade 2 events, withhold therapy with ezabenlimab (BI 754091) and BI 1387446, 
urgent ophthalmology referral is recommended. Initiate topical treatment, consider 
systemic therapy if needed. Restart of ezabenlimab (BI 754091) and BI 1387446 is 
permitted once resolved to grade 1 or less, and off systemic steroids (for the ocular 
condition, if steroids needed for other irAEs, up to 10 mg prednisone or equivalent are 
permitted). Continuation of topical/ocular steroids is permitted and does not prohibit 
resuming ezabenlimab (BI 754091) and BI 1387446 therapy. 

For Grade 3 or 4 events, permanently discontinue ezabenlimab (BI 754091) and BI 
1387446 therapy. Seek emergent ophthalmology consultation. Initiate adequate local and 
systemic treatment.   
Autoimmune-haemolytic anaemia (AIHA)

For Grade 1 AIHA, continue treatment with ezabenlimab (BI 754091) and BI 1387446. 
Close follow-up of anaemia and other lab values. 

For Grade 2-4 AIHA, discontinue ezabenlimab (BI 754091) and BI 1387446
permanently. Initiate systemic therapy as per guideline. Consult Haematology.
Acquired thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome. 
Timely recognition upon suggestive findings is essential, timely/immediate involvement of 
haematology consultancy may be beneficial. 

For any grade TTP, permanently discontinue ezabenlimab (BI 754091) and BI 1387446. 

For HUS (TTP excluded), withhold ezabenlimab (BI 754091) and BI 1387446 for grade 
1 and grade 2, provide supportive care. Upon full recovery, ezabenlimab (BI 754091)
and BI 1387446 may be restarted after carefully weighing of risks and benefits. 

For Grade 3 or Grade 4 HUS, discontinue ezabenlimab (BI 754091) and BI 1387446 
permanently. 
Immune thrombocytopenia (ITP)

In case of Grade 1 ITP, ezabenlimab (BI 754091) and BI 1387446 can be continued. 

For Grade 2 or Grade 3 ITP, withhold ezabenlimab (BI 754091) and BI 1387446 and 
initiate systemic therapy. Ezabenlimab (BI 754091) and BI 1387446 may be restarted 
upon resolution to at least grade 1. 

For Grade 4 ITP, permanently discontinue ezabenlimab (BI 754091) and BI 1387446. 


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Infusion related reactions (IRRs):
Signs and symptoms of IRRs usually develop during or shortly after ezabenlimab (BI 
754091) infusion and generally resolve completely within 24 hours of completion of infusion. 
If symptoms develop during infusion, they may be managed with slowing or transient 
interruption of infusion (Section 4.1.4.3).
10.2
MANAGEMENT OF CRS
CRS grading should be performed according to ASBMT consensus grading [R19-0309]. 
Treatment of CRS should be based on published recommendations [R19-0310, R19-0311], 
the recommendations in Table 10.2: 1 should be considered by the Investigator as guidance.
Table 10.2: 1
CRS grading, treatment and management of trial drugs
Grade
Definition of 
grade
Recommendation for treatment of CRS
Management of trial drugs
Grade 1
Fever >38°C 
without 
hypotension or 
hypoxia
-
symptomatic management of fever 
with acetaminophen or ibuprofen 
unless contraindicated
-
maintenance fluids for hydration
-
symptomatic management of 
constitutional symptoms or organ
toxicities
-
for persistent and refractory fever (>3 
days) in absence of infection consider 
corticosteroids
-
stop administration of BI 
1387446 and ezabenlimab 
(BI 754091) if not fully 
administered
-
continue treatment with the 
subsequent administration 
of BI 1387446 and 
ezabenlimab (BI 754091)
provided that all symptoms 
have completely resolved 
for at least 48 hours
-
delay/skip the subsequent 
administration if needed to 
ensure that all symptoms 
have completely resolved 
for at least 48 hours


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Table 10.2: 1
CRS grading, treatment and management of trial drugs (cont.)
Grade
Definition of 
grade
Recommendation for treatment of CRS
Management of trial drugs
Grade 2
Fever >38°C 
with either 
hypotension 
not requiring 
vasopressors 
and/or hypoxia 
requiring low-
flow nasal 
cannula or 
blow-by
-
manage fever and constitutional 
symptoms as in grade 1
-
supplemental oxygen as needed
-
IV fluid bolus of normal saline (500-
1000 mL)
-
consider second IV fluid bolus if 
systolic blood pressure remains <90 
mmHg
-
dexamethasone 10 mg IV every 6h
-
if hypotension persists after 2 fluid 
boluses and dexamethasone, start 
vasopressors and consider transfer to 
ICU
-
anti-IL6-therapy, e.g. tocilizumab or 
siltuximab, may be considered
-
symptomatic management of organ 
toxicities as per standard guidelines
-
stop administration of BI 
1387446 and ezabenlimab 
(BI 754091) if not fully 
administered
-
continue treatment with the 
subsequent administration 
of BI 1387446 and 
ezabenlimab (BI 754091)
provided that all symptoms 
have completely resolved 
for at least 48 hours
-
delay/skip the subsequent 
administration if needed to 
ensure that all symptoms 
have completely resolved 
for at least 48 hours
-
at the subsequent 
administration of the 
respective drug, patients 
should be under close 
surveillance of appropriate 
duration
Grade 3
Fever >38°C 
with either 
hypotension 
requiring one 
vasopressor 
with or without 
vasopressin 
and/or hypoxia 
requiring high-
flow nasal 
cannula, 
facemask, non-
rebreather 
mask or 
Venturi mask
-
IV fluid boluses and vasopressors as 
needed
-
transfer to ICU, initiate hemodynamic 
monitoring
-
dexamethasone 10 mg IV every 6h, if 
refractory increase to 20 mg IV every 
6h
-
supplemental oxygen as needed
-
manage fever and constitutional 
symptoms as indicated for grade 1
-
anti-IL6-therapy, e.g. tocilizumab or 
siltuximab, may be considered
-
symptomatic management of organ 
toxicities as per standard guidelines
-
stop administration of BI 
1387446 and ezabenlimab 
(BI 754091) if not fully 
administered
-
if CRS is considered 
unequivocally related to BI 
1387446: do not re-expose 
the patient to BI 1387446, 
ezabenlimab (BI 754091)
may be continued as per 
protocol once CRS has 
completely resolved for at 
least 7 days
-
if CRS is unequivocally 
related to ezabenlimab (BI 
754091): permanently 
discontinue ezabenlimab 
(BI 754091)
-
If there is uncertainty about
causality assessment: 
permanently discontinue BI 
1387446 and ezabenlimab 
(BI 754091)
-


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Table 10.2: 1 CRS grading, treatment and management of trial drugs (cont.)
Grade
Definition of 
grade
Recommendation for treatment of CRS
Management of trial drugs
Grade 4
Fever >38°C 
with either 
hypotension 
requiring 
multiple 
vasopressors 
(excl. 
vasopressin) 
and/or hypoxia 
requiring 
positive 
pressure, e.g. 
continuous 
positive airway 
pressure 
(CPAP), 
bilevel positive 
airway pressure 
(BiPAP), 
intubation and 
mechanical 
ventilation
-
ICU transfer, IV fluids, vasopressors 
and hemodynamic monitoring as 
indicated for grade 3
-
manage fever and constitutional 
symptoms as indicated for grade 1
-
methylprednisolone 1 g/day IV
-
respiratory support including 
mechanical ventilation
-
anti-IL6-therapy, e.g. tocilizumab or 
siltuximab, may be considered
-
symptomatic management of organ 
toxicities as per standard guidelines
-
same as for grade 3
10.3
TUMOUR ASSESSMENTS
Tumour assessments will be performed according to Response criteria for intratumoural 
immunotherapy in solid tumours (itRECIST) (R20-2734). 
At baseline, tumour lesions and lymph nodes will first be categorised as measurable or non-
measurable. Measurable lesions are then classified as target (selected to be observed 
quantitatively) or non-target (selected to be observed qualitatively), and the decision about 
which lesion is to be injected is made. In this trial, a lesion selected for injection must be 
measurable (see Section 10.3.1 for details).
At baseline, one lesion projected for injection should be classified as target injected (T-I), 
only in exceptional cases, two lesions may be projected for injection and thus be classified as 
T-I (refer to Section 4.1.4.1). Up to 5 lesions can be classified as target non-injected (T-NI). 
All lesions not chosen as target are observed qualitatively as non-target. See Figure 10.3: 1
for details on the classifications of lesions at baseline. As in this trial, a lesion selected for 
injection must be measurable, lesions selected for injection at baseline can only be target
(refer to Section 4.1.4.1).


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Figure 10.3: 1
Classification of lesions at baseline
Lesions designated as T-I will be used to evaluate the injected lesion response. Lesions 
designated as T-NI should remain non-injected for as long as possible to allow assessment of 
the maximal non-injected lesion response. However, in the case that there is no other lesion 
available for injection, or the T-NI lesions are enlarging, T-NI lesions may be injected and 
recategorized to T-I, if they meet the criteria for injection.
Similarly to T-NI lesions, also NT-NI lesions may be injected and recategorized to NT-I, if 
they meet the criteria for injection (in particular if they are measurable according to 
Section 10.3.1). However, even though measurable, these lesions will contribute to the 
overall response only with their qualitative assessment.
A sum of diameters (SOD; longest diameters for extranodal lesions and short axis for lymph 
nodes) will be calculated for all target lesions combined and separately for T-I and T-NI-
lesions. 
The overall response for each visit will be based on the changes in the SOD of all target 
lesions together (SOD of T-I and T-NI combined versus combined SOD at baseline and at 
nadir), the qualitative assessment of all non-target lesions, and the evaluation for possible 
new lesions. The same response categories and their logical combination as with RECIST 1.1
will be used. The following overall response categories may be assigned: Complete Response 
(itCR), Partial Response (itPR), Stable Disease (itSD), Unconfirmed Progressive Disease 
(itUPD), and Confirmed Progressive Disease (itCPD). See Figure 10.3: 2 for details. 


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Figure 10.3: 2
Overall response by itRECIST
For the purpose of this trial, assessment of individual lesions, injected and non-injected, as 
well as the overall response assessment for each visit will be reported in the eCRF, but the 
injected and non-injected response (including the quantitative best percentage change from 
baseline in size of injected and non-injected lesions) will only be derived retrospectively for 
the final analysis. Both, the non-injected lesion response and the injected lesion response, will 
be based on the respective target lesions’ SODs (See Section 7 for details).  
10.3.1
Injected lesions
At screening the Investigator will select a tumour lesion which is projected to be injected. All 
injected tumour lesions need to be measurable as per RECIST 1.1, i.e. the longest diameter 
must have a minimum size of

10 mm if measured by CT scan or MRI (lymph nodes have to be at least 15mm in 
short axis) 

20 mm by chest X-ray.
The following modifications to RECIST 1.1 apply according to itRECIST:

Ultrasound is acceptable to guide injection into any lesion location for which 
ultrasound guidance is indicated. For tumour assessments ultrasound may be used for 
measurement of lesions classified as superficial, e.g. soft tissue lesions, which cannot 
be effectively imaged by CT scan. However, ultrasound is not acceptable for tumour
assessments of deep/visceral lesions which can be measured on CT or MRI scans. The 
longest diameter of a non-visible lesion measured by ultrasound must have a 
minimum size of 10 mm.

All visible tumour lesions potentially suitable for injection need to be assessed at 
baseline by digital photography with the use of a caliper/digital scale. The longest 
diameter of a visible lesion has to be at least 1 cm to qualify for injection. The 
injected lesion has to be measured and documented by digital photography with 
caliper/digital scale at each tumour assessment timepoint. If more than one visible 


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lesion is present, non-injected visible lesions may be selected as target lesions if the 
longest diameter meets the minimum criteria as required per RECIST 1.1 (see Section 
10.3.2.1).
One measurable lesion will be selected for injection at baseline and classified as target 
injected (T-I) according to itRECIST. Only in exceptional cases, two lesions may be selected 
for injection and classified as T-I. Each lesion selected for injection will be unequivocally 
identified in the eCRF. Radiologic images as well as photographic images of visible lesions 
will be collected for central review. If available, additional information, e.g. screenshots or 
marks on imaging studies submitted for central review may be considered in addition. Visible 
tumour lesions, e.g. skin lesions, have to be documented by digital photography with the use 
of a caliper/digital scale. 
Measurable lesions not pre-selected for injection at baseline can be re-categorized as injected 
lesions during the course of the trial if the decision is made to inject them after baseline 
assessment. In case different lesions are injected during the course of the trial, all injected 
lesions need to be identified at baseline or in retrospect on the imaging study or 
photodocumentation at baseline and captured in the eCRF. 
Location of lesions will be classified as skin, other connective tissue, lymph node, liver, other 
organ.
10.3.2
Non-injected lesions
Photodocumentation for visible lesions as outlined in Section 10.3.1 and ultrasound for 
superficial lesions not measurable on CT may be used for the assessment of non-injected 
lesions too.
Optimal anatomic coverage of imaging studies should encompass all areas of known 
predilection for metastases in the disease under evaluation, and should additionally 
investigate areas that may be involved based on signs and symptoms of individual patients. 
Because a lesion later identified in a body part not scanned at baseline would be considered 
as a new lesion representing disease progression, careful consideration should be given to the 
extent of imaging coverage at baseline and at subsequent follow-up time points. This will 
enable better consistency not only of tumour measurements but also identification of new 
disease.
10.3.2.1
Target non-injected (T-NI) lesions
Measurable non-injected tumour lesions must be accurately measured in at least one 
dimension, the longest diameter in the plane of measurement is to be recorded with a 
minimum size of 

10 mm by CT scan, 

10 mm by caliper measurement by clinical exam or ultrasound, or 

20 mm by chest X-ray. 
Malignant lymph nodes must be ≥15 mm in short axis.


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When more than one measurable non-injected lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
all tumour assessment timepoints indicated in the Flow Chart.
Preferably, a non-injected lesion which is selected for biopsy should not be classified as 
target non-injected lesion. 
10.3.2.2
Non-target non-injected (NT-NI) lesions
Non-measurable non-injected lesions, e.g. malignant effusions, lymphangitic involvement of 
skin or lung, leptomeningeal disease, or measurable lesions not selected as target lesions will 
be captured as non-target lesions and qualitatively assessed at the tumour assessment 
timepoints indicated in the Flow Chart.
10.3.2.3
Confirmation of response
According to RECIST1.1, a CR or PR should be confirmed if possible at the subsequent 
planned scanning timepoint at least 4 weeks later.
10.4
PHARMACOKINETIC METHODS AND ANALYSES
Pharmacokinetic analysis
The exploratory parameters (refer to Section 5.3.1) will be calculated according to internal 
SOPs. All evaluable patients who received at least one dose of BI 1387446 or ezabenlimab 
(BI 754091) and provide at least one plasma concentration value will be included in the PK 
analysis. Patients who are considered as not evaluable will be listed with their individual 
plasma concentrations and individual PK parameters, and will be not included in descriptive 
statistics for plasma concentrations, PK parameters or other statistical assessment.
The following descriptive statistics will be calculated for all analyte concentrations as well as 
for all PK parameters: N, arithmetic mean, standard deviation, minimum, median, maximum, 
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. 
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations.
Handling of missing data
Drug concentration - time profiles
Concentration data identified with NOS (no sample available), NOR (no valid result), NOA
(not analysed), and BLQ (below the limit of quantification) will be ignored and not replaced
by zero at any time point (applies also to the lag phase including the pre-dose value(s)).
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR and NOA
will not be considered. BLQ values in the lag phase will be set to zero. The lag phase is


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defined as the period between time 0 and the first time point with a concentration above the 
quantification limit. All other BLQ and NOP values of the profile will be ignored.
Pharmacokinetic parameters which cannot be determined will be identified by "not 
calculated" (NC).
Every effort will be made to include all concentration data in an analysis. If not possible, a
case to case-to-case decision is required whether the value should only be excluded from
half-life estimation or the complete analysis.

If a concentration is only excluded from half-life determination, it will be used for all
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented
graphically or used for the calculation of descriptive statistics and parameter
determination. However, the excluded concentration itself will be listed in the CTR
associated with an appropriate flag.
If the actual sampling time will not be recorded or will be missing for a certain time point, the 
planned time will generally be used for this time point instead. Pharmacokinetic parameters 
which cannot be determined will be identified by "not calculated" (NC).
10.5
STATISTICAL APPENDIX
A joint BLRM with overdose control will be used to guide dose escalation in Arms A and B 
of the trial. The model is introduced in Section 7, which also specifies the priors for the 
model. After patients in each cohort have completed at least one cycle of treatment, the prior 
distribution will be updated through No-U-Turn sampling procedures (Hamiltonian Monte 
Carlo, [R21-3791]) with the accumulated DLT data from the MTD evaluation period. 
Posterior probabilities for the rate of DLTs will be summarised from the joint BLRM for 
Arms A and B. Selection of the next dose in each arm will be based on these probabilities as 
well as on other safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD under various 
dose-toxicity relationships through computer simulation. These results are summarised in 
Table 10.5: 3. For simplicity reasons, a cohort size of 3 patients who are all evaluable starting 
at 50 µg (Arms A and B) is assumed for calculation of the operating characteristics.
In addition, recommendations of the next dose level in each arm by the joint BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios to 
show how it facilitates on-trial dose-escalation decisions (see Table 10.5: 1). 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5: 1 for Arms A and B. These scenarios 
reflect potential on-trial data constellations and related escalation as allowed by the model 
and the 100% escalation limit. For each scenario and each arm, the probability of overdose 
for the current dose, as well as the next potential dose and related probabilities of under-
dosing, target dose and over-dosing are shown.




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Scenarios 6 and 10 explicitly show the characteristics of the joint model. If DLTs are only 
observed in one of the three arms, escalation is also influenced in the other arms. For example 
in Scenario 10, although no DLTs are observed in Arm B, no escalation 
 
is allowed by the overdose control implemented in the model since 3 of 6 
patients in Arm A experienced DLTs 
In Scenario 6, the DLTs that are observed in 
Arm B
result in de-escalation of the dose in Arm A 
 
although in Arm A no DLTs have been observed. 
Finally, Scenarios 13 and 14 illustrate cases where escalation has proceeded up to the highest 
dose 
 in Arm A and
 in Arm B. In both Arms, this dose
(combination) could be declared as MTD as it satisfies the conditions for MTD declaration 
specified in Section 7.










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characteristics of the joint model for these arms. The toxicity scenarios reflect a wide range of 
possible cases as follows:

Scenario 1: moderate-toxicity scenario

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: non-logistic dose-toxicity scenario

Scenario 5: all planned doses in overdose range
For Arms A and B, two additional scenarios were used to assess the operating characteristics, 
especially to assess the effect of the interaction between BI 1387446 and ezabenlimab (BI 
754091).

Scenario 6: data for ezabenlimab (BI 754091) largely deviates from data for BI 
1387446, represented by a very flat dose-toxicity curve (as indicated by currently 
available data on ezabenlimab (BI 754091)) that lies in the overdose range (indicating 
a quite toxic behaviour of BI 1387446, contrarily to the ezabenlimab (BI 754091)
data, which indicate a very low toxicity overall)

Scenario 7: Large interaction effect between BI 1387446 and ezabenlimab (BI 
754091)




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Table 10.5: 3
Simulated operating characteristics for Arms A and B
 
In Scenario 1 which reflects the case of a moderate true dose-toxicity, around 29% of trials in 
Arm A have found an MTD with true DLT rate in the target interval. In addition to that, 288
trials 
as MTD, which has an assumed true toxicity probability of 0.136
which is very close to the lower boundary of the target interval. In Arm B, around 82% of the
simulated trials have declared a dose as MTD that has an assumed true DLT rate in the target 
range.
In Scenario 2 (high-toxicity scenario), around 41% of trials in Arm A and around 27% of 
trials in Arm B have been stopped prematurely due to too toxic doses. This is an expected 
situation for a high-toxicity scenario. Nevertheless, around 55% of trials in Arm A and 
around 61% of trials in Arm B declared a dose as MTD that has an assumed true DLT rate in 
the target interval.
Scenario 3 (low-toxicity scenario) shows that in Arm A around 63% of trials declared MTDs 
with true DLT rate in the target interval. The majority of the rest of the trials (256 trials) 
as the MTD, which has a true DLT rate in the underdose interval. In Arm B 
around 90% of trials declared a dose as MTD that has an assumed true toxicity rate in the 
target interval. 
Scenario 4 represents a case where the assumed true dose-toxicity curve does not follow a 
logistic shape. In this scenario, 40.3% of trials in Arm A determined a dose as MTD which 


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has a true DLT rate in the target interval. Additionally, 475 trials in Arm A declared 
 
as the MTD, which has an assumed true toxicity probability of 0.112. In Arm B, 67.9% of 
trials declared a dose as MTD which has a true DLT rate in the target interval. In addition to 
that, 207 trials declared the combination of 
240 mg as MTD which has an assumed 
true toxicity probability of 0.383, which is close to the upper boundary of the target interval.
In scenario 5, all specified dose levels have an assumed toxicity rate in the overdose interval. 
In this case most of the simulated trials stop prematurely because all specified dose levels are 
too toxic. In all 3 arms several simulated trials (Arm A: 13.8%, Arm B: 12.4%) declare doses 
as MTD with true DLT rate in the overdose interval. Most of these trials choose 
or 
as MTD. These doses have assumed true toxicity rates not too far away from the 
target rate therefore this is still acceptable for such overly toxic scenarios.  
In scenario 6, the data for ezabenlimab (BI 754091) largely deviates from the data for BI 
1387446. While a flat dose-toxicity curve that lies in the overdose range is assumed for BI 
1387446, very low toxicity is assumed for ezabenlimab (BI 754091). This results in high-
toxicity for the combination arm B: Many of the simulated trials in Arm B stop prematurely 
because all specified dose levels are too toxic. Additionally, around 56% of trials in Arm B
declare doses as MTD with true DLT rate in the overdose interval. Most of these trials choose 
 or 
as MTD. These combinations have assumed true toxicity 
rates not too far away from the target rate. In Arm A, 51.6% of the simulated trials declare a 
dose as MTD which has an assumed true DLT rate in the underdose interval. In almost all of 
these cases 
were chosen as MTD and these dose levels have an assumed 
true toxicity probability of 0.099 
and 0.136 
In scenario 7 (high interaction between BI 1387446 and ezabenlimab (BI 754091)), 44.9% of 
the trials in Arm A declared a dose as MTD which has a true DLT rate in the underdose 
interval. 314 of these trials declared 
as the MTD which has a true toxicity probability 
of 0.136 which is close to the lower boundary of the target interval. In Arm B around 74% of 
trials determined an MTD that has an assumed true toxicity rate in the target interval. 
The mean patient numbers in Arm A range from approximately 5.6 patients (Scenario 5) to 
17.3 patients (Scenario 3) and the maximum number of patients was 36 (Scenario 3). 
Similarly, for Arm B, the mean patient numbers range from 5.0 (Scenario 5) to 15.6 
(Scenario 3), with a maximum number of 45 patients in a simulated trial under Scenario 3.
Therefore, the patient numbers are as expected and increase when moving away from the 
high-toxicity scenario.
By reviewing the metrics presented in Table 10.5: 3, it can be seen that the joint model is not 
sensitive to different scenarios of truth. Even under misspecification results are satisfactory. 
In general, these models are conservative due to the overdose control criteria. In all scenarios, 
the probabilities of recommending a dose with true P(DLT) ≥33% as MTD are much smaller 
than probabilities of recommending a dose with true P(DLT) between 16% and 33% as MTD.


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On-trial recommendations based on the joint model for Arms A and B are consistent with the 
clinical decision making process, and should be considered in conjunction with other 
available clinical information by the BI clinical trial team and trial investigators in deciding 
the dose levels to be tested in order to determine the MTD estimate. R version 4.0.5 and the 
rstan package version 2.21.2 were used for data scenarios and simulations.
Table 10.5: 4 provides a comparison between trials 1426-0001 and 1381-0001 regarding 
study population, DLT definition and treatment schedule.
Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Signed and dated written informed consent 
in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
Provision of signed and dated, written ICF 
prior to any trial-specific procedures, 
sampling, or analyses. 
Patients ≥18 years
Patients ≥18 years
Women of childbearing potential eligible if 
on highly effective methods of birth control
Women of childbearing potential eligible if 
on highly effective methods of birth control
Male patients must be willing to use barrier 
contraception methods
Male patients must be willing to use barrier 
contraception methods
ECOG 0 or 1
ECOG 0 or 1
Life expectancy at least 12 weeks
Life expectancy of at least 12 weeks


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Histologically or cytologically confirmed 
diagnosis of an advanced, unresectable 
and/or metastatic malignant solid tumour
and indication for treatment.
Patients with a histologically confirmed 
diagnosis of advanced, unresectable, and/or 
metastatic solid tumours (any type).
Patients with a histologically confirmed 
diagnosis of select advanced, unresectable, 
and/or metastatic solid tumours with 
specific histology/tumour types and/or 
specific genetic profiles
Patient must have exhausted established 
treatment options known to prolong 
survival for the malignant disease, or is not 
eligible for established treatment options
Patients who have received all therapy 
known to confer clinical benefit (including 
anti-PD-1 or anti-PD-L1 therapies, if 
relevant), or for whom no therapy of 
proven efficacy exists, or who are not 
amenable to standard therapies.
Adequate organ function or bone marrow 
reserve as demonstrated at screening by the 
following laboratory values:
absolute neutrophil count (ANC) ≥ 1.5 x 
109/L (≥ 1.5 x 103/µL, ≥ 1,500/mm3)
platelet count ≥ 100 x 109/L (≥ 100 x 
103/µL, ≥ 100 x 103/mm3)
hemoglobin ≥ 90 g/L (≥9.0 g/dL, ≥5.6 
mmol/L)
total bilirubin ≤ 1.5 times the upper limit of 
normal (ULN), except for patients with 
Gilbert’s syndrome: total bilirubin ≤ 3 x 
ULN or direct bilirubin ≤ 1.5 x ULN.
alanine aminotransferase (ALT)/Aspartate 
aminotransferase (AST): 
patients without liver metastases: 
ALT/AST ≤2.5 x ULN  
patients with liver metastases with planned 
injection into liver lesion: ALT/AST ≤2.5 x 
ULN
patients with liver metastases without 
planned injection into liver lesions: 
Inadequate organ function or bone marrow 
reserve as demonstrated by the following 
laboratory values:
Absolute neutrophil count <1.5 x 109/L 
(<1500/mm3)
Platelet count <100 x 109/L
Haemoglobin <90 g/L (<9 g/dL)
Total bilirubin >1.5 times ULN, except for 
patients with Gilbert's syndrome who are 
excluded if total bilirubin >3.0 times ULN 
or direct bilirubin >1.5 times ULN
Alanine aminotransferase (ALT) >2.5 times 
the upper limit of normal (ULN) if no 
demonstrable liver metastases or >5 times 
ULN in the presence of liver metastases
Aspartate aminotransferase (AST) >2.5 
times ULN if no demonstrable liver 
metastases or >5 times ULN in the 
presence of liver metastases


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
ALT/AST ≤ 5 x ULN
Creatinine ≤ 1.5 x ULN. If creatinine is > 
1.5 x ULN, patient is eligible if concurrent 
creatinine clearance ≥ 45 ml/min (measured 
or calculated by CKD-EPI formula).
prothrombin time (PT) ≤ 1.5 x ULN
activated partial thromboplastin time 
(aPTT) ≤1.5 x ULN
Creatinine >1.5 times ULN or creatinine 
clearance <50 mL/min (measured or 
calculated by Chronic Kidney Disease 
Epidemiology (CKD-EPI) Collaboration
equation); confirmation of creatinine 
clearance is only required when creatinine 
is >1.5 times ULN


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
Any investigational or antitumour 
treatment (including antibodies targeting 
PD1- or PD-L1) within 4 weeks or 5 half-
life periods (whichever is shorter) prior to 
the initial administration of BI 1387446
Any investigational or antitumour treatment 
within 4 weeks or 5 half-life period 
(whichever is shorter) prior to the initial 
administration of BI 754091.
Persistent toxicity from previous 
treatments (including irAEs) that has not 
resolved to ≤ Grade 1, except for alopecia, 
xerostomia, and immunotherapy related 
endocrinopathies which may be included if 
clinically stable on hormone supplements 
or antidiabetic drugs as per investigator 
judgement
History or evidence of active, non-
treatment related autoimmune disease, 
except for endocrinopathies which may be 
included if clinically stable on hormone 
supplements or antidiabetic drugs.
Active autoimmune disease or a 
documented history of autoimmune disease, 
except vitiligo or resolved childhood 
asthma/atopy
History of pneumonitis related to prior 
immunotherapy
History of pneumonitis within the last 5 
years
Immunosuppressive corticosteroid doses 
(>10 mg prednisone daily or equivalent) 
within 2 weeks prior to the first dose of BI 
1387446 or ezabenlimab (BI 754091)
Immunosuppressive corticosteroid doses 
(>10 mg prednisone daily or equivalent) 
within 4 weeks prior to the first dose of BI 
754091
The tumour at the projected injection site 
has a high risk for local complications, e.g. 
bleeding related to encasement/infiltration 
of major blood vessels or contact with liver 
capsule, compression of vital structures in 
case of swelling of injected lesion, in the 
opinion of the investigator (see Section 
4.1.4.2).


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
Presence or history of uncontrolled or 
symptomatic brain or subdural metastases, 
unless local therapy was completed and 
metastases considered stable by the 
investigator
Untreated brain metastasis(es) that may be 
considered active. Patients with previously 
treated brain metastases may participate 
provided they are stable (i.e., without 
evidence of PD by imaging for at least 4 
weeks prior to the first dose of trial 
treatment, and any neurologic symptoms 
have returned to baseline), and there is no 
evidence of new or enlarging brain 
metastases
Presence of other active invasive cancers 
other than the one treated in this trial 
within 5 years prior to screening, with the 
exception of appropriately treated basal-
cell carcinoma of the skin, in situ 
carcinoma of the uterine cervix, or other 
local tumours considered cured by local 
treatment
Presence of other active invasive cancers 
other than the one treated in this trial within 
5 years prior to screening, with the 
exception of appropriately treated basal-cell 
carcinoma of the skin, in situ carcinoma of 
the uterine cervix, or other local tumours 
considered cured by local treatment.
Known history of human 
immunodeficiency virus (HIV) infection
Active infection requiring systemic therapy 
at the start of treatment in the trial, 
including active viral hepatitis infection or 
active tuberculosis infection
Known history of human 
immunodeficiency virus infection or an 
active hepatitis B or C virus infection. 
(exceptions for some specific expansion 
cohorts defined)
Has received a live vaccine within 30 days 
prior to first dose of BI 1387446
Patients who must or wish to continue the 
intake of restricted medications (see Section 
4.2.2.2) or any drug considered likely to 
interfere with the safe conduct of the trial 
Section 4.2.2.2: Live attenuated vaccines 
during the trial through 30 days after the 
last dose of investigational product are 
prohibited)


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
-
Significant resting ECG abnormalities 
defined as ventricular tachyarrhythmias, 
presence of unstable atrial fibrillation 
(defined as ventricular response >100 bpm), 
significant bradycardia (defined as a heart 
rate of <50 bpm), complete left bundle 
branch block, right bundle branch block and 
left anterior hemiblock, third degree AV 
block, or a mean resting corrected QT 
interval (QTc) >470 msec
-
Any factors that increase the risk of QTc 
prolongation or risk of arrhythmic events 
including congenital long QT syndrome, 
family history of sudden unexpected death 
from cardiac related causes, myocardial 
infarction or major cardiac surgery within 3
months prior to enrollment, history or 
presence of uncontrolled hypertension 
(>150 mmHg systolic or >100 mmHg 
diastolic bp)
-
Left ventricular ejection fraction < 50% 
measured by echocardiography or MUGA 
scan
-
Cardiac insufficiency NYHA III or IV
Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) 
>470 msec
- Any clinically important abnormalities (as 
assessed by the Investigator) in rhythm, 
conduction, or morphology of resting ECGs, 
e.g., complete left bundle branch block, third 
degree heart block
- Any factors that increase the risk of QTc 
prolongation or risk of arrhythmic events such 
as heart failure, hypokalaemia, congenital long 
QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 
40 years-of-age, or any concomitant medication 
known to prolong the QT interval
- Ejection fraction (EF) <55% or the lower limit 
of normal of the institutional standard will be 
excluded. Only in cases where the Investigator 
(or the treating physician or both) suspects 
cardiac disease with negative effect on the EF 
will the EF be measured during screening using 
an appropriate method according to local 
standards to confirm eligibility (e.g., 
echocardiogram [ECHO], multi-gated 
acquisition scan [MUGA]). A historic 
measurement of EF no older than 6 months 
prior to first administration of study drug can be 
accepted provided that there is clinical evidence 
that the EF value has not worsened since this 
measurement in the opinion of the Investigator 
or of the treating physician or both.


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
History of severe hypersensitivity reactions 
to mAbs
History of severe hypersensitivity reactions 
to other mAbs
Patients who must or wish to continue the 
intake of restricted medications (see 
Section 4.2.2.1) or any drug considered 
likely to interfere with the safe conduct of 
the trial in the opinion of the investigators
Patients who must or wish to continue the 
intake of restricted medications (see Section 
4.2.2.2) or any drug considered likely to
interfere with the safe conduct of the trial
Chronic alcohol or drug abuse
Chronic alcohol or drug abuse or any 
condition that, in the Investigator’s opinion, 
makes him/her an unreliable trial subject, 
unlikely to complete the trial, or unable to 
comply with the protocol procedures
Major surgery (major according to the 
investigator’s assessment) performed 
within 4 weeks prior to first trial treatment
Major surgery (major according to the 
Investigator’s assessment) performed 
within 12 weeks prior to first trial treatment 
or planned within 12 months after 
screening, e.g., hip replacement
Any pre-existing or concurrent disease or 
condition that, in the investigator’s 
opinion, would compromise patient safety, 
poses an undue risk to the patient, makes 
him/her an unreliable trial subject, unlikely 
to complete the trial, or unable to comply 
with the protocol procedures
Chronic alcohol or drug abuse or any 
condition that, in the Investigator’s opinion, 
makes him/her an unreliable trial subject, 
unlikely to complete the trial, or unable to 
comply with the protocol procedures
Women who are pregnant, nursing, or who 
plan to become pregnant or nurse during 
the trial or within 6 months after the last 
dose of study treatment
Inclusion criterion 7 on females of child 
bearing potential
Presence of any absolute contraindications 
to cataract surgery


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Table 10.5: 4  
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
n.a. (cross over and re-screening 
permitted)
Previous enrolment in this trial
Interstitial lung disease
DLT definition 
Haematological Toxicity
Haematological Toxicity
Any grade 5 toxicity
Neutropenia grade 4 lasting for >5 days
Neutropenia ≥ Grade 4 present for >7 days
Neutropenia grade ≥3 with documented 
infection
Neutropenia Grade 3 with documented 
infection
Febrile neutropenia
Febrile neutropenia
Thrombocytopenia grade 4
≥ Grade 4 thrombocytopenia (platelets 
<25,000/µL)
Thrombocytopenia grade 3 with 
concomitant bleeding grade ≥2 (i.e. 
bleeding requiring intervention) (grade 2)
Any Grade 3 thrombocytopenia with 
bleeding or a requirement for platelet 
transfusions
Grade 4 anaemia
Non-Hematological toxicity
Non-Hematological toxicity
AST or ALT >3 times ULN and 
concurrent total bilirubin >2 times ULN 
without initial findings of cholestasis (e.g. 
findings consistent with Hy's law or the 
FDA definition of potential DILI)
AST or ALT >3 times ULN and concurrent 
total bilirubin >2 times ULN without initial 
findings of cholestasis (e.g., findings 
consistent with Hy's law or the FDA 
definition of potential DILI)
AST or ALT elevation grade ≥ 4
≥Grade 4 AST or ALT of any duration
CRS grade ≥3


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Table 10.5: 4  
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
Any other ≥Grade 3 non-haematologic 
toxicity with the following exceptions:
o
Grade 3 irAE that resolves to ≤ Grade 
1 or to baseline with 
immunosuppressive therapy within 2 
weeks
o
Grade 3 fatigue that persists <7 days
o
Grade 3 rash that resolves to ≤ Grade 1 
within 2 weeks
o
Grade 3 or 4 elevation in serum 
amylase and/or lipase that is not 
associated with clinical or radiographic 
evidence of pancreatitis
o
Grade 3 electrolyte abnormality that 
lasts <72 hours, is not clinically 
complicated, and resolves 
spontaneously or responds to 
conventional medical intervention
o
Grade 3 nausea or vomiting that lasts 
<48 hours, and resolves to ≤ Grade 1 
either spontaneously or with 
conventional medical intervention
o
Alopecia
o
Grade 3 endocrine disorders (thyroid, 
pituitary, and/or adrenal insufficiency) 
that are managed with or without 
systemic corticosteroid therapy and/or 
hormone replacement therapy, and the 
patient is asymptomatic
o
Grade 3 tumour flare syndrome
Any ≥Grade 3 non-haematologic toxicity 
with the following exceptions:
o
Grade 3 irAE that resolves to ≤ Grade 1 
or to baseline with immunosuppressive 
therapy within 2 weeks
o
Grade 3 fatigue that persists <7 days
o
Grade 3 rash that resolves to ≤ Grade 1 
within 2 weeks
o
Grade 3 or 4 elevation in serum 
amylase and/or lipase that is not 
associated with clinical or radiographic 
evidence of pancreatitis
o
Grade 3 electrolyte abnormality that 
lasts <72 hours, is not clinically 
complicated, and resolves 
spontaneously or responds to 
conventional medical intervention
o
Grade 3 nausea or vomiting that lasts 
<48 hours, and resolves to ≤ Grade 1 
either spontaneously or with 
conventional medical intervention
o
Alopecia
o
Grade 3 endocrine disorders (thyroid, 
pituitary, and/or adrenal insufficiency) 
that are managed with or without 
systemic corticosteroid therapy and/or 
hormone replacement therapy, and the 
patient is asymptomatic.
o
Grade 3 tumour flare
Any Grade 4 or 5 AE
Pneumonitis Grade 2


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Table 10.5: 4
Comparison of trials 1426-0001 and 1381-0001 (cont.)
Trial 1426-0001
Trial 1381-0001
Study population
Inclusion criteria
Inclusion criteria
Lab criteria (IC)
Lab criteria (EC)
Exclusion criteria
Exclusion criteria
Any Grade 2 related uveitis, eye pain, or 
blurred vision that does not respond to 
topical therapy and does not improve to 
Grade 1 severity within 2 weeks or 
requires systemic treatment
Any Grade 2 drug-related uveitis or eye 
pain or blurred vision that does not respond 
to topical therapy and does not improve to 
Grade 1 severity within 2 weeks or requires 
systemic treatment
Any Grade ≥2 toxicity that persists and 
results in a delay of >14 days of Cycle 2 
Day 1
Any treatment-related ≥ Grade 2 toxicity 
that persists and results in an inability to 
administer BI 754091 on Cycle 2 Day 1
Administration of treatment
Ezabenlimab (BI 754091): intravenous 
infusion (i.v.) of 240 mg every 3 weeks
BI 1387446: intratumoural injection (i.tu.) 
BI 754091: intravenous infusion (i.v.) 
every 3 weeks
11
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
25 Nov 2019
EudraCT number
EU number
2019-001082-32  
BI Trial number
1426-0001
BI Investigational Medicinal 
Product(s)
BI 1387446
BI 754091
Title of protocol
Phase I, first in human trial evaluating 
BI 1387446 alone and in combination with
BI 754091 in solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Synopsis


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Description of change
Revised description of established treatment 
options known to prolong survival to remove the 
word meaningfully. 
Rationale for change
Revision in response to FDA review comment to 
remove the word “meaningfully” from this 
requirement as it is not clear/specific.
Section to be changed
Synopsis
Description of change
Revised description of Main Exclusion criteria
Rationale for change
Revision to align with Exclusion criteria #1 in 
Section 3.3.3
Section to be changed
Flowchart
Description of change
, at the 30-day safety follow-up, and at any time 
during the treatment period, if clinically 
indicated.
Rationale for change
Based on non-clinical data and the 
pharmacological activity of BI 1387446, it is 
considered that a potential risk of eye lens 
toxicity cannot be completely ruled out and 
therefore mitigation procedures must be in place 
in this FIH study.
Section to be changed
Flowchart
Description of change
Revised requirement for pregnancy test to be 
performed in serum in flowchart and footnote #5.
Rationale for change
Revision in response to MHRA review comment 
that pregnancy tests must be in serum.
Section to be changed
Flowchart
Description of change
Revised Footnote #10
Rationale for change
Revision added to clarify that a single ECG will 
be obtained as clinically indicated prior to drug 
administration, at least every two to three cycles.  
Section to be changed
Flowchart
Description of change
Revised Footnote #13 to clarify that injection of 
BI 1387446 should be preferably performed 
immediately after completion of BI 754091 
infusion.
Rationale for change
Revision added to align with Blood sampling 
flowcharts for Arms B and C. 
Section to be changed
Flowchart
Description of change
Revision to footnote #27 to clarify safety 
parameters


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Rationale for change
Revision added to clarify that prior to biopsy of 
deep visceral lesions appropriate safety lab 
parameters taken within 24h must be available.
Section to be changed
Flowchart
Description of change
Addition of Footnote #36 for lens opacity 
assessment.
Rationale for change
Based on non-clinical data and the 
pharmacological activity of BI 1387446, it is 
considered that a potential risk of eye lens 
toxicity cannot be completely ruled out and 
therefore mitigation procedures must be in place 
in this FIH study.
Section to be changed
Description of change
Footnote #37 created and added to 
echocardiography
Rationale for change
Addition of footnote #37 to clarify that although 
echocardiography is the preferred method, 
MUGA scans are permitted to quantify LVEF. 
The same method should be used in a single 
patient throughout the trial.
Section to be changed
Description of change
Rationale for change
Section to be changed
Flowchart
Description of change
Revised Footnote #23
Rationale for change
Revision added to clarify imaging should be 
performed via CT/MRI. PET-CT may be 
performed if clinically indicated based on tumour
type, however, in this case a diagnostic-quality
CT scan needs to be acquired as part of the PET-
CT for RECIST measurements. The CT portion 
of a PET-CT can be used as the basis for RECIST 
measurements if the site has documented that a 
CT with appropriate radiation dose for diagnostic 
quality and IV/oral contrast was used (if not 
medically contraindicated).
Section to be changed
Blood Sample Flowchart: Arm A
Description of change
Description regarding triplicate ECGs at C1V1, 
moved from ECG to Event column. Description 


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regarding triplicate ECGs at C2V1, and C5V1 
updated and move from ECG to Event column. 
Rationale for change
Revised column placement for clarity. For C2V1 
and C5V1, revised to clarify that only 1 set of 
triplicate ECGs is required prior to sampling.
Section to be changed
Blood Sample Flowchart: Arm A, Blood Sample 
Flowchart: Arm B
Description of change
Revised to add footnote 6. 
Rationale for change
Revision added to clarify that when triplicate 
ECGs are scheduled prior to blood sampling, the 
3 single ECG recordings should be performed 
within a maximum period of 5 minutes prior to 
blood sampling.
Section to be changed
Blood Sample Flowchart: Arm B, Blood Sample 
Flowchart: Arm C 
Description of change
Revised timing for BI 754091 administration 
Rationale for change
Revision to clarify timing between BI 754091 and 
BI 1387446 administration on visits when both 
drugs are scheduled to be administered.
Section to be changed
Abbreviations
Description of change
Revised to align with check of abbreviations 
throughout document
Rationale for change
Revision to align with content updates for lens 
opacity assessment.
Section to be changed
Section 1.4.2
Description of change
Revised to add description of potential risk of eye 
lens toxicity. Clarification on classification of 
risks and terminology.
Rationale for change
Based on non-clinical data and the 
pharmacological activity of BI 1387446, it is 
considered that a potential risk of eye lens 
toxicity cannot be completely ruled out and 
therefore mitigation procedures must be in place 
in this FIH study.
Section to be changed
Section 3.1
Description of change
Revised to extend the DLT monitoring period to 
include echocardiographic/MUGA scan 
measurements acquired on Day 1 of Cycle 2 and 
related findings for MTD evaluability. 
Rationale for change
Revision in response to FDA review comment.  


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Section to be changed
Section 3.1
Description of change
Revised to add statement that during dose 
escalation the BLRM will be evaluated after the 
occurence of each DLT before enrolling any 
further patients at the respective dose level.
Rationale for change
Revision in response to MHRA review comment. 
Section to be changed
Section 3.1
Description of change
Revised to remove statement “Further patients 
may be included to confirm this MTD estimate, 
i.e. to confirm that the EWOC criterion is still 
fulfilled.”
Rationale for change
Section to be changed
Section 3.1.2
Description of change
Revised to clarify that following the occurrence 
of a drug related Grade 2 or greater AE, 
excluding asymptomatic Grade 2 laboratory 
abnormalities that resolve without medical 
intervention within 48 hours and transient Grade 
2 local injection site reactions that resolve within 
48 hours (whereby supportive treatment is 
allowed), a minimum of 3 patients will be 
required per dose cohort. 
Rationale for change
Revised in response to FDA review comment. 
Section to be changed
Section 3.1.3 
Description of change
Revised description of locations where 
administration of BI 1387446 is not permitted. 
Rationale for change
Revision in response to FDA review comment 
that injection into lesions which would be most 
often require the use of techniques other than  
percutaneous intratumoural injection, such 
endoscopic injection, is not permitted
Rationale for change
Section 3.3
Section to be changed
Revision to update wording regarding patient(s) 
determined eligible in error. 
Description of change
Revision added to clarify that patients who may 
not meet eligibility are to be reported to the 
sponsor immediately. Patients are considered 
enrolled once informed consent has been signed 
and would be proceed to be assessed for 
eligibility.
Section to be changed
Section 3.3.2


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Description of change
Revised Inclusion criteria #7 to remove word 
meaningfully. 
Rationale for change
Revision in response to FDA review comment to 
remove the word “meaningfully” from this 
requirement as it is not clear/specific.
Section to be changed
Section 3.3.2
Description of change
Revised Inclusion criteria #11 to adjust 
concurrent creatinine clearance from ≥ 50 ml/min
to ≥ 45 ml/min.
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.3
Description of change
Revised Exclusion criteria #14 to exclude patients 
with any clinically important resting ECG 
abnormalities and factors that may increase the 
risk of QTc prolongation or risk of arrhythmic 
events. 
Rationale for change
Revision in response to MHRA review comment. 
This change to exclusion criteria will ensure 
patient safety while allowing to enroll a 
population that more closely represents the 
intended future population. 
Section to be changed
Section 3.3.3
Description of change
Added Exclusion criteria #22 for presence of any 
absolute contraindication to cataract surgery.
Rationale for change
Revision in response to MHRA review comment.
Based on non-clinical data and the 
pharmacological activity of BI 1387446, it is 
considered that a potential risk of eye lens 
toxicity cannot be completely ruled out and 
therefore mitigation procedures must be in place 
in this FIH study.
Section to be changed
Section 3.3.3
Description of change
Added Exclusion criteria #23 for any factors that 
increase the risk of QTc prolongation or risk of 
arrhythmic events. 
Rationale for change
Revision in response to MHRA review comment. 
This change to exclusion criteria will ensure 
patient safety while allowing to enroll a 
population that more closely represents the 
intended future population.
Section to be changed
Section 3.3.4.4




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Description of change
Revision to Table 4.1.4.5: 1 for clarification of 
collection of vital signs
Rationale for change
Revision to collection for superficial and non-
visceral deep lesions. 
Section to be changed
Section 4.1.4.6
Description of change
Revised to include minimum 8 hours of 
monitoring for CRS post-administration of Cycle 
2 Day 1 dose of BI 1387446. 
Rationale for change
Revision in response to FDA review comment.  
Section to be changed
Section 4.2.2.1
Description of change
Revised to clarify that in Arms B and C, the use 
of live attenuated viruses has to be delayed until 
70 days after the last dose of BI 754091 or 30 
days after the last dose of BI 1387446, whatever 
comes later.
Rationale for change
Revision in response to MHRA review comment. 
The use of live vaccines should be prohibited 
until the end of the relevant systemic exposure (5 
half-lives after the last dose) of the IMP with the 
longest half-life.
Section to be changed
Section 5.2.3
Description of change
Revised requirement in Table 5.2.3: 1 for 
pregnancy test to be performed in serum.
Rationale for change
Revision in response to MHRA review comment 
that pregnancy tests must be in serum. 
Section to be changed
Section 5.2.3
Description of change
Revised Footnote #2 in Table 5.2.3: 1 to clarify if
Nt proBNP not available, it may be replaced with 
a decline in preference by mid-regional pro-ANP, 
total BNP or ANP.
Rationale for change
Revision due to typographical error.
Section to be changed
Section 5.2.3
Description of change
Revised entry for Coagulation in Table 5.2.3: 1 to 
add PT
Rationale for change
Revision included to align with Inclusion criteria 
#11 in Section 3.3.2
Section to be changed
Section 5.2.3
Description of change
Revised footnote #4
Rationale for change
Revision included to clarify reference to FACS 
and to align with Section 5.4.2 and Flowchart


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Section to be changed
Section 5.2.4
Description of change
Revised to clarify that in Arm C, single ECGs 
will be taken as clinically indicated, at least every 
two to three cycles. In case emerging data from 
the ECGs in Arm A and/or B suggest any 
potential signal, additional ECG measurements 
will be introduced in Arm C.
Rationale for change
Revision in response to FDA review comment.  
Section to be changed
Section 5.2.4
Description of change
Revision to clarify that all ECGs will be 
transmitted to the central vendor for analysis.
Rationale for change
Revision included to clarify that central reading 
of all ECGs needed in support assessment of 
ECGs in relation to PK. 
Section to be changed
Section 5.2.4
Description of change
Revised to add clarification that when triplicate
ECGs are scheduled prior to blood sampling, the 
3 single ECG recordings should be performed 
within a maximum period of 5 minutes prior to 
sampling.
Rationale for change
Revision added to align with Blood Sample 
Flowchart: Arm A and Blood Sample Flowchart: 
Arm B
Section to be changed
Section 5.2.6
Description of change
, at the 30-day safety follow-up, and at any time 
during the treatment period, if clinically 
indicated.
Rationale for change
Based on non-clinical data and the 
pharmacological activity of BI 1387446, it is 
considered that a potential risk of eye lens 
toxicity cannot be completely ruled out and 
therefore mitigation procedures must be in place 
in this FIH study.
Section to be changed
Section 5.2.7.2.2
Description of change
Revised to clarify that SAEs may be submitted to
BI by means other than Fax.
Rationale for change
Revision to add administrative update. 
Section to be changed
Section 6.2.1


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Description of change
Revised to clarify the patient’s reason(s) for not 
being eligible for established treatment options 
will be documented in the patient record and in 
the eCRF.
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 7.5
Description of change
Revised to remove statement “Fewer or more 
patients might be needed based on the 
recommendation of the SMC.”
Rationale for change
Revision in response to FDA review comment.  
Section to be changed
Section 8.6
Description of change
Revised to clarify the definition of the LPLVPE 
as the date on which the last patient finalised the 
first cycle and underwent 
echocardiogram/MUGA scan on Day 1 of Cycle 
2. 
Rationale for change
Revision in response to FDA review comment. 
Section to be changed
Section 9.1
Description of change
Update of references 
Rationale for change
Revised to align with check of references 
throughout document
Section to be changed
Section 10.1.2
Description of change
Revised management for immune-related AEs
Rationale for change
Revision to align with current instructions for the 
management of irAEs under treatment with PD1-
inhibitor. 
Section to be changed
Section 10.2 


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Description of change
Revised text for management of trial drugs for 
treatment of CRS. 
Rationale for change
Revision to align with Section 4.1.4.3. 
Section to be changed
Section 10.5
Description of change
Revised to add description of scenarios 02-06 and 
to updated Table 10.5: 1 to add scenarios 01-06. 
Rationale for change
Revision in response to FDA review comment to 
address the possibility of enrolling cohorts of 1 at 
doses 
 in particular 
investigating scenarios in which the first dose 
level enrols one patient who experiences a DLT. 
Section to be changed
Section 10.5
Description of change
Revised Table 10.5: 4 to reflect the Inclusion and 
Exclusion criteria changes described for Sections 
3.3.2 and 3.3.3. 
Rationale for change
Revision to align with updates to other sections.
Section to be changed
Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. Revision to update description of dose 
tier(s) to dose level(s). 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates and/or alignment of 
terms throughout document that do not affect 
protocol content and will not be listed as separate 
changes.  
11.2
GLOBAL AMENDMENT 2
Date of amendment
26 May 2021
EudraCT number
EU number
2019-001082-32  
BI Trial number
1426-0001
BI Investigational Medicinal 
Product(s)
BI 1387446
Ezabenlimab (BI 754091)
Title of protocol
Phase I, first in human trial evaluating 
BI 1387446 alone and in combination with
ezabenlimab (BI 754091) in solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x


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Section to be changed
Miscellaneous
Description of change
Revisions to denote that the start of Arm C will 
be postponed. 
Rationale for change
The start of Arm C will be postponed until further 
evidence supporting a development in deep 
visceral tumours becomes available from Arms A 
and B.
Section to be changed
Miscellaneous
Description of change
Change BI 754091 to ezabenlimab (BI 754091)
Rationale for change
Compound name has been assigned. Updates 
have been added throughout the protocol in 
relevant sections. 
Section to be changed
Synopsis, Section 2.1.3
Description of change
Revision to secondary endpoints
Rationale for change
Objective response will be based on Response 
Criteria for Intratumoural Immunotherapy in 
Solid Tumours (itRECIST). The best percentage 
change from baseline will be analysed in size of 
injected target lesions and in size of non-injected 
target lesions. 
Section to be changed
Blood Sample Flowchart: Arm A
Description of change
Removal of blank timepoint at C5V1 12:00. 
Rationale for change
Typographical error. 
Section to be changed
Blood Sample Flowchart: Arm B
Description of change
Addition of triplicate ECGs at C1V1 at -1:15 and 
-1:35 and at C2V1 -1:05. 
Rationale for change
Typographical error.
Section to be changed
Flowchart
Description of change
Addition of new footnote #4
Rationale for change
Clarification added that at Cycle 2 Day 1, an 
overnight stay is recommended if logistically 
possible due to sampling planned at the visit.
Footnotes renumbered from this point forward. 
Section to be changed
Flowchart
Description of change
Revision to footnote #34
Rationale for change
Clarification of the collection of 
echocardiography at Cycle 4 (within -7 days) and 
at Cycle 2 Day 1 (within 72 hours). Footnote is 
renumbered as #35 due to addition of footnote #4 
described above. 
Section to be changed
Section 1.4.2
Description of change
Revision to general safety measures for the trial. 
Rationale for change
Addition of description of sequential start of 
backfill enrolment.  
Section to be changed
Section 1.4.2 


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Description of change
Addition of language regarding potential 
identification of a confirmed SARS-CoV-2 
infection. 
Rationale for change
Adjustment added based upon an assessment of the 
COVID-19 related risks to trial participants. 
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.1
Description of change
Clarification added regarding the start of the 
study arms and backfill enrollment. 
Rationale for change
Arm A and B will start in a staggered manner 
(refer to Section 3.1.1). The start of Arm C will 
be postponed until further evidence supporting a 
development in deep visceral tumours becomes 
available from Arms A and B.
To acquire additional data to more fully inform 
dose selection, additional patients may be 
enrolled to backfill cohorts at dose levels that 
have been previously cleared (refer to Section 
3.1.1).
Section to be changed
Section 3.1.1, Figure 3.1.1:1
Description of change
Revisions to describe postponement of Arm C 
and clarification of handling of cross-over 
patients for MTD analysis. 
Rationale for change
Figure 3.1.1: 1 revised to reflect postponement to 
start of Arm C. 
For the main analysis of the MTD, cross-over 
patients will only be included while being treated 
with BI 1387446 monotherapy in Arm A. 
However, cross-over patients will be included in 
the sensitivity analyses of the MTD and thus be 
considered in addition. 
Section to be changed
Section 3.1.2
Description of change
Clarification added regarding the starting dose in 
Arm C and handling of DLTs in backfill patients. 
Rationale for change
The starting dose in Arm C will depend on the 
highest dose determined to be safe for patients in 
Arm B. The starting dose may be delayed to a 
higher dose level to avoid putting patients at 
procedural risks for doses with lack of activity. 


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However, the starting dose in Arm C will fulfill 
the EWOC criterion and will be lower than the 
MTD and recommended dose, respectively, 
established for the combination of BI 1387446 
and ezabenlimab (BI 754091) in superficial 
tumours. Furthermore, dose escalation in Arm C 
will start at least one dose level lower than the 
recommended starting dose based on the joint 
BLRM.   
Backfill patients who have either experienced a 
DLT or have been observed for at least the MTD 
evaluation period without experiencing a DLT 
will be included into the main BLRM at the next 
subsequent SMC meeting. Particularly, in case 
DLTs are observed in 'backfill' patients, this 
information may affect the magnitude of dose 
escalation or even result in dose de-escalation.
In case of the occurrence of DLTs, the SMC may 
decide about intervals between enrollment of 
patients, if applicable.
Section to be changed
Section 3.2 
Description of change
Addition of language for the postponement to 
start of Arm C. 
Rationale for change
The start of Arm C will be postponed. 
Section to be changed
Section 3.3.2, Section 4.1.4.5, Section 10.5.4
Description of change
Addition of commonly used SI units. 
Rationale for change
To provide clarification for laboratory parameters 
which are used for eligibility assessment and 
management of AEs. 
Section to be changed
Section 3.3.4.1
Description of change
Revision to the criteria for discontinuation of trial 
treatment to address if a patient experiences an 
infection with SARS-CoV-2. 
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact to trial 
participants. 
Section to be changed
Section 3.3.4.4
Description of change
Clarification regarding replacement of patients
Rationale for change
A patient who misses the 
echocardiography/MUGA scan measurements 
acquired on Day 1 of Cycle 2 may be replaced. 
Section to be changed
Section 4.1.2.3
Description of change
Clarification of treatment beyond progression
Rationale for change
PD assessment will be based on itRECIST and 
refers to the overall response assessment 


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including all injected and non-injected lesions. 
Overall PD assessment after initial progression is 
comparable to iUPD with iRECIST (the 
possibility of iTPD will not be considered in this 
study).
Section to be changed
Section 4.1.3
Description of change
Clarification regarding the method of assigning 
patients to treatment groups. 
Rationale for change
The start of Arm C will be postponed. The start 
of Arm A and Arm B will be started sequentially. 
Section to be changed
Section 4.1.4
Description of change
Revision to clarify that injection of BI 1387446 
should be performed as soon as possible but not 
to exceed 4 hours after completion of 
ezabenlimab (BI 754091) infusion.
Rationale for change
Revision to align with description in other 
sections of the protocol.  
Section to be changed
Section 4.1.4
Description of change
Clarification of visit handling due to potential 
disrupting circumstances.
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact to trial 
participants.
Section to be changed
Section 4.1.4.5
Description of change
Clarification of BI 1387446 administration and 
the decline in haemoglobin that must result in a 
prolongation of surveillance.
Rationale for change
BI 1387446 may only be administered by a 
physician who is experienced in diagnostic 
biopsy or intratumoural injection of 
immunotherapy drugs (physician, 
radiologist/interventional radiologist, or surgeon).
A decline in Hgb by ≥2.0 g/dL (≥ 20 g/L, ≥ 1.24 
mmol/L) must result in a prolongation of 
surveillance.
Section to be changed
Section 4.1.4.6
Description of change
Revisions to surveillance for CRS
Rationale for change
Revisions added that in patients with clinically 
manifested CRS, it is recommended to measure 
cytokines in the local laboratory at onset of 
symptoms, approximately 24 hours, and 48 hours 
thereafter or upon discharge from hospitalization 
(whichever occurs earlier).
Section to be changed
Section 4.1.8
Description of change
Clarification of investigational drug handling


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Rationale for change
Unused and partially used trial drug will be 
destroyed on site according to local site 
procedure after relevant reconciliations have been 
completed.
Section to be changed
Section 4.2.2.1
Description of change
Revision to include information regarding 
COVID-19 vaccination 
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact.
Section to be changed
Section 5.1, Section 5.7, Section 10.3
Description of change
Clarification of tumour assessment 
Rationale for change
Response assessment will be performed 
according to response criteria for intratumoural 
immunotherapy in solid tumours (itRECIST)
(R20-2734). 
Section to be changed
Section 5.2.7.1.4
Description of change
Revision to the definition of hepatic injury
Rationale for change
Revisions added for the alterations of hepatic 
laboratory parameters that define a hepatic injury 
in patients with abnormal liver parameters at 
baseline. 
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 6.1
Description of change
Clarification of handling of COVID-19 related 
deviations from the original schedule of visits and 
procedures. 
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact to trial 
participants.
Section to be changed
Section 6.2.1
Description of change
Addition of collection of molecular 
characteristics of the tumour
Rationale for change
Microsatellite status, Tumour mutational burden 
(TMB), Expression levels of PD-L1, ER, PR, 
HER2, HPV status and any available information 
on tumour mutations will be recorded in the
eCRF.
Section to be changed
Section 7
Description of change
Revisions to Statistical Methods


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Rationale for change
Changes included minor formatting updates and 
additional details on when the MTD may be 
considered reached. 
Section to be changed
Section 7.2.3
Description of change
Revision to the secondary endpoint 
Rationale for change
Removal of OR based on RECIST 1.1, addition 
of OR based on itRECIST.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 8.3.2
Description of change
Clarification regarding direct access to data.
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact.
Section to be changed
Section 9.1
Description of change
Update of references 
Rationale for change
Revised to align with check of references 
throughout document
Section to be changed
Miscellaneous
Description of change
Clarification of laboratory units throughout
Rationale for change
Laboratory values used for determination of 
patient eligibility or other medical decisions are 
presented in SI and conventional units. 
Section to be changed
Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates and/or alignment of 
terms throughout document that do not affect 
protocol content will not be listed as separate 
changes.  
11.3
GLOBAL AMENDMENT 3
Date of amendment
10-Feb-2022
EudraCT number
EU number
2019-001082-32  
BI Trial number
1426-0001


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BI Investigational Medicinal 
Product(s)
BI 1387446
Ezabenlimab (BI 754091)
Title of protocol
Phase I, first in human trial evaluating 
BI 1387446 alone and in combination with
ezabenlimab (BI 754091) in solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis-Trial Rationale, 
Trial Objective, Trial Endpoints
Description of change
Added trial rationale, trial objective, trial 
endpoints for new arm, Arm C (radiotherapy)
Rationale for change
Describe Arm C (radiotherapy), a new trial arm
Section to be changed
Clinical Trial Protocol Synopsis-Total Number of 
Patients Entered, Total Number of Patients on 
Treatment; Section 3.3
Description of change
Updated the total number of patients to 120 and 
the number of patients in Arm C to 42
Rationale for change
42 patients are needed to enrolled in Arm C to 
evaluate the study objectives and endpoints
Section to be changed
Clinical Trial Protocol Synopsis-Main in- and 
exclusion criteria
Description of change
Added inclusion and exclusion criteria specific for 
Arm C
Rationale for change
Arm C has some inclusion and exclusion criteria 
different from Arms A and B due to the 
radiotherapy component 
Section to be changed
Clinical Trial Protocol Synopsis-dose and mode of 
administration
Description of change
Added dose and mode of administration for 
radiotherapy 
Rationale for change
Defined the dose of radiotherapy and mode of 
radiotherapy administration that will be used in 
Arm C
Section to be changed
Clinical 
Trial 
Protocol 
Synopsis-Statistical 
Methods


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Description of change
Defined Arm C statistical methods 
Rationale for change
  Clarify that a separate BLRM with overdose      
  control will guide dose escalation in Arm C
Section to be changed
Flow Chart
Description of change
Separated Arm A/Arm B and Arm C into 2 
separate Flow Charts
Rationale for change
  Highlight the different assessments and        
  assessment schedule between Arms A and B    
  compared to Arm C 
Section to be changed
Flow Chart Arm A and B, Flow Chart Arm C, 
Section 6.2.3.1, Section 7.2.5
Description of change
Added safety follow-up visit at 90 days after EoT 
visit
Rationale for change
To 
continue 
to 
monitor 
safety, 
namely 
AEs/SAEs/AESIs and concomitant treatments, 90 
days after EoT
Section to be changed
Blood Sample Flow Chart-Arm C
Description of change
Updated assessments for Arm C
Rationale for change
Blood Sample Flow Chart updated to match new 
Flow Chart Arm C, accounting for radiotherapy
Section to be changed
Section 1.2.3
Description of change
Added statement regarding the combination of 
radiotherapy, BI 1387446, and Ezabenlimab
Rationale for change
Explain 
the 
potential 
response 
the 
triple 
combination of radiotherapy, BI 1387446, and 
ezabenlimab vs the double combination of BI 
1387446 and ezabenlimab
Section to be changed
Section 1.3
Description of change
Added the triple combination of radiotherapy, BI 
1387446, and ezabenlimab to study rationale
Rationale for change
Explain the objective of the triple combination 
Section to be changed
Section 1.4.1
Description of change
Added radiotherapy to the benefits section
Rationale for change
Explained why radiotherapy may be beneficial in 
this trial


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Section to be changed
Section 1.4.2
Description of change
Added 
potential 
risks 
of 
radiotherapy 
in 
combination with BI 1387446 and ezabenlimab
Rationale for change
Explained potential risks of local radiation therapy 
combined with BI 1387446 and ezabenlimab
Section to be changed
Section 2.1.1
Description of change
Update Main Objective
Rationale for change
Main Objective updated to include triple 
combination of BI 1387446 and ezabenlimab 
following local radiotherapy
Section to be changed
Section 2.1.2, Section 8.6
Description of change
Update MTD for Arm C
Rationale for change
With the introduction of radiotherapy to Arm C 
and the shift of the start of ezabenlimab treatment 
to C2D1 , the MTD was increased from 3 weeks 
to 6 weeks
Section to be changed
Section 3.1, Section 3.2
Description of change
Removed references to injection into deep visceral 
lesions in Arm C and summarized the revised Arm 
C radiotherapy cohort
Rationale for change
Describe the new study design, priority of cohorts, 
and dose escalation plan in the revised Arm C 
radiotherapy cohort
Section to be changed
Section 3.3.2
Description of change
Updated 
inclusion 
criteria 
#9 
to 
include 
radiotherapy requirement for Arm C
Rationale for change
A patient must have a lesion suitable for injection 
and local radiation therapy to be included in Arm 
C 
Section to be changed
Section 3.3.3
Description of change
Added requirement for Arm C that patient should    
not have had radiation therapy of the lesion 
proposed for injection within 6 months of initial 
administration of BI 1387446. Removed 
requirement for Arm C that patients cannot be on    
therapeutic doses of anticoagulants.




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lesions; added statement that a suitable lesion for 
injection within the area of radiation should be 
prioritized if feasible for Arm C.
Rationale for change
Arm C no longer requires deep/visceral lesions for 
injection and also includes radiation
Section to be changed
Section 4.1.4.2
Description of change
Removed liver lesion injection requirements
Rationale for change
Since deep/visceral lesions will no longer be 
injected in Arm C, this section is not applicable
Section to be changed
Section 4.1.4.4
Description of change
Defined late DLT for Arm C
Rationale for change
Since the MTD evaluation period for Arm C is 
different from Arms A and B, late DLT will also 
be defined differently in Arm C
Section to be changed
Table 4.1.4.3:1
Description of change
Removed deep visceral lesions from table
Rationale for change
Deep visceral lesions are no longer injected in 
Arm C
Section to be changed
Section 4.2.2.1
Description of change
Removed restrictions on anti-coagulant usage in 
Arm C
Rationale for change
Since Arm C no longer involves injections into 
deep/visceral lesions, anti-coagulant usage is no 
longer restricted
Section to be changed
Section 5.1
Description of change
Revised/clarified when tumour assessments would 
be performed in each arm 
Rationale for change
Tumour assessments in Arm C are now performed 
at the same visits as in Arms A and B
Section to be changed
Section 5.2.7.1.1
Description of change
Removed progressive disease as an AE that needs 
to be reported
Rationale for change
  Align with oncology standards and not consider   
  progressive disease as a reportable AE
Section to be changed
Section 5.1.7.2.3


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Description of change
Remove requirement for cancers of new histology 
and exacerbations of existing cancer to be 
classified and reported as serious events
Rationale for change
Align with oncology standards and not consider 
cancers of new histology and exacerbations of 
existing cancer to be reportable serious adverse 
events
Section to be changed
Section 5.2.7.2.4
Description of change
Added new section, Exemptions to AE/SAE 
reporting
Rationale for change
Provide rules to be followed for reporting disease 
progression and associated signs and symptoms 
for the safety analysis
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 7
Description of change
Defined the two separate BLRM modelling 
approaches for 1.)Arms A and B and 2.) Arm C 
and recalculated doses used to determine the MTD 
Rationale for change
With the introduction of radiotherapy in Arm C, 
the BLRM modelling was updated as well as the 
MTD
Section to be changed
Section 7.2.2, Section 10.5
Description of change
Described the separate methods that will be used 
for the main analyses of MTD in 1.)Arms A and B 
and 2.) Arm C
Rationale for change
The additional of radiotherapy in Arm C required 
an update to the BLRM method used to determine 
MTD
Section to be changed
Description of change


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Rationale for change
Section to be changed
Section 7.2.6
Description of change
Revised sample size calculations based on new 
Arm C (radiotherapy)
Rationale for change
New triple treatment combination in Arm C 
required a sample size different from the 
previously defined Arm C
Section to be changed
Section 10.5
Description of change
Updated the performance metrics used to estimate 
the MTD; updated the joint BLRM hypothetical 
outcome scenarios to make recommendations of 
the next dose in each arm
Rationale for change
Due to the addition of Arm C and the doses 
already tested in Arms A and B of the study, this 
appendix, specifically the performance metrics 
used to estimate the MTD as well as the joint 
BLRM hypothetical outcome scenarios needed to 
be revised.
Section to be changed
  Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates and/or alignment of 
terms throughout document that do not affect 
protocol content will not be listed as separate 
changes.  
11.4
GLOBAL AMENDMENT 4
Date of amendment
05 Oct 2022
EudraCT number
EU number
2019-001082-32  
BI Trial number
1426-0001
BI Investigational Medicinal 
Product(s)
BI 1387446
Ezabenlimab (BI 754091)


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Title of protocol
Phase I, first in human trial evaluating 
BI 1387446 alone and in combination with 
ezabenlimab (BI 754091) in solid tumours 
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis-Trial Rationale, 
Trial Objective, Trial Endpoints
Description of change
Removed trial rationale, trial objective, trial 
endpoints for Arm C (radiotherapy)
Rationale for change
Eliminating Arm C
Section to be changed
Clinical Trial Protocol Synopsis-Total Number of 
Patients Entered, Total Number of Patients on 
Treatment; Section 3.3
Description of change
Updated the total number of patients planned to 
78 and removed mention of Arm C
Rationale for change
Eliminate Arm C and the patient count associated 
with it
Section to be changed
Clinical Trial Protocol Synopsis-Main in- and 
exclusion criteria
Description of change
Removed inclusion and exclusion criteria specific 
for Arm C
Rationale for change
Eliminate Arm C and the patient inclusion and 
exclusion criteria associated with it
Section to be changed
Clinical Trial Protocol Synopsis-dose and mode 
of administration
Description of change
Removed dose and mode of administration for 
radiotherapy 
Rationale for change
Eliminating Arm C and thus the mention of the 
dose of radiotherapy and mode of radiotherapy 
administration that was to have been used in Arm 
C
Section to be changed
Clinical Trial Protocol Synopsis-Statistical 
Methods
Description of change
Removed Arm C statistical methods 
Rationale for change
Eliminating arm C and thus the methods section


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Section to be changed
Flow Chart: Overview Arm C
Description of change
Removed Arm C Flow Chart
Rationale for change
Eliminating Arm C 
Section to be changed
Blood Sample Flow Chart: Arm C
Description of change
Removed Blood Sample Flow Chart Arm C
Rationale for change
Arm C eliminated so Blood Sample Flow Chart 
not needed
Section to be changed
Section 1.2.3
Description of change
Removed statement regarding the combination of 
radiotherapy, BI 1387446, and ezabenlimab
Rationale for change
Arm C combination with radiotherapy eliminated 
so no need to explain the potential response of 
the triple combination of radiotherapy, BI 
1387446, and ezabenlimab vs the double 
combination of BI 1387446 and ezabenlimab
Section to be changed
Section 1.3
Description of change
Removed the triple combination of radiotherapy, 
BI 1387446, and ezabenlimab from study 
rationale
Rationale for change
Arm C being eliminated so no need for an 
objective of the triple combination 
Section to be changed
Section 1.4.1
Description of change
Removed radiotherapy from the benefits section
Rationale for change
Arm C being eliminated so no need to explain 
why radiotherapy may be beneficial in this trial
Section to be changed
Section 1.4.2 and Section 1.4.3
Description of change
Removed potential risks of radiotherapy in 
combination with BI 1387446 and ezabenlimab 
and associated discussion
Rationale for change
Arm C being eliminated so no need to explain the 
potential risks of local radiation therapy 
combined with BI 1387446 and ezabenlimab
Section to be changed
Section 2.1.1
Description of change
Main Objective updated to remove the triple 
combination of BI 1387446 and ezabenlimab 
following local radiotherapy


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Rationale for change
Eliminated Arm C
Section to be changed
Section 2.1.2, Section 8.6
Description of change
Remove mention of MTD for Arm C
Rationale for change
No longer need mention since Arm C eliminated
Section to be changed
Section 3.1, Section 3.2, and Figure 3.1.1: 1
Description of change
Removed mention of Arm C in the outline and 
figure of the trial design and its discussion
Rationale for change
Arm C eliminated
Section to be changed
Section 3.3
Description of change
Changed approximate number of patients planned 
for the trial from 120 to 78
Rationale for change
Decrease in patient number due to elimination of 
Arm C
Section to be changed
Section 3.3.2
Description of change
Updated inclusion criteria #9 to remove mention 
of  radiotherapy requirement for Arm C
Rationale for change
Elimination of Arm C 
Section to be changed
Section 3.3.3
Description of change
Removed requirement for Arm C patients and 
prior radiation therapy
Rationale for change
Change in exclusion criteria due to elimination of 
Arm C design
Section to be changed
Section 3.3.4.5
Description of change
Eliminated requirements for patient replacement 
in Arm C, Parts 1 and 2.
Rationale for  change
Elimination of Arm C
Section to be changed
Section 3.3.5
Description of change
Added text stating sponsor may stop enrolment 
for the trial if development of compound is 
terminated 
Rationale for  change
BI 1387446 development discontinued
Section to be changed
Section 4.1.2.1.1
Description of change
Removed references to Arm C dosing
Rationale for change
Elimination of Arm C


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Section to be changed
Table 4.1.2.1.1: 2
Description of change
Removed table referencing Arm C dosing
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.2.3
Description of change
Removed section on the dose of radiation to be 
used in Arm C
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.2.4, Table 4.1.2.4: 3
Description of change
Removed text and table describing treatment 
schedule for Arm C
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.3
Description of change
Remove mention of Arm C for patient allocation
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.4.1
Description of change
Removed statement that a suitable lesion for 
injection within the area of radiation should be 
prioritized if feasible for Arm C.
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.4.3
Description of change
Removed reference to with or without local 
radiation
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.4.4
Description of change
Removed definition of late DLT for Arm C
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.1.4.6
Description of change
Removed details of length of surveillance for 
CRS for patients in Arm C
Rationale for change
Elimination of Arm C
Section to be changed
Section 4.2.2.1
Description of change
Removed reference to Arm C in the vaccine 
section


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Rationale for change
Elimination of Arm C
Section to be changed
Section 5.1
Description of change
Removed reference to when tumour assessments 
would be performed for patients on Arm C  
Rationale for change
Elimination of Arm C
Section to be changed
Section 5.2.4
Description of change
Removed reference to Arm C ECGs
Rationale for change
Arm C eliminated
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 6.2.3.1
Description of change
Removed reference to Arm C Flow Chart
Rationale for change
Eliminated Arm C
Section to be changed
Section 7, Figure 7.1 and 7.2, Table 7.2 and 7.5
Description of change
Eliminated mention of BLRM modelling 
approach for Arm C and associated revisions to 
Figure 7.1 and elimination of Figure 7: 2, Table 
7: 2, and Table 7: 5
Rationale for change
With the elimination of Arm C,  aspects of 
BLRM modelling and discussion are not needed
Section to be changed
Section 7.2.2, Section 10.5
Description of change
Remove mention of analytical methods for Arm 
C 
Rationale for change
Elimination of Arm C
Section to be changed
Section 7.5
Description of change
Removed sample size calculations based on Arm 
C
Rationale for change
Elimination of Arm C
Section to be changed
Section 10.3.2.3
Description of change
Removed sentences describing methodology for 
confirming tumour response for Arm C
Rationale for change
Elimiation of Arm C


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Section to be changed
Section 10.5
Description of change
Updated the performance metrics used to 
estimate the MTD; updated the joint BLRM 
hypothetical outcome scenarios to make 
recommendations of the next dose in each arm
Rationale for change
Due to the removal of Arm C and the doses 
already tested in Arms A and B of the study, this 
appendix, specifically the performance metrics 
used to estimate the MTD as well as the joint 
BLRM hypothetical outcome scenarios needed to 
be revised.
Section to be changed
Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates and/or alignment of 
terms throughout document that do not affect 
protocol content will not be listed as separate 
changes.  
11.5
GLOBAL AMENDMENT 5
Date of amendment
18 Oct 2023
EudraCT number
EU number
2019-001082-32  
BI Trial number
1426-0001
BI Investigational Medicinal 
Product(s)
BI 1387446
Ezabenlimab (BI 754091)
Title of protocol
Phase I, first in human trial evaluating 
BI 1387446 alone and in combination with 
ezabenlimab (BI 754091) in solid tumours 
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Table 4.1.1:3


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Description of change
New table added with additional ezabenlimab 
drug substance description
Rationale for change
Required due to change in CMC (chemistry, 
manufacturing, and controls) for ezabenlimab


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26016868
6.0
clinical-trial-protocol-version-06
Phase I, first in human trial evaluating BI 1387446 alone and in combination with
ezabenlimab (BI 754091) in solid tumours
Approval-Clinical Trial Leader
19 Oct 2023 17:14 CEST
Author-Trial Statistician
19 Oct 2023 18:18 CEST
Approval-Clinical Program Leaders
19 Oct 2023 22:27 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
ABCD
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
TRIAL STATISTICAL ANALYSIS PLAN
 
Document No.:
c44138015-01
BI Trial No.:
1426-0001
Title:
Phase I, first in human trial evaluating BI 1387446 alone and in 
combination with ezabenlimab (BI 754091) in solid tumours
Including global protocol amendments 1 - 4
Investigational
Product(s):
BI 1387446
Ezabenlimab (BI 754091)
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
8 Apr 2024
Version:
1.0
Page 1 of 30
Proprietary confidential information
© 2024 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
LIST OF FIGURES.................................................................................................................5
2.
LIST OF ABBREVIATIONS ..............................................................................6
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS(S) ....................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENT(S)................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
INTERCURRENT EVENTS .............................................................................13
6.4
SUBJECT SETS ANALYSED...........................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY OBJECTIVE ANALYSIS..............................................................18
7.4.1
Main analysis.......................................................................................................18
7.4.4
Supplementary analysis......................................................................................20
7.5
SECONDARY OBJECTIVE ANALYSIS........................................................20
7.5.1
Key secondary objective analysis.......................................................................20
7.5.1.1
Main analysis ........................................................................................................20




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LIST OF TABLES
Table 6.3: 1
Overview of intercurrent event handling strategies for the primary analysis 
of the MTD .......................................................................................................14
Table 7.4.1: 1 Estimands table for primary objective analysis................................................19
Table 11:1
History table .....................................................................................................30


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LIST OF FIGURES
Figure 6.1: 1 On-treatment periods and MTD evaluation period for cross-over patients......13


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ADA
AE
AESI
BLRM
BMI
CR
DLT
ECOG
EOT
EoT
RECIST
itRECIST
iRECIST
MTD
OR
ORR
PKS
PR
RECIST
REP
SCS
TS
ULN
Anti-Drug Antibody
Adverse Event
Adverse Event of Special Interest
Bayesian Logistic Regression Model
Body Mass Index
Complete Response
Dose Limiting Toxicity
Eastern Cooperative Oncology Group
End of Treatment
End-of-Text
Response Evaluation Criteria in Solid Tumours
Response Criteria for Intratumoural Immunotherapy in Solid Tumours
Immune Response Evaluation Criteria In Solid Tumours
Maximum Tolerated Dose
Objective Response
Objective Response Rate
Pharmacokinetic parameter set
Partial Response
Response Evaluation Criteria In Solid Tumours
Residual Effect Period
Screened Set
Treated Set
Upper Limit of Normal


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3. INTRODUCTION
As per ICH E9 (9.1), 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), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
SAS® Version 9.4 (or a newer version) and Phoenix TM WinNonlin® Version 8.1 (or a 
newer version) will be used for PK analyses. R version 4.0.1 (or a newer version) and Stan 
will be used for all analyses related to BLRM. SAS® Version 9.4 (or a newer version) will be 
used for all other analyses.




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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The main objective of this trial is to determine the maximum tolerated dose (MTD) for BI 
1387446 as single agent (Arm A) and for BI 1387446 in combination with ezabenlimab (Arm 
B). The number of patients with Dose Limiting Toxicities (DLTs) during the MTD evaluation 
period will be used to determine the MTD in each arm.
The primary endpoints are:

MTD based on number of Dose-limiting toxicities (DLTs) 

Number of patients with DLT in the MTD evaluation period 
The MTD is defined as the highest dose with less than 25% risk of the true DLT rate being 
above 33% during MTD evaluation period. For definition of DLTs, see CTP Section 4.1.4.4.
The MTD evaluation period is defined as the first treatment cycle including 
echocardiographic/MUGA scan measurements acquired on Day 1 of Cycle 2. 
For analyses, the MTD evaluation period will be derived as the time from the first
administration of study drug to the start of the second treatment cycle, i.e. in more detail as 
the time from the first administration of (any) trial medication to the start of the 2nd
administration of ezabenlimab or 4th administration of BI 1387446 (whatever from the latter 
two comes first). In the case that the 2nd administration of ezabenlimab and/or the 4th 
administration of BI 1387446 are not given, the MTD evaluation period ends 90 days after the 
last administration.
Patients who were replaced during the MTD evaluation period will not be considered for 
MTD determination. Patients who experience a DLT will not be replaced. The decision on 
replaced patients will be collected in a separate file and stored in the TMF. Patients that have 
not been replaced will be referred to as patients evaluable for MTD determination (MTD set).
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable, no key secondary endpoints have been specified in the CTP.
5.2.2
Secondary endpoint(s)
The secondary endpoints of this trial are:
For CTP Version 1 and 2:

Objective response based on Response Evaluation Criteria in Solid Tumors (RECIST)

Best percentage change from baseline in size of injected lesions

Best percentage change from baseline in size of target lesions


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For CTP Version 3 and later:

Objective response based on Response Criteria for Intratumoural Immunotherapy in 
Solid Tumours (itRECIST)

Best percentage change from baseline in size of injected target lesions

Best percentage change from baseline in size of non-injected target lesions
All secondary endpoints will be assessed separately for Arm A and Arm B.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
In this Phase I trial treatments are not randomized. In Arm A and Arm B, different dose levels 
of BI 1387446 alone (Arm A) or of BI 1387446 in combination with 240 mg of ezabenlimab 
(Arm B) are being administered. 
If not specified otherwise, all analyses will be performed for each treatment arm separately. 
Data will be presented by initial treatment, i.e. within each treatment arm for all dose cohorts 
separately and in total over all dose cohorts of that arm.
For safety summaries, events that start from the first administration of any trial medication 
until 90 days after the last administration of any trial medication (residual effect period, REP) 
will be assigned to the on-treatment period for evaluation. If not specified otherwise, all safety 
tables will be based on the on-treatment period. Adverse events that have an onset during the 
screening or the follow-up period will be displayed in separate listings from those that 
occurred during the on-treatment period.
The MTD evaluation period will be derived as the time from the first administration of study 
drug to the start of the second treatment cycle, i.e., in more detail as the time from the first 
administration of (any) trial medication to the start of the 2nd administration of ezabenlimab 
or 4th administration of BI 1387446 (whatever from the latter two comes first). In the case 
that the 2nd administration of ezabenlimab and/or the 4th administration of BI 1387446 are 
not given, the MTD evaluation period ends 90 days after the last administration.
Handling of cross-over patients:
Patients with progressive disease on BI 1387446 monotherapy (Arm A) may cross over to the 
combination (Arm B) after completion of cycle 1 and will be treated at the highest dose level 
declared to be safe by the SMC at this time. Instead of completing the REP after 
monotherapy, these patients will continue treatment in combination by re-starting treatment at 
Cycle 1 Day 1 in Arm B (with limited set of screening assessments).
After crossing over from Arm A to Arm B, patients will be considered in the safety and 
efficacy analyses in Arm B. That is, if not specified otherwise, they will be included in the 
tabulation of safety and efficacy data of both arms. A footnote will be used in the outputs to 
indicate that cross-over patients are depicted in Arm A and Arm B. 
In particular, for patients who cross over from Arm A to Arm B, two on-treatment periods 
will be defined, one for Arm A and a separate one for Arm B: The on-treatment period in Arm 
A will be derived as the time from first administration of BI 1387446 in Arm A until 90 days 
after the last administration in Arm A (including) or until the first administration of any trial 
drug in Arm B (excluding), whatever is first. The on-treatment period in Arm B will be 
derived as the time from first administration of study drug in Arm B until 90 days after the 
last administration of any trial medication. Figure 6.1: 1 provides a visualization of the two 


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on-treatment periods for a patient who crosses over to Arm B without completing the REP in 
Arm A.
The analyses of Arm A data will be presented by the patient’s initial treatment in Arm A, the 
analyses of arm B data will be presented by the treatment the patient receives first after the 
crossover to Arm B.
For cross-over patients, the MTD evaluation period will only be defined for their treatment in 
Arm A.
Figure 6.1: 1
On-treatment periods and MTD evaluation period for cross-over patients
6.2
IMPORTANT PROTOCOL DEVIATIONS
The documentation of the iPD categories and how to handle iPDs in the analysis are done in 
the DV domain specifications, which is stored within the TMF in EDMS. 
6.3
INTERCURRENT EVENTS
The expected intercurrent events of interest in this trial are:

Treatment discontinuation during the MTD evaluation period due to DLT

Treatment discontinuation during the MTD evaluation period due to other reason than 
DLT

Dose reduction during the MTD evaluation period due to a DLT

Dose reduction during the MTD evaluation period due to other reason than DLT

Progressive disease during the MTD evaluation period

Death during the MTD evaluation period where the death event is not a DLT

Any events other than DLT that cause missed visits during the MTD evaluation period
The strategy for handling intercurrent events in this trial is as follows:
Modified principal stratum: This is the effect of the treatment in the principal stratum of 
patients who do not discontinue treatment, miss visits, progress, or die during the MTD 
evaluation period for any reason other than DLT. That means patients experiencing one of the 


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following intercurrent events are excluded from the analysis: “Treatment discontinuation 
during the MTD evaluation period due to other reason than DLT”, “Dose reduction during the 
MTD evaluation period due to other reason than DLT”, “Progressive disease during the MTD 
evaluation period”, “Death during the MTD evaluation period where the death event is not a 
DLT”, “Any events other than DLT that cause missed visits during the MTD evaluation 
period”. The intercurrent events “Treatment discontinuation due to DLT” and “Dose 
reduction due to DLT” will be handled using a composite strategy, that is, patients
experiencing the intercurrent events “Treatment discontinuation due to DLT” and “Dose 
reduction due to DLT” are included in the analysis. 
Refer to ICH E9 R1 (9.2) for definitions of the principal stratum strategy and the composite 
strategy. Table 6.3: 1 provides an overview of the intercurrent events and the respective 
handling strategies. The modified principal stratum strategy is applied to the primary analysis 
of this trial. 
Table 6.3: 1
Overview of intercurrent event handling strategies for the primary analysis of 
the MTD
Intercurrent event
Modified principal stratum strategy
Treatment discontinuation during the MTD 
evaluation period due to DLT
Composite
Treatment discontinuation during the MTD 
evaluation period due to other reason than 
DLT
Principal stratum
Progressive disease during the MTD 
evaluation period
Principal stratum
Death during the MTD evaluation period 
where the death event is not a DLT
Principal stratum
Dose reduction during the MTD evaluation 
period due to a DLT
Composite
Dose reduction during the MTD evaluation 
period due to other reason than DLT
Principal stratum
Any events other than DLT that cause 
missed visits during the MTD evaluation 
period
Principal stratum


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6.4
SUBJECT SETS ANALYSED

Screened set (SCR):
This patient set includes all patients who signed the main informed consent. The screened set 
will be used for patient disposition tables.

Treated set (TS):
This patient set includes all patients who were documented to have received at least one dose 
of any study medication. The treated set will be used for all demographic and baseline 
analyses as well as all safety and efficacy analyses (besides the MTD determination). 

MTD set:
The MTD set includes all treated patients who are considered evaluable as per CTP, that is, all 
patients who have completed the required number of administrations of BI 1387446 (and 
ezabenlimab in arm B) in cycle 1 and who underwent the Echo/MUGA scan in cycle 2 visit 1. 
In case a patient has not completed the required number of study drug administrations due to 
DLT(s), he/she will be considered evaluable and included in the MTD set. Patients who cross 
over from Arm A to Arm B will only be included in the MTD set if they are evaluable in Arm 
A. The MTD set will be used for the main analysis of the MTD.

PK parameter set (PKS):
This patient set includes all patients in the treated set who provide at least one evaluable 
observation for at least one PK endpoint and no PK relevant protocol deviations. The PK 
parameter analysis set will be used for all PK analyses.

Biomarker analysis set:
This patient set includes all patients in the treated set who provide at least one evaluable 
observation for at least one biomarker endpoint. The biomarker analysis set will be used for 
any biomarker analysis.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
No imputation will be performed on missing efficacy data. Missing baseline laboratory values 
will be imputed by the respective values from the screening visit. Every effort will be made to 
obtain complete information on all adverse events, with particular emphasis on potential 
DLTs.
Potential outliers will be reported and analysed as observed.
Missing or incomplete AE dates will be imputed according to BI standards (9.3). 
Handling of missing PK data will be performed according to the current relevant BI standards 
(9.4). PK parameters that cannot be reasonably calculated based on the available drug 
concentration time data will not be imputed.


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In general, missing data not discussed in the BI standards will not be imputed unless required 
for the following analyses and definitions. Then the rules as described below apply.
Change of laboratory values from baseline 
Laboratory values at baseline: For missing laboratory data at cycle 1 day 1 (before the first 
administration of any study medication) the data of preceding visits will be used if available.
Definition of on-treatment period and actual treatment
Date of permanent discontinuation of study medication: All reasonable efforts should be 
undertaken during the study to obtain the dates of permanent discontinuation of study 
medication. However, if the date of the very last administration is missing this will be 
imputed with:
-
If only month and year are given, the last day of the month will be used for imputation
-
If only the year is given, the 31st of December of this year will be used for imputation
If the imputed date leads to a date that is later than the date of the EOT visit, then the imputed 
date is the date of the EOT visit. If the imputed date leads to a date that is later than the death 
date, then the imputed date is the date of death.
6.7 BASELINE, TIME WINDOWS AND CALCULATED VISITS
Unless otherwise specified baseline is defined as the time point closest to but prior to the first 
administration of any study medication. If no time is specified and the date is the same as the 
first administration date, then it will still be considered baseline if not specified otherwise. If 
there is no measurement earlier than the first administration of study medication, then no 
baseline will be derived. 
For the analysis of ‘Best percentage change from baseline in size of injected lesions’ (CTP 
version 1 and 2) and ‘Best percentage change from baseline in size of injected target lesions’ 
(CTP version 3 and later) the derivation of baseline will follow the itRECIST publication, 
details are given in Section 7.5.2.
Study days and visits will be labelled according to the flowchart in the CTP.


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7.
PLANNED ANALYSIS
The labelling and display format of statistical parameters will follow the BI guideline (9.5).
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard deviation 
(StD) / Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
For plasma concentrations as well as for all PK parameters the set of summary statistics will 
also include: arithmetic coefficient of variation (CV), geometric mean (gMean), geometric 
coefficient of variation (gCV). Furthermore, for PK parameters the following descriptive 
statistics will be calculated in addition: 10th percentile (P10), 1st quartile (Q1), 3rd quartile 
(Q3), 90th percentile (P90). For PK parameters, summary statistics will be calculated using 
the individual values with the number of decimal places as provided by the evaluation 
program. The individual values as well as the summary statistics will then be reported with 
three decimal places.
For Bayesian logistic regression model (BLRM) analysis tables, the set of summary statistics 
is: Mean, StD, Median and quartiles.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective dose cohort (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
Sort order for general categorical variables: If categories correspond to the collected 
categories in the eCRF and the table shells do not explicitly specify the ordering, the “default 
ordering” defined by the eCRF is to be used in such cases. If categories are derived, the 
ordering as specified in the table shell document should be used; in general, ordinal data (e.g. 
categorized continuous data) are to be displayed in ascending order. 
Abbreviations (e.g. Wors.) should not be displayed without any explanations. They will be 
either spelled out in the table or explained in footnotes (whatever is more reasonable from the 
programming point of view).
If applicable, conversion from days to weeks, months and years will be as follows:
•
Weeks = Days / 7
•
Months = (Days * 12) / 365.25
•
Years = Days / 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases will be coded similarly as adverse events based on the most current 
Medical Dictionary for Regulatory Activities (MedDRA) version. Concomitant therapies 
(CTs) will be coded according to World Health Organization Drug Dictionary (WHO DD). 
CTs will be classified according to the Anatomical Therapeutic Chemical (ATC) 
classification system. The third ATC level will be used to categorize CTs by therapy type. In 
situations where a medical product may be used for more than one equally important 
indication, there are often several classification alternatives. As appropriate, patients receiving 
CTs with more than one possible ATC level 3 category will be counted more than once. 
Footnotes will clarify this possible double counting in tables.
7.3
TREATMENT COMPLIANCE
Not applicable as compliance is not recorded in the eCRF. Drug administration is supervised
by the study personnel and will be assessed via drug concentrations (PK data) and exposure
data.
7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
The primary endpoints of the trial are the MTD of BI 1387446 as single agent and the MTD
of BI 1387446 in combination with ezabenlimab, and the respective number of patients with 
DLTs in the MTD evaluation period.
The number of patients with DLTs during the MTD evaluation period at each dose level will 
be presented. Patients who were replaced during the MTD evaluation period will be excluded 
from the evaluation of the MTD. 
The analysis of the MTD in each treatment arm is based on a joint BLRM for both arms 
guided by the escalation with overdose control principle. 
The MTD in each arm is defined as the highest dose that is expected to cause less than 25% 
risk of the true DLT rate being above or equal to 33% during the MTD evaluation period. 
Estimation of the MTD will be based upon the estimation of the posterior probability of the 
incidence of DLT in toxicity categories during the MTD evaluation period for all evaluable 
patients, i.e. patients in the MTD set as defined in Section 6.4.
Using the joint BLRM model specified in CTP Section 7, tables and bar charts displaying for 
each dose the posterior probabilities of the true DLT rates being in either the under-toxicity 
interval, the targeted toxicity interval or the over-toxicity interval will be produced.
The modified principal stratum strategy as defined in Section 6.3 will be applied for handling 
intercurrent events in the primary objective analysis. The MTD set will be used for the 
analysis of the primary endpoint.


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The primary analysis is aligned with the estimands described in the Table 7.4.1: 1 below.
Table 7.4.1: 1 Estimands table for primary objective analysis
Estimand attribute
Population
Patients with different types of advanced or metastatic cancer 
(solid tumours)
Treatment condition(s)
BI 1387446 monotherapy or
BI 1387446 in combination with ezabenlimab
Variable (outcome)
Occurrence of DLTs in the MTD evaluation period
Handling of 
intercurrent events

Treatment discontinuation or dose reduction during the 
MTD evaluation period due to DLT: Composite – patients 
will be included in the analysis contributing to the 
analysis with their DLT

Treatment discontinuation or dose reduction during the 
MTD evaluation period due to other reason than DLT: 
Principal stratum – patients will be excluded from the 
analysis and replaced

Progressive disease during the MTD evaluation period: 
Principal stratum – patients will be excluded from the 
analysis and replaced

Death during the MTD evaluation period where the death 
event is not a DLT: Principal stratum – patients will be 
excluded from the analysis and replaced

Any events other than DLT that cause missed visits 
during the MTD evaluation period: Principal stratum –
patients will be excluded from the analysis and replaced
Summary measure
Posterior probability of the incidence of DLT in toxicity 
categories during the MTD evaluation period per dose level for 
all evaluable patients


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7.4.4
Supplementary analysis
As a supplementary analysis, the joint BLRM may be analyzed using DLT data from the 
whole on-treatment period instead of DLT data from the MTD evaluation period. This 
analysis will include all treated patients, including ‘backfill’ patients and cross-over patients.
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.1.1 Main analysis 
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.1.4
Supplementary analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary objective analysis
OR based on RECIST 1.1: (CTP version 1 and 2) 
Objective response (OR) by RECIST 1.1 will be presented in terms of objective response rate 
(ORR), which is defined as the rate of patients whose best overall response is confirmed CR 
or PR as determined by the Investigator’s assessment according to RECIST 1.1 from date of 
first treatment administration until the earliest of disease progression, death or last evaluable 
tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or 
withdrawal of consent.
OR based on itRECIST: (CTP version 3 and later)
Objective response (OR) by itRECIST will be presented in terms of objective response rate 
(ORR), which is defined as the rate of patients whose best overall response is confirmed itCR 
or itPR as determined by the Investigator’s assessment according to itRECIST from date of 
first treatment administration until the earliest of confirmed disease progression, death or last 
evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up 
or withdrawal of consent.
Each patient treated under CTP version 1 or 2 will be assigned to one of the following best 
overall response categories according to RECIST 1.1: CR, PR, stable disease (SD), 
progressive disease (PD), not evaluable (NE).




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7.7
EXTENT OF EXPOSURE
Duration of treatment with BI 1387446 and Duration of treatment with ezabenlimab will be 
summarized descriptively. 
The Cumulative total dose for both trial drugs and the Number of cycles initiated will also be 
summarized.
The Number of patients with at least one dose reduction of BI 1387446 will be displayed.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set, besides the analyses for MTD 
determination. These will be performed on the MTD set. Treated patients will be analyzed 
separately for each treatment arm and according to their initial planned treatment.
Patients who cross over from Arm A to Arm B will be considered for both treatment arms: in 
Arm A according to their initial planned treatment and in Arm B according to their planned 
combination treatment at cross-over to Arm B. See Section 6.1 for details.
Safety data recorded during the Residual Effect Period (REP) of 90 days will be considered as 
on-treatment.
7.8.1
Adverse Events
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and NOT on the number of AEs. The analysis will be based on 
BI standards (9.6). AEs will be coded using the most recent version of MedDRA. The severity 
of AEs will be scaled according to the Common terminology Criteria for Adverse Events 
(CTCAE) version 5.0.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring between first administration of trial medication until 90 days after last 
administration of trial medication will be considered treatment-emergent and assigned to the 
initial planned treatment. 
All AEs occurring before first administration of trial medication will be assigned to 
‘screening’ and all AEs occurring after last administration of trial medication + 90 days will 
be assigned to ‘follow-up’ (for listings only). For details on the treatment definition, see
Section 6.1.
AEs will be reported with start day and end day as calculated from the first day of treatment 
with trial medication. For listings displaying AEs during the screening or follow-up period, 
the start and stop day are calculated from the start of the respective analysis period.


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An overall summary of AEs will be presented.
AEs will be displayed by the initial planned dose of trial medication administered on the first 
day of treatment. Patients who undergo a cross-over from Arm A to Arm B during the trial 
will be displayed in both treatment arms: by the initial planned dose of study medication in 
Arm A and by the planned combination dose in Arm B. 
The frequency of patients with AEs during the on-treatment period will be summarized by 
treatment, primary system organ class (SOC) and preferred term (PT) for each of the 
following AE tables:
The frequency of patients with AEs during the on-treatment period will be summarized by 
treatment, primary system organ class (SOC) and preferred term (PT) for each of the 
following AE tables: 

DLTs

All AEs by highest CTCAE grade

Serious AEs by highest CTCAE grade

Investigator assessed BI 1387446 related AEs by highest CTCAE grade

Investigator assessed ezabenlimab related AEs by highest CTCAE grade

Investigator assessed BI 1387446 related SAEs by highest CTCAE grade

Investigator assessed ezabenlimab related SAEs by highest CTCAE grade

Investigator assessed Adverse Events of Special Interest (AESI) by highest CTCAE 
grade

Investigator assessed infusion-related AEs by highest CTCAE grade

Investigator assessed immune-related AEs by highest CTCAE grade

Investigator assessed procedural complication (biopsy/injection) AEs by highest 
CTCAE grade

AEs leading to treatment discontinuation of BI 1387446 by highest CTCAE grade

AEs leading to treatment discontinuation of ezabenlimab by highest CTCAE grade

AEs leading to dose reduction of BI 1387446 by highest CTCAE grade

AEs leading to death
The SOC will be sorted alphabetically, preferred terms will be sorted by frequency (within 
SOC).
Listings of DLTs, fatal AEs, serious AEs, AEs leading to treatment discontinuation of BI 
1387446, AEs leading to treatment discontinuation of ezabenlimab and AEs leading to dose 
reduction of BI 1387446 will be provided.
7.8.2
Laboratory data
The analysis of laboratory data will be descriptive in nature and will be based on BI standards 
(9.7). The same on-treatment period as considered for the analysis of AEs will be applied for 
laboratory values. Patients having at least one post-baseline laboratory value will be displayed 
in the descriptive analyses.


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CTCAE grades for applicable laboratory parameters will be calculated according to CTCAE 
v5.0. Patients with missing CTCAE grade at baseline or no baseline value but with post-
baseline values will be displayed as “Missing” for those laboratory parameters where CTCAE 
grading is applicable. For some laboratory parameters which cannot be assigned a CTCAE 
grade at baseline, CTCAE shift tables will be replaced by shift tables of pre-defined 
categories based on Upper Limit of Normal (ULN) values. A similar approach will also be 
adopted for creatinine due to the ambiguity of CTCAE grading for grade 2 and 3. The 
predefined categories will follow BI standards (9.8).
The following outputs will be presented:

Descriptive statistics, including baseline and change from baseline

Frequency of patients with shifts from baseline:
o
Transitions of CTCAE grade from baseline to worst laboratory value,
o
Transitions of CTCAE grade from baseline to last laboratory value

Frequency of patients with possible clinically significant abnormalities (according to 
the BI standard definitions)
Possible clinically significant abnormal laboratory values:
Possible clinically significant abnormal laboratory values are defined as those laboratory 
values that are of CTCAE grade ≥ 2 and show an increase from baseline value by at least one 
CTCAE grade. For those parameters for which no CTCAE grade has been defined, BI 
standard definitions will be used to determine possible clinical significance. Frequency of 
patients with possible clinically significant abnormal laboratory values will be provided 
whenever applicable. If no baseline value is available (or CTCAE grading at baseline cannot 
be assigned) but the patient has a post-baseline laboratory value of CTCAE grade ≥ 2, an 
increase from baseline will be assumed, i.e. the laboratory value will be considered as 
possibly clinically significant.
Corrected calcium:
The grading of hypocalcaemia is based on corrected calcium as calcium can be falsely low if 
hypoalbuminemia is present. The following corrective calculation will be performed:
Corrected calcium (mg/dL) = Total Calcium (mg/dL) – 0.8[Albumin (g/dL)-4]
No correction of the reference range has to be done. The reported reference range of total 
calcium will be used for analyses. Corrected calcium can be only derived at a certain time 
point in case both laboratory values total calcium and albumin have been reported for the 
patient in the same laboratory sample.
Hepatic enzyme elevations (potential Hy’s law cases):
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT and/or AST > 3ULN (upper limit of normal) with total 
bilirubin ≥ 2ULN and ALKP < 2ULN. The events can occur in any order, but must occur 
within 30 days of the previous event, i.e. the second event must occur within 30 days of the 
first event, and the third event must occur within 30 days of the second event, etc. Patients 
with missing laboratory values for liver enzymes will be excluded from these analyses, but 
presented separately.






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8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
The treatment information will be loaded into the trial database at trial initiation.


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9.
REFERENCES
9.1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
9.2
Committee for Medicinal Products for Human Use: ICH E9 (R1) addendum on 
estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials: step 5 (17 February 2020, 
EMA/CHMP/ICH/436221/2017) [R21-0743]
9.3
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version, Group “Med Biostatistics & Data Sciences”, KMED.
9.4
BI-KMED-TMCP-MAN-0014: “Noncompartmental PK/PD Analyses of Clinical 
Studies”, current version; KMED.
9.5
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and 
Project Summaries", current version, Group “Med Biostatistics & Data Sciences”; 
KMED.
9.6
BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version, Group “Med Biostatistics & Data 
Sciences”; KMED.
9.7
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory 
Data", current version, Group “Med Biostatistics & Data Sciences”; KMED.
9.8
BI-KMED-BDS-HTG-0036: “CTCAE Grading for Laboratory Values”, current 
version, Group “Med Biostatistics & Data Sciences”; KMED.
9.9
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and 
PK/PD Data Files”; KMED.


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11. HISTORY TABLE
Table 11:1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
08-APR-24
None
This is the final TSAP.