Clinical trial NCT04138823
Conditions: Neoplasm
Sponsor: Boehringer Ingelheim
Start date: 2019-11-26; Completion date: 2023-05-17
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this trial is:

Part A

\- To determine the Maximum tolerated dose (MTD) and/or the recommended dose (RD) of BI 891065 monotherapy for further development in Asian patients with advanced solid tumours

Part B

\- To determine the MTD and/or the RD of BI 891065 in combination with a fixed dose of BI 754091 at 240 mg for further development in Asian patients with advanced solid tumours

The secondary objectives are:

Part A

\- To document the safety and tolerability, and characterise pharmacokinetics (PK) of BI 891065 as monotherapy in Asian patients with advanced solid tumours

Part B

\- To document the safety and tolerability, and characterise PK of the combination therapy of BI 891065 and BI 754091 in Asian patients with advanced solid tumours

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: BI 891065
Intervention descriptions: intervention 1: film-coated tablets

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
02 Jul 2019
Revision date
30 Apr 2021
BI trial number
1379-0006
Title of trial
An open label, Phase I study of BI 891065 monotherapy and 
combination therapy of BI 891065 and BI 754091 in Asian patients 
with advanced solid tumours
Coordinating 
Investigator
Telephone: +
Trial site(s)
Multi-centre trial conducted in Asia
Clinical phase
I
Trial rationale
The trial is required to evaluate the safety of BI 891065 monotherapy 
and combination therapy of BI 891065 and BI 754091 in Asian
patients for the later phase clinical development in Asian populations.
Trial objective(s)
The main objectives of this trial are:
Part A (monotherapy part)
∀
To determine the Maximum tolerated dose (MTD) and/or the 
recommended dose (RD) of BI 891065 monotherapy in Asian 
patients with advanced solid tumours
∀
To document the safety and tolerability, and characterise 
pharmacokinetics (PK) of BI 891065 as monotherapy in Asian 
patients with advanced solid tumours
In Part B (combination therapy part)
∀
To determine the MTD and/or the RD of BI 891065 in 
combination with a fixed dose of BI 754091 at 240 mg in Asian 
patients with advanced solid tumours 
∀
To document the safety and tolerability, and characterise PK of 
the combination therapy of BI 891065 and BI 754091 in Asian 
patients with advanced solid tumours
Trial endpoints
Part A (monotherapy part)
Primary:
∀
Maximum tolerated dose (MTD)
∀
Number of patients with Dose Limiting Toxicities (DLTs) in the 
MTD evaluation period and thereafter


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Secondary:
∀
PK parameters of BI 891065 in cycle 1: Cmax(,ss), AUC0-24 and 
AUCτ,ss of BI 891065
Part B (combination therapy part)
Primary:
∀
Maximum tolerated dose (MTD)
∀
Number of patients with Dose Limiting Toxicities (DLTs) in the 
MTD evaluation period
Secondary:
∀
PK parameters of BI 891065 and BI 754091 in cycle 1: Cmax(,ss), 
AUC0-24 and AUCτ,ss of BI 891065
Cmax and AUC0-504 of BI 754091
Trial design
Open label, uncontrolled, non-randomised, dose-escalation design
Total number of patients
randomised
Approximately 21
Number of patients on 
each treatment
Approximately 21
Diagnosis
Patients with a confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours
Main in- and exclusion 
criteria
Main inclusion criteria:
∀
Patients with a confirmed diagnosis of advanced, unresectable 
and/or metastatic solid tumours, who have failed standard 
treatment, or for whom no therapy of proven efficacy exists, 
or who are not amenable to standard therapies
∀
Eastern Cooperative Oncology Group (ECOG) performance 
status: 0 to 1
∀
Presence of at least one measureable lesion according to 
response evaluation criteria in solid tumours (RECIST) 1.1
Main exclusion criteria:
∀
Presence of active invasive cancers other than the one treated 
in this trial within 5 years prior to screening
∀
HIV, HBV, or HCV infection
∀
Inadequate organ function or bone marrow reserve as 
demonstrated by laboratory values
∀
Active, known or suspected autoimmune disease
∀
History (including current) of interstitial lung disease or 
pneumonitis within 5 years
∀
Serious concomitant disease or medical condition affecting 
compliance with trial requirements
∀
Patients with brain metastases
∀
Patients receiving systemic treatment with any 
immunosuppressive medication within 1 week prior to 
treatment start


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Test product(s)
BI 891065
BI 754091 (Part B only)
dose
Part A: 
BI 891065: starting dose 100 mg once daily
Part B:
BI 891065: starting dose 200 mg per day
BI 754091: fixed dose of 240 mg every three weeks
mode of 
administration
BI 891065: p.o.
BI 754091: i.v. infusion
Comparator product(s)
Not applicable
dose
Not applicable
mode of
administration
Not applicable
Duration of treatment
Administration will continue until progressive disease (PD), 
unacceptable toxicity, or other withdrawal criteria.
Statistical methods
In Parts A and B, dose escalation is guided by Bayesian Logistic
Regression Models (BLRMs) with overdose control that will be fitted
to binary toxicity outcomes. The estimate of parameters will be
updated as data are accumulated using the BLRMs. At the end of the
dose escalation, the toxicity probability at each dose level will be
calculated to determine an estimate of the MTD and/or the RD.
Descriptive analysis (summary statistics) will be used to describe the
safety and efficacy endpoints.


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FLOW CHART
Trial period
Screening
Treatment period (Cycle = 21 days)*
Post-Treatment Period*
Cyclea
Cycle 1t
Cycle 2 
onwards
End-of-
Treatment
(EOT) Visitv
30-day 
Safety 
follow-up
Follow-up
for PDp
Visit number
1a
1b
1c
2
3
4
5
1
Day; visit window [days]
-14 to -1 unless 
otherwise 
specifieds
1
2
3
(Part A 
only)
8
(±1)
12
(±1)
15u
16u
1 (±2)
Within 7 (+7) 
days after 
decision of 
discontinuation
30 (+7) 
days after 
last dose 
At least 
every 12 
weeks
Informed consent
X
Inclusion / exclusion criteria
X
X
Medical history and demographics
X
Physical examination, height (screening only), 
and weight
X
X
X
X
X
ECOG Performance status
X
X
X
X
X
Vital signs (BP, PR, BT and SpO2)b
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG (Triplicate)c
X
X
X
X
X
12-Lead ECG (single, local assessment only)c
X
X
Ejection fraction (only if clinically indicated)d
X
Pregnancy teste,f
X
X
X
X
X
Haematology and biochemistrye
X
X
X
X
X
X
Coagulation teste
X
X
X
X
Urinalysise
X
X
X
X
X
X
Virology testg
X
Blood, urine sampling for BI 891065 
pharmacokineticsh
X
X
X
X
X
X
X
X (C2)


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Trial period
Screening
Treatment period (Cycle = 21 days)*
Post-Treatment Period*
Cyclea
Cycle 1t
Cycle 2 
onwards
End-of-
Treatment
(EOT) Visitv
30-day 
Safety 
follow-up
Follow-up
for PDp
Visit number
1a
1b
1c
2
3
4
5
1
Day; visit window [days]
-14 to -1 unless 
otherwise 
specifieds
1
2
3
(Part A 
only)
8
(±1)
12
(±1)
15u
16u
1 (±2)
Within 7 (+7) 
days after 
decision of 
discontinuation
30 (+7) 
days after 
last dose 
At least 
every 12 
weeks
(Part B only) Blood sampling for BI 754091 
pharmacokineticsi
X
X
X
X
X
Xi
X
X
(Part B only) Blood sampling for anti-drug 
antibodies (ADAs)j
X
X
Xj
X
X
Alpha-1 acid glycoprotein (AGP)
X
X (C2)
Blood sampling for Cytokinesk
X
X
X
X
X (C2)
X
Blood sampling for Coproporphyrinl
X
X
X
X
X
Blood sampling for PGxm
X
(Part B only) Tumour biopsyn
X
X (C2)
BI 891065 intakeo
Continuous dosing of once or twice daily, with exceptions for PK 
assessment
(Part B only) BI 754091 infusion
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Check of disease progressionp
X
Review Patient Diary
X
X
X
X
X
X
X
X
X
X
(Part B only) Chest X-raye,q
X
X
X
X
Tumour assessmentr
X
(-28 to -1)
Every 6 weeks ±3 days for 24 weeks (then every 9 weeks ±3 days thereafter)


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* After implementation of protocol version 05, the patient will have assessments as medically indicated to monitor the safety at the discretion of the investigator. These 
assessments may include: ECG, safety lab, and vital signs at a frequency decided by the investigator. The study treatment is administered as continuous daily dosing and the 
administration information will be documented in the eCRF. Tumour assessment will be performed according to standard of care based on medical opinion of the 
investigator. The results of any assessments will be documented in the source data, but will not be collected in the eCRF. The blood sampling for cytokines at the EOT visit is 
not required. Findings which qualify as an (S)AE will be reported in the eCRF and in case of an SAE, on the SAE form (timelines and distribution requirements for SAEs 
apply).
The data collection is required only for the following items:
-
Adverse events
-
Concomitant medications that are used to treat adverse events
-
Drug dispensing
-
Dose changes
-
At each cycle visit: visit date and medication compliance to BI 891065
-
At EOT visit: visit date, end of treatment – BI 891065, and subject retention
-
At safety follow-up visit: visit date and end of study page
-
Death details (if applicable)
a
Treatment cycles are 21 days (3 weeks). Patients will continue treatment with the study drug(s) until they meet any of the discontinuation criteria (CTP 
section 3 "withdrawal from study treatment"). All circumstances for withdrawal of trial treatment are presented in section 3.3.4.1.
b
Vital signs (blood pressure, pulse rate, body temperature, and arterial oxygen saturation rate [SpO2] measured by non-invasive pulse oximeter) are checked at 
every visit prior to blood sampling and trial treatment. The measurement of SpO2 is required in Part B only.
c
Triplicate 12-lead electrocardiograms (ECGs) will be done for local and central assessments as outlined in section 5.2.4 in cycle 1 at the time points specified in 
section 10.3 and whenever the Investigator deems it necessary. ECG machines will be provided to facilitate central readings. From cycle 2 onwards, single 
ECGs will be done for local assessment on visit 1 before the study drug administration.
d
Refer to section 3.3.3 for details on which patients require an ejection fraction assessment (e.g., echocardiogram (ECHO)/multi-gated acquisition (MUGA) 
scan).
e
For haematology, clinical biochemistry, coagulation test, urinalysis, pregnancy test and chest X-ray, if screening tests for these items are performed within 3 
days prior to the initiation of treatment, they do not need to be repeated on Cycle 1 Day 1.
f
Pregnancy tests are mandatory for women with child-bearing potential. A serum (or plasma) beta human chorionic gonadotropin (β-HCG) pregnancy test must 
be done at screening. Thereafter, either a serum (or plasma) or urine pregnancy test will be done on Day 1 of each cycle, at the EOT visit, and at the 30-day 
safety FU visit.


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g
HBV, HCV, and HIV testing should be performed at screening (see section 5.2.3.6 for HBV and HCV test requirements). In Part A, these tests are exempted if 
test results obtained in routine clinical practice within 6 months before the informed consent date are available. In part B, HBV and HCV tests are mandatory 
but HIV testing is not mandatory if test results obtained in routine clinical practice within 6 months before the informed consent date are available.
h
Pharmacokinetic (PK) sampling for BI 891065 (blood and urine) will be done during Cycles 1 and 2 (see tables in section 10.3). Patients will be asked to fast 
overnight (minimum of 10 hours) prior to the following intensive PK days
- Cycle 1 day 1
- Cycle 1 day 15
Urine samples are taken in Part A in once daily (q.d.) dosing schedule cohorts only.
i
Pharmacokinetic (PK) sampling for BI 754091 will be done in Part B only in Cycles 1, 2, 3, 4, 8, 12, 16, and at the EOT and 30-day safety FU visits (see tables 
in section 10.3).
j
Blood samples to test for anti-drug antibodies (ADAs) will be collected from all patients in Part B pre-treatment on Day 1 and 15 of Cycle 1, pre-treatment to 
Cycles 3, 4, 8, 12, 16, and at the EOT and 30-day safety FU visits (see tables in section 10.3).
k
Blood samples for the quantification of cytokines will be taken during Cycle 1 on Day 1 pre-treatment and at 1, 3 and 8 hours post treatment, on Day 2 (no 
treatment day) at 24 hours after first drug intake on the previous day, and pre-treatment on Days 8, 15, and C2D1, as well as at the EOT visit (see tables in 
section 10.3).
l
Coproporphyrin plasma level will be assessed as biomarker to assess the potential inhibition of OATP1B1/B3. Plasma sampling for CPI and CPIII is detailed in 
section 10.3.
m
To perform the pharmacogenetic analysis, patients will provide a blood sample for DNA isolation at Visit 1 of Cycle 1 (C1V1) or at a later visit during 
treatment. Refer to section 5.4.4.
n
The following tumour biopsies will be mandatory for all patients in Part B of the trial:
-
One fine needle biopsy must be freshly taken between screening and first trial drug treatment.
-
One fine needle biopsy from the same lesion on treatment as soon as possible after the 21-day observation period is completed and the patient has been on 
the uninterrupted and unchanged dose of BI 891065 for at least two continuous weeks. Biopsy collection should be delayed until these conditions are met. 
If it is absolutely impossible to obtain a biopsy from the same lesion, another lesion may be chosen.
o
BI 891065 is taken either once daily (q.d.) or twice daily (b.i.d.), depending on the assigned treatment regimen. BI 891065 doses should be taken orally at 
approximately the same time each morning (and evening for patients with b.i.d. dosing). There are exceptions depending on the part (Part A or Part B) and 
dosing regimen (q.d. or b.i.d.):
-
Part A q.d. dosing: a dose will be skipped on cycle 1 day 2
-
Part A b.i.d. dosing: following doses will be skipped in cycle 1 – day 1 evening, day 2 morning and evening, and day 15 evening
-
Part B q.d. dosing: no exceptions
-
Part B b.i.d. dosing: following doses will be skipped in cycle 1 – day 1 evening and day 15 evening


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p
The follow-up visits for progression will be performed for patients whose disease has not progressed by the 30-day follow-up visit, at least once every 12 weeks 
(preferably in person, but if the patient cannot visit the study sites, collecting information by telephone is accepted) until PD, introduction of a new anti-cancer 
treatment, death, loss to follow-up, withdrawal of consent, or end of the whole trial (section 6.2.3.3).
q
Chest X-ray is to be performed in Part B only, on Day 1 of every treatment cycle. Except for cycle 1, the chest X-ray examination for each cycle may be omitted 
if a chest CT scan is performed within 7 days prior to the drug administration on Day 1 for that cycle.
r
Tumour assessments should be done according to RECIST v1.1 and iRECIST and should include CT scans of the chest and abdomen and, if clinically 
indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT scan or MRI). The same radiographic 
procedure must be used throughout the trial. In case of suspected (but not otherwise confirmed) bone metastasis at screening, tumour assessment at screening 
should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT scan) should be performed. 
Correlative imaging should then be repeated at each tumour assessment. Assessments will be performed by the Investigator at screening and once every 6 weeks 
±3 days for the first 24 weeks of treatment, once every 9 weeks ±3 days thereafter, at the EOT visit (if not performed within the previous 4 weeks), and at the 
discretion of the Investigator. The timing of on-treatment imaging assessments is not affected by delays in treatment cycles. Copies of the imaging may be 
collected by the sponsor or designee. Tumour assessments performed prior to informed consent as part of routine clinical practice will be accepted if they meet 
the requirements of the protocol and are performed within 28 days prior to the first administration of study drug(s).
s
Screening should take place within 14 days of start of study treatment unless otherwise specified (e.g., virology tests and tumour assessment for which results 
obtained in routine clinical practice are accepted). However, it may be extended as outlined in section 6.2.1.1.
t
Patients will remain hospitalised for at least three days after the first administration of BI 891065. On day four or later, the investigator will then evaluate 
whether it is appropriate to discharge the patient based on the patient's condition. For this evaluation, the investigator will perform the assessment of adverse 
events and if necessary haematology and clinical chemistry examination.
u
Visits 4 and 5 can be shifted one day before or after (i.e., there's an allowance window of +/- 1 day), but these visits should be performed on two consecutive 
days.
v
An EOT visit should be performed for all patients who permanently discontinue trial medication, preferably within 7 days and no later than 14 days after the 
decision of discontinuation. However, if the assessments specified for EOT have been performed within 7 days prior to the decision of discontinuation, these 
assessments do not need to be repeated. If the decision to permanently discontinue treatment is taken at a scheduled visit, the EOT visit should be performed 
instead of the scheduled visit.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................20
1.2.1
BI 891065 (SMAC mimetic) ...............................................................................20
1.2.2
BI 754091 (anti-PD-1 mAb)................................................................................21
1.2.3
Combination of BI 891065 and BI 754091........................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................23
1.4
BENEFIT - RISK ASSESSMENT.....................................................................23
1.4.1
Benefits.................................................................................................................23
1.4.2
Risks .....................................................................................................................23
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................31
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................32
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................33
3.3.2
Inclusion criteria .................................................................................................33
3.3.3
Exclusion criteria ................................................................................................34
3.3.4
Withdrawal of patients from treatment or assessments..................................36
3.3.4.1
Discontinuation of trial treatment .........................................................................36
3.3.4.2
Withdrawal of consent to trial participation .........................................................37
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................37
4.
TREATMENTS...................................................................................................38
4.1
INVESTIGATIONAL TREATMENTS ...........................................................38
4.1.1
Identity of the Investigational Medicinal Products..........................................38


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4.1.2
Selection of doses in the trial and dose modifications......................................38
4.1.2.1
Starting dose of BI 891065 ...................................................................................38
4.1.2.2
Dose of BI 754091................................................................................................39
4.1.3
Dose-finding scheme ...........................................................................................40
4.1.4
Method of assigning patients to treatment groups...........................................40
4.1.5
Drug assignment and administration of doses for each patient......................41
4.1.5.1
Administration of BI 891065................................................................................41
4.1.5.2
Administration of BI 754091................................................................................42
4.1.6
Dose modifications (pause, delay, dose reduction, and discontinuation).......42
4.1.7
Dose limiting toxicities........................................................................................44
4.1.8
Blinding and procedures for unblinding...........................................................45
4.1.9
Packaging, labelling, and re-supply...................................................................45
4.1.10
Storage conditions...............................................................................................46
4.1.11
Drug accountability.............................................................................................46
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................47
4.2.1
Other treatments and emergency procedures..................................................47
4.2.1.1
Permitted concomitant medications......................................................................47
4.2.1.2
Caution for concomitant medication and/or food .................................................47
4.2.2
Restrictions ..........................................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment ......................................................48
4.2.2.2
Restrictions on diet and life style..........................................................................50
4.2.2.3
Contraception requirements..................................................................................51
4.3
TREATMENT COMPLIANCE........................................................................51
4.3.1
BI 891065 .............................................................................................................51
4.3.2
BI 754091 .............................................................................................................51
5.
ASSESSMENTS..................................................................................................52
5.1
ASSESSMENT OF EFFICACY........................................................................52
5.1.1
Tumour assessments ...........................................................................................52
5.2
ASSESSMENT OF SAFETY.............................................................................53
5.2.1
Physical examination ..........................................................................................53
5.2.2
Vital signs.............................................................................................................53
5.2.3
Safety laboratory parameters ............................................................................53
5.2.3.1
Haematology.........................................................................................................53
5.2.3.2
Biochemistry.........................................................................................................54
5.2.3.3
Coagulation...........................................................................................................54
5.2.3.4
Urinalysis ..............................................................................................................54
5.2.3.5
Pregnancy test .......................................................................................................54
5.2.3.6
Virology ................................................................................................................54
5.2.3.7
Alpha-1 acid glycoprotein.....................................................................................55
5.2.4
Electrocardiogram ..............................................................................................55
5.2.5
Other safety parameters.....................................................................................56
5.2.5.1
ECOG performance status ....................................................................................56
5.2.5.2
Ejection fraction....................................................................................................56
5.2.5.3
Chest X-ray (Part B only) .....................................................................................56
5.2.6
Assessment of adverse events.............................................................................57


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5.2.6.1
Definitions of AEs ................................................................................................57
5.2.6.2
Adverse event collection and reporting ................................................................63
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................64
5.3.1
Assessment of pharmacokinetics .......................................................................64
5.3.2
Methods of sample collection .............................................................................65
5.3.2.1
Plasma sampling for BI 891065 pharmacokinetics and for coproporphyrin ........65
5.3.2.2
Plasma sampling for BI 754091 pharmacokinetics...............................................65
5.3.2.3
Urine sampling and analysis for pharmacokinetics of BI 891065........................66
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................67
5.4.1
Methods of sample collection .............................................................................67
5.4.3
Storage period of samples...................................................................................68
5.4.4
Pharmacogenomic biomarkers ..........................................................................68
5.5
BIOBANKING ....................................................................................................68
5.6
OTHER ASSESSMENTS...................................................................................69
5.6.1
Immunogenicity testing ......................................................................................69
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................69
6.
INVESTIGATIONAL PLAN.............................................................................70
6.1
VISIT SCHEDULE.............................................................................................70
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................70
6.2.1
Screening..............................................................................................................70
6.2.1.1
Screening Period ...................................................................................................71
6.2.1.2
Baseline Conditions ..............................................................................................71
6.2.1.3
Medical History.....................................................................................................71
6.2.1.4
Concomitant medications......................................................................................72
6.2.2
Treatment period(s)............................................................................................72
6.2.3
Follow-up period and trial completion..............................................................72
6.2.3.1
End-of-treatment (EOT) visit................................................................................72
6.2.3.2
30-day safety follow-up visit (end of residual-effect period) ...............................72
6.2.3.3
Follow-up visits for PD (extended follow-up period)...........................................72
6.2.3.4
Trial completion for an individual patient ............................................................73
6.2.3.5
Study procedures modification after implementation of protocol version 5 ........73
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................75
7.1
STATISTICAL DESIGN – MODEL ................................................................75
7.1.1
Part A ...................................................................................................................75
7.1.2
Part B ...................................................................................................................78


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7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................82
7.3
PLANNED ANALYSES.....................................................................................82
7.3.1
General considerations .......................................................................................83
7.3.1.1
Patient analysis sets...............................................................................................83
7.3.1.2
Pharmacokinetics ..................................................................................................84
7.3.2
Primary endpoint analyses.................................................................................84
7.3.2.1
Part A ....................................................................................................................84
7.3.2.2
Part B.....................................................................................................................84
7.3.3
Secondary endpoint analyses .............................................................................84
7.3.5
Safety analyses.....................................................................................................85
7.3.6
Interim Analyses .................................................................................................85
7.4
HANDLING OF MISSING DATA ...................................................................86
7.5
RANDOMISATION ...........................................................................................86
7.6
DETERMINATION OF SAMPLE SIZE .........................................................86
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........87
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................87
8.2
DATA QUALITY ASSURANCE ......................................................................88
8.3
RECORDS...........................................................................................................88
8.3.1
Source documents ...............................................................................................89
8.3.2
Direct access to source data and documents.....................................................90
8.3.3
Storage period of records ...................................................................................90
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................90
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........90
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................91
8.6
TRIAL MILESTONES.......................................................................................91
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................91
9.
REFERENCES....................................................................................................93
9.1
PUBLISHED REFERENCES............................................................................93
9.2
UNPUBLISHED REFERENCES......................................................................96
10.
APPENDICES.....................................................................................................98
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....98
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS............101
10.3
TIME SCHEDULE FOR ECG, BLOOD AND URINE SAMPLING FOR 
PK, AND BLOOD SAMPLING FOR BIOMARKER ..................................108
10.4
STATISTICAL APPENDICES .......................................................................112
10.4.1
Part A .................................................................................................................112
10.4.2
Part B .................................................................................................................116
10.5
IRECIST RESPONSE ASSESSMENT...........................................................121
10.5.1
Confirming progression....................................................................................121
10.5.2
New lesions.........................................................................................................121


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................125
11.1
GLOBAL AMENDMENT 1 ............................................................................125
11.2
GLOBAL AMENDMENT 2 ............................................................................130
11.3
GLOBAL AMENDMENT 3 ............................................................................131
11.4
GLOBAL AMENDMENT 4 ............................................................................140


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ABBREVIATIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
AGP
Alpha-1 Acid Glycoprotein
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase 
AUC
Area under the Curve
BCRP
Breast Cancer Resistance Protein
β-HCG
Beta Human Chorionic Gonadotropin
BI
Boehringer Ingelheim
b.i.d.
Twice a day, Twice daily
BLRM
Bayesian Logistics Regression Model
CA
Competent Authority
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology
Cmax
Maximum Concentration
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
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid


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ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EF
Ejection Fraction
EOT
End of Treatment
EWOC
Escalation With Overdose Control
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBc
Hepatitis B core
HBs
Hepatitis B surface
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
IAP
Inhibitor of apoptosis
iCPD
Confirmed Immune Progression
iCR
Immune Complete Response
IDMS
Isotope Dilution Mass Spectroscopy
IEC
Independent Ethics Committee
IL
Interleukin
ILD
Interstitial Lung Disease
IRB
Institutional Review Board
iPD
Immune Progressive Disease
iPR
Immune Partial Response
irAE
Immune related Adverse Event
IRT
Interactive Response Technology
iUPD
Unconfirmed Immune Progression
iSD
Immune Stable Disease
ISF
Investigator Site File
i.v.
intravenous
LC
Liquid Chromatography


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LC-MS/MS
Liquid Chromatography Tandem Mass Spectrometry
mAb
Monoclonal Antibody
MAP
Meta-Analytic Predictive
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
MS
Mass Spectroscopy
MSI
Microsatellite Instability
MTD
Maximum Tolerated Dose
MUGA
Multi-Gated Acquisition Scan
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
OR
Objective Response
p.o.
per os (oral)
PD
Progressive disease
PD-1
Programmed-cell-death-protein-1
PD-L1
Programmed-cell-death ligand-1
P-gp
P-glycoprotein
PK
Pharmacokinetics
PT
Prothrombin Time
PR
Partial Response
q.d.
Once a day, Once daily
QTcF
Corrected QT interval by Fredericia
RD
Recommended Dose
RECIST
Response Evaluation Criteria In Solid Tumours
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Stable Disease
SMAC
Second Mitochondrial Activator of Caspases
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SpO2
Arterial oxygen saturation


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SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half Life Time
TSH
Thyroid Stimulating Hormone
tmax
Timepoint of Maximum Plasma Concentration
TMB
Tumour Mutation Burden
TNFα
Tumour necrosis factor alpha
TNM
Tumour, Node, Metastasis
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
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 2018, the estimated number of new cancer cases was approximately 18 million, 
and 9.5 million cancer-related deaths worldwide (R18-3204). In the majority of cases, the 
disease is diagnosed in late stages and the vast majority of patients progress on available 
treatment and succumb to their disease. These statistics clearly highlight the urgent need for 
novel therapeutic agents and treatment strategies to improve the treatment outcome for cancer
patients.
Inhibitors of apoptosis (IAP) proteins are critical regulators of cell death and survival, and 
thus attractive targets for the development of novel anticancer drugs. Degradation of IAP 
following treatment with second mitochondrial activator of caspases (SMAC) mimetics 
lowers the threshold of apoptosis and therefore may be potentially beneficial for treatment of 
cancer. The SMAC protein is an endogenous antagonist of X-linked IAP (XIAP), cellular 
IAP 1 (cIAP1), and cIAP2. In the last decade, intense research efforts have resulted in the
design and development of several small-molecule SMAC-mimetics now in clinical trials for 
cancer treatment (R16-1600). Clinical studies revealed the potency of SMAC-mimetics to 
cause IAP depletion at clinically achievable blood levels and some evidence of antitumour 
activity (complete response [CR], disease stabilization, and tumour regression) when 
SMAC-mimetics were used as monotherapy (R16-0378; R16-0671; R16-0871; R16-4718;
R16-4805; R16-4958). However, the therapeutic potential of these compounds will likely be 
fully exploited in rational combination protocols by taking advantage of synergistic drug 
effects (R16-0379).
The normal role of the immune system is to protect the body against the invasion of foreign 
antigens such as bacteria, viruses, and parasites as well as the body’s own malfunctioning 
cells. Once a mounted immune response (adaptive or innate) completes its task of eliminating 
the threat, the immune system deploys the immune checkpoint program to dampen the 
immune response and minimise collateral immune-mediated damage to healthy tissue. 
Programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway is 
one of the major immune checkpoint master switches. Treatment of patients with advanced 
melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, and many other 
tumour types with anti-PD-1 (nivolumab or pembrolizumab) or anti-PD-L1 (atezolizumab, 
durvalumab and avelumab) Monoclonal Antibodies (mAbs) results in highly durable 
responses in approximately 15% to 30% of patients (R15-3588; R15-3715; R15-3776;
R15-3778; R15-6023; R16-0663; R16-0864; R16-0876; R16-1225; R16-1588; R16-3547).
The majority of patients do not respond and require more effective treatments.


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1.2
DRUG PROFILE
1.2.1
BI 891065 (SMAC mimetic)
The SMAC mimetic, BI 891065, is a new chemical entity with a molecular weight of
704 g/mol that is being developed as film-coated tablets for oral administration. BI 891065 is 
characterised by a medium bioavailability in rats (37%) with low plasma clearance. Excretion 
of [14C]BI 891065 applied to rats was rapid with more than 90% of dosed radioactivity 
excreted in the faeces within 48 hours.
BI 891065 showed a high and similar protein binding in investigated animal species and 
human plasma. Considerable and comparatively long-lasting (yet reversible) exposure of 
radioactivity to ocular tissues and relevant yet rather short-lived exposure of radioactivity to 
the integumentary system was observed.
BI 891065 is an in vitro inhibitor of various cytochrome P450 (CYP) enzymes that play a role 
in drug metabolism, with 2C8 being the most susceptible. No irreversible inhibition of the 
CYP enzymes was observed. BI 891065 was shown to be an in vitro inducer of CYP1A2. 
BI 891065 inhibited P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and 
MATE2-K. BI 891065 potently inhibits cIAPs protein function with selectivity for cIAP1 
versus cIAP2 and XIAP. Binding of BI 891065 to the BIR3 domain of cIAP1 induces 
auto-ubiquitination and subsequent degradation by the proteasome.
Based on the nonclinical studies summarised in the BI 891065 Investigator’s Brochure 
(c14463420), the nonclinical safety profile of BI 891065 is considered to be acceptable for 
the intended oncological indications. Clinical side effects in adult patients may be related to a 
tumour necrosis factor alpha (TNFα)-mediated release of pro-inflammatory cytokines.
Several SMAC-mimetics have been investigated in patients with various malignancies. In 
general, they were well tolerated, and the majority of adverse events (AEs) were mild to 
moderate, fatigue and gastrointestinal AEs being most frequently reported. Adverse events of 
higher grade considered drug related, serious, or dose-limiting included cytokine release 
syndrome, elevations of liver enzymes, elevations of pancreatic enzymes, facial nerve palsy, 
lymphocytopenia, and pneumocystis jirovecii pneumonia (R16-0671; R16-0871; R16-4718; 
R16-4805; R16-4958; R17-0287). Thus, close safety monitoring and precautions to mitigate 
the risk for severe cytokine release syndrome, elevations of liver or pancreatic enzymes, 
monitoring of lymphocytes, and facial nerve palsy will be implemented.
As of March 2019, the first-in-man trial of BI 891065 (1379-0001) is being conducted in 
Western countries. The trial consists of three parts, BI 891065 monotherapy dose escalation 
part, BI 891065 and BI 754091 (anti-PD-1 mAb) combination dose escalation part, and BI 
891065 and BI 754091 combination expansion part. In the monotherapy dose escalation part, 
dose levels ranging from 5 mg to 400 mg were tested and no dose limiting toxicity (DLT)
was reported in a total of 25 treated patients. Currently the combination dose escalation part 
is ongoing.


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1.2.2
BI 754091 (anti-PD-1 mAb)
BI 754091 is a humanised IgG4Pro isotype anti-PD-1 mAb being developed as an i.v. 
infusion for the treatment of cancer. BI 754091 has highly human frameworks and a low 
predicted immunogenicity score. The BI 754091 molecule has a molecular weight of 
approximately 148 kilodaltons. The antibody is composed of 2 heavy chains (446 amino 
acids each) and 2 light chains (218 amino acids each). The 4 polypeptide chains of the 
antibody are linked together by disulfide bonds. Each heavy chain contains one consensus 
sequence for N-linked glycosylation.
BI 754091 shows strong anti-tumour effects in several mice tumour models with some mice 
showing a CR. Single and repeat dosing studies showed that BI 754091 was well tolerated (as 
judged by body weight changes and clinical signs) and resulted in significant tumour growth 
inhibition (≥83%) (BI 754091 Investigator’s Brochure; c07895879).
As of March 2019, BI 754091 is under clinical development and the status of clinical trials 
are as follows:
∀
The first-in-man trial of BI 754091 (1381-0001) is being conducted in Western countries. 
The trial consists of a dose escalation part and an expansion part. In the dose escalation 
part, dose levels ranging from 80 mg to 400 mg were tested and no DLT was reported. 
240 mg was selected as the recommended dose for the expansion part and following 
clinical trials. As of the data cut-off point of 01 November 2018, 50 patients were treated 
in total (dose escalation cohorts and expansion cohorts) and the objective response rate 
was 12% (6 patients with partial response).
∀
There is an ongoing clinical trial of BI 754091 in Asia (1381-0004). This trial consists of 
several parts including a dose-finding part for BI 754091 monotherapy. BI 754091 as 
single agent of 240 mg was administered to six Japanese patients, and no DLT was 
reported.
∀
BI 754091 is also being tested in combination with other investigational products in 
several clinical trials.
1.2.3
Combination of BI 891065 and BI 754091
The rationale for combining BI 891065 and anti-PD-1 is the “one-two-punch” combination 
model. The first punch is given to the tumour cells directly by the SMAC mimetic BI 891065 
in combination with cell death triggers released by the immune system or by the tumour cells 
themselves (e.g., TNFα), while the second punch leading to decisive, tumour knock-out 
occurs only after concomitant blockade of the co-inhibitory receptor PD-1 that restores T-cell
activity. The killing of tumour cells mediated by SMAC-mimetic may lead to immunogenic 
cell death (R16-0468; R16-4658), followed by activation of dendritic cells and ultimately 
increased T-cell infiltration. Thus, the SMAC-mimetic/PD-1 combination may be effective in 
tumours with low T-cell infiltrate as suggested by an increased efficacy in syngeneic mouse 
models that respond poorly to anti-PD-1 monotherapy. In these models, complete tumour
regression with high response rates (80% to 90%) can be achieved upon combination of 
BI 891065 and an anti-PD-1 mAb.


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The SMAC mimetics induce rapid degradation of cIAP1, which leads, amongst others, to the 
activation of the alternative NF-Kb pathway within subsets of immune cells, and stimulation 
of cytokine secretion. Changes in cytokine levels, as contributors to the ‘first punch’ will be 
monitored in peripheral blood.
SMAC-mimetics have been shown to have an immunomodulatory function mediating the 
induction of systemic cytokines (e.g., Interleukin-6, TNFα etc.) and chemokines (e.g.,
MCP-1) when administered to animals or humans (R16-0671 and Boehringer Ingelheim [BI]
in-house data).
To assess the potential of the combination of BI 891065 (SMAC-mimetic) and BI 754091 
(anti-PD-1 mAb) to cause cytokine release different from that induced by the administration 
of BI 891065, a combination study was conducted in cynomolgus monkeys, the animal 
species used for the non-clinical program of the monoclonal antibody BI 754091. This study 
did not provide evidence for a clinically relevant change in the cytokine release profile of 
BI 891065.
Combination of BI 891065 with BI 754091 did not affect the pharmacokinetics (PK) of BI 
754091 in cynomolgus monkeys. Under the conditions of this study, BI 891065 at 15 
mg/kg/day was well tolerated in the cynomolgus monkey in the presence or absence of BI 
754091 dosed at 10 mg/kg.
For a more detailed description of BI 891065 and BI 754091 profiles, please refer to the
current Investigator’s Brochures (c14463420 and c07895879).
At a data cut-off date of 29 March 2019, 3 patients have been treated in a single cohort 
(BI 891065 200 mg + BI 754091 240 mg). No patient has experienced an SAE, death on 
study, an AE leading to treatment discontinuation or a ≥ Grade 3 AE. One patient has 
experienced non-serious irAEs (hyperthyroidism and pruritus, both grade 1) which were not 
treated nor did they lead to dose modification of study drugs.
At the same cut-off date (29 March 2019) seven patients (out of 25, 28 %) in the 
monotherapy portion (Part A) and two patients (out of 3, 66 %) in the combination therapy 
portion (Part B) of study 1379-0001 had elevated bilirubin based on safety laboratory 
measurements. The blood bilirubin increases appeared to be dose-dependent. There were no 
concomitant abnormalities in other parameters like AST, ALT, Alkaline phosphatase and 
LDH which could not be explained otherwise (e.g. underlying disease). All increased 
bilirubin values were maximum Grade 2 and did not lead to dose-reduction or discontinuation 
of study drug. Aetiology and clinical significance are still under investigation.
Of note, after the data cut-off date, a non-serious immune-related adverse reaction of 
pneumonitis grade 2 was reported which was considered as a DLT as per Clinical Trial 
Protocol (CTP) in the highest dose combination cohort (BI 891065 400 mg + BI 754091 
240 mg). The event started 16 days after first study drug administration and the patient 
responded well to high-dose steroids.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
Most patients with locally advanced or metastatic tumours will succumb to their disease, 
justifying the substantial need for novel therapeutic strategies to improve the outcome for 
these patients. Immune checkpoint inhibition has been shown to be a promising therapeutic 
strategy. Despite encouraging clinical results with immune checkpoint inhibitors, up to 80% 
of treated patients do not respond to current checkpoint inhibitor monotherapy (R15-3588;
R15-3778).
Preclinical studies generated evidence of a tumour regression effect of the combination of 
second mitochondrial activator of caspases (SMAC) mimetic BI 891065 and 
programmed-cell-death-protein-1 (PD-1) antagonists. In particular, the strong combinatorial 
effect observed in several syngeneic models in combination with anti-PD-1 supports the 
combination with PD-1 inhibitors. The PD-1 inhibitor BI 754091 will serve as a combination 
partner for the SMAC-mimetic BI 891065.
Further clinical development of BI 891065 is planned in combination with BI 754091. This 
requires phase I clinical investigation of BI 891065 monotherapy in Caucasian and Asian 
patients. In particular, establishment of clinical safety of BI 891065 monotherapy unaffected 
by a combination treatment is needed. The first-in-human clinical trial of BI 891065
monotherapy and combination of BI 891065 and BI 754091 (trial 1379-0001) is being 
conducted in Western countries. This trial (trial 1379-0006) is intended to assess the safety, 
efficacy and PK of BI 891065 monotherapy and combination of BI 891065 and BI 754091 in 
Asian patients to establish a safe combination dose for the clinical development in Asia.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
This trial is for patients with no therapy options of proven efficacy, or who are not amenable 
to standard therapies. BI 891065 and BI 754091 inhibit tumour growth and induce tumour 
regression in pre-clinical models. Based on pre-clinical results, BI 891065 showed single 
agent anti-tumour activity in several tumour models. Furthermore, the inhibitory effects of 
the combination of both compounds have been demonstrated in tumour models and may 
translate into clinical benefit in cancer patients.
1.4.2
Risks
Table 1.4.2: 1 displays the anticipated side effects of the study drugs, based on the 
mechanism of action, observed clinical data from ongoing studies, and published clinical data 
for drugs targeting SMAC mimetic and PD-1.


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Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy
Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product BI 891065
Unexpected adverse events
and laboratory abnormalities
Due to limited clinical 
experience of this drug.
Close monitoring, including 
implementation of safety 
monitoring committee (SMC).
Cytokine release syndrome
(CRS)
Mode of action of the drug 
may cause CRS because it 
promotes release of cytokines.
(No safety relevant increases 
of cytokines measured were 
observed in the first in human 
trial 1379-0001 (as of 29 
March 2019))
To keep patients hospitalised 
for 3 days after the first 
administration of BI 891065. 
Provide recommendation for 
the management of CRS in the 
clinical trial protocol.
Cytokine levels are measured.
Photosensitivity
SMAC mimetics may sensitize
neoplastic as well as 
non-neoplastic cells to 
radiation. Preliminary data for 
BI891065 from a standard 
phototoxicity assay in 3T3 
mouse fibroblasts seem to 
confirm this hypothesis.
Patients should be instructed to 
avoid of exposure to direct 
sunlight (including sunlamps), 
to use a sunblock and to wear 
clothing and sunglasses that 
protect against sun exposure 
during treatment and for 4 
weeks after the last 
administration of BI 891065.
Drug-induced liver injury 
(DILI)
Rare but can be a potentially 
severe event, thus under 
constant surveillance by 
sponsors and regulators for all 
drugs in development.
Timely detection, evaluation, 
and follow-up of laboratory 
alterations in selected liver 
laboratory parameters to 
ensure patients' safety.


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Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy (continued)
Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product BI 754091
Unexpected adverse events 
and laboratory abnormalities 
Due to limited clinical 
experience of this drug.
Close monitoring, including 
implementation of safety 
monitoring committee (SMC).
Immune-related adverse 
events (irAEs)
irAEs are associated with 
immune mediated mode of 
action and can be potentially 
severe.
Recommendations for the 
management of irAEs are 
provided according to 
international guidelines and 
product labels of approved 
PD-1 inhibitors.
Infusion related reactions
As with any mAb, 
hypersensitivity reactions to 
study medication 
administration are possible 
and they are potentially 
severe.
Patients with history of severe 
hypersensitivity reactions to 
other mAbs are excluded.
Recommendations for the 
management of infusion 
related reactions are given in 
section 5.2.6.1.4.
Drug-induced liver injury 
(DILI)
Rare but can be a potentially 
severe event, thus under 
constant surveillance by 
sponsors and regulators for all 
drugs in development.
Timely detection, evaluation, 
and follow-up of laboratory 
alterations in selected liver
laboratory parameters to 
ensure patients' safety.
Trial procedures
Tumour biopsy related AEs
(Part B only)
Tumour biopsies are 
mandatory in Part B. There are 
known risks associated with 
biopsies such as pain or 
bleeding.
The risks are clearly explained 
in the informed consent 
document.
Other risks
NA
1.4.3
Discussion
Both BI 891065 and BI 754091 are currently tested in early phase clinical trials. In general, 
the observed safety data from the ongoing clinical trials have been consistent with the 
anticipated safety profiles of these compounds. No DLTs were reported in preceding trials of 
BI 891065 and BI 754091 in single agent setting. Pre-clinical results showed that BI 891065 
exhibited anti-tumour activity as single agent in several tumour models. Target engagement 


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(cIAP degradation in Peripheral Blood Mononuclear Cells) was observed in patients in the 
dose escalation part of trial 1379-0001. At a dose of 100 mg BI 891065, cIAP1 degradation in 
blood (mode of action biomarker) of >60% was observed in 2 out of 3 patients. Based on the 
pre-clinical data, as well as clinical data obtained with BI 754091, the inhibitory effects of 
PD-1 by BI 754091 may translate into clinical benefit in cancer patients.
A Bayesian Logistic Regression Model (BLRM) design will be used in order to escalate the 
dose into a range where efficacy or target engagement are expected while still minimizing the 
risk of undue toxicity.
The starting doses of this trial was selected based on the available data from preceding trials, 
and are considered to minimise the exposure of patients to sub-therapeutic doses.
Patients will remain under surveillance for 10 hours after the first administration of 
BI 891065 (i.e., until the blood sampling for PK on day 1 is completed). All trial sites will 
have emergency resuscitation services and access to intensive care.
Specific attention will be given to immune-mediated adverse events (irAEs), infusion-related 
reactions, and cytokine release syndrome (CRS). Infusion-related reactions or CRS, amongst 
others, are defined as adverse events of special interest (AESI) and have to be reported 
according to the rules defined for serious AE (SAE)-reporting.
A Safety Monitoring Committee (SMC) will be established for the assessment of the trial 
data to ensure the overall safety of the patients and for making dose escalation decisions and 
defining the recommended dose (RD) for further development.
In summary, the present trial will implement a number of safety measures to mitigate 
potential risks. A potential benefit is offered to patients with advanced and/or metastatic 
malignancies by SMAC-mimetic monotherapy and even more by the combination of a 
SMAC mimetic with a PD-1 inhibitor. Therefore, treatment with both compounds is 
considered to have the potential to provide patients with clinical benefit at an acceptable risk.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this trial is:
Part A
∀
To determine the Maximum tolerated dose (MTD) and/or the recommended dose (RD) of 
BI 891065 monotherapy for further development in Asian patients with advanced solid 
tumours
Part B
∀
To determine the MTD and/or the RD of BI 891065 in combination with a fixed dose of 
BI 754091 at 240 mg for further development in Asian patients with advanced solid 
tumours 
The definition of MTD and RD are as follows:
∀
MTD: the highest dose with less than 25% risk of the true DLT rate being equal or above 
33% during the MTD evaluation period
∀
RD: RD is determined by SMC and it may be any dose which fulfil the escalation with 
overdose control (EWOC) criterion. The SMC may decide to declare a dose as RD
without determining the MTD, in consideration of all available data including that from 
preceding trials.
The MTD will be determined based on the frequency of patients experiencing DLTs during 
the MTD evaluation period. The MTD evaluation period is defined as first treatment cycle
(21 days). At the end of the dose escalation, the BLRM will be rerun using DLTs from all 
treatment cycles. This result as well as all available data will be used to define the RD.
The secondary objectives are:
Part A
∀
To document the safety and tolerability, and characterise pharmacokinetics (PK) of 
BI 891065 as monotherapy in Asian patients with advanced solid tumours
Part B
∀
To document the safety and tolerability, and characterise PK of the combination therapy 
of BI 891065 and BI 754091 in Asian patients with advanced solid tumours
2.1.2
Primary endpoint(s)
∀
Maximum tolerated dose (MTD). 


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∀
Number of patients with Dose Limiting Toxicities (DLTs) in the MTD evaluation period
and thereafter. 
A BLRM employing the EWOC principle will be used during the escalation phase for 
selection of doses and for estimation of the MTD. Cohorts of patients will receive escalating 
doses of BI 891065 single agent or combination of BI 891065 and BI 754091 until the MTD 
is reached or the highest planned dose has been tested (see section 4.1.3). Each cohort will 
consist of newly enrolled patients. Estimation of the MTD will be based upon the estimation 
of the probability of a DLT in the MTD evaluation period in the set of evaluable patients for 
MTD (section 3.3.4.1). 
2.1.3
Secondary endpoint(s)
Part A
∀
The following pharmacokinetics (PK) parameters of BI 891065 will be calculated in cycle 
1:
o
Cmax(,ss), AUC0-24 and AUCτ,ss of BI 891065
Part B
∀
The following PK parameters of BI 891065 and BI 754091 will be calculated in cycle 1:
o
Cmax(,ss), AUC0-24 and AUCτ,ss of BI 891065; 
o
Cmax and AUC0-504 of BI 754091


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I, open-label, non-randomised, multicentre trial of BI 891065 given as single 
agent (Part A) and in combination with BI 754091 (Part B). The data obtained from the trial 
will determine the MTD estimate for each Part based on a Bayesian logistic regression model 
(BLRM) with overdose control (R13-4803). The BLRM estimates the MTD by updating 
estimates of the probability of observing a DLT in the MTD evaluation period for each dose 
level in the trial as patient information becomes available. At any time in the trial, it will not 
be permitted to escalate to a dose which does not fulfil the EWOC principle (refer to 
section 7). Dose-escalation will be restricted to a maximum of 100 % from the previous dose.
In Part A, successive cohorts of patients will receive increasing doses of BI 891065. The 
starting dose of BI 891065 is 100 mg once daily. The dose escalation continues until the 
MTD is reached, or the safety in the highest planned dose level (400 mg total daily dose of BI 
891065) is confirmed. Depending on the occurrence of DLTs or other relevant safety 
information, SMC may decide to decrease the dose of BI 891065. For any dose-escalation 
cohort, at least three patients will be enrolled. SMC may decide enrolment of further patients. 
However, in the case that only two patients are evaluable (i.e. one patient is not evaluable)
and neither has experienced a DLT within the MTD evaluation period, then dose-escalation 
can occur based on these two patients.
A Safety Monitoring Committee decides the size for the next dose escalation cohort. After all 
patients in a 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. The overdose risk will then be calculated for each dose, and 
escalation will be permitted to all doses which fulfil the EWOC criterion and the additional 
100 % escalation rule. Based on the model and on other available information, the members 
of the SMC will reach a joint decision on the next dose level to be investigated.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The BLRM will re-run to confirm that 
the dose level still fulfils the EWOC principle. Based on this information, the SMC will 
evaluate whether the next patients will be enrolled at the same dose level, or if they are
enrolled at a lower dose level. 
The SMC may decide to stop the dose escalation phase after the criterion for MTD is fulfilled, 
or the safety in the highest planned dose level is confirmed in the absence of an MTD. 
Further patients may be included to confirm this MTD estimate, i.e., to confirm that the 
EWOC criterion is still fulfilled. 
The SMC can declare any dose fulfilling the EWOC criterion as RD, independent of the 
MTD estimate.
In Part B, successive cohorts of patients will receive escalating daily dose of BI 891065 in 


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combination with a fixed dose of BI 754091 at 240 mg once every 3 weeks. The planned 
starting dose of BI 891065 in Part B is 200 mg, and this cohort will commence after the 
safety of the same dose level in Part A is confirmed. Other doses may be investigated 
depending on the safety data obtained from Part A and from the preceding first-in-human trial 
(1379-0001). SMC will make the decision based on recommendation from BLRM as well as 
other safety information. BLRM with overdose control will be implemented in Part B 
incorporating all available information of BI 891065 and BI 754091 to quantify the 
probability of observing a DLT once patient information becomes available. 
The dose escalation will continue until any of the following occurs:
1. the MTD is reached
2. the safety in the highest planned dose level (400 mg) is confirmed
3. the safety at the highest dose tolerated in Part A is confirmed (applicable when this dose 
is less than 400 mg). 
In Part B the dose escalation will follow the approach as described for Part A.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is a single-arm trial with multiple dose cohorts and there is no control group. This is 
a standard design in Phase I trials in Oncology clinical trials where the assessment of MTD, 
safety and PK are the main objectives. 
A Bayesian Logistic Regression Model (BLRM) will be used to guide the dose-finding, in 
order to escalate the dose into a dose range where efficacy or target engagement may be seen 
while still minimizing the risk of undue toxicity.
A SMC will be established to ensure the patient safety (for details, see section 8.7). The SMC 
will monitor the safety data on an ongoing basis, interpret the DLT risk estimate provided by 
BLRM, and make decisions regarding the dose level to be investigated, the MTD and/or RD, 
and the necessity of trial plan modifications in case of emerging safety issues.
3.3
SELECTION OF TRIAL POPULATION
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
Approximately 21 patients (12 in Part A, 9 in Part B) are planned to be included. This trial 
will be conducted in Japan and Taiwan. Japanese patients will be recruited in all treatment 
cohorts, and Taiwanese patients will be recruited in the highest planned dose in Part A and all 
cohorts in Part B (for details, please refer to section 4.1.3). This design provides the 


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safety/PK data in Japanese patients in multiple dose levels, and also gives the safety/PK data 
in Taiwanese patients.
3.3.1
Main diagnosis for trial entry
Patients with a confirmed diagnosis of advanced, unresectable and/or metastatic solid 
tumours, who have failed standard treatment, or for whom no therapy of proven efficacy 
exists, or who are not amenable to standard therapies.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
The grade of adverse events mentioned in this protocol is based on Common terminology 
criteria for adverse events (CTCAE) version 5.0 (R18-1357).
3.3.2
Inclusion criteria
1. Of legal age (according to local legislation) at screening. No upper limit.
2. Signed and dated written informed consent in accordance with International Council on 
Harmonisation (ICH) Good Clinical Practice (GCP) and local legislation prior to 
admission to the trial.
3. Male or female patients. Women of childbearing potential (WOCBP)1 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, starting with the screening visit and through 6 months after the 
last dose of study treatment. A list of contraception methods meeting these criteria is 
provided in the patient information. The requirement of contraception does not apply to 
women of no childbearing potential and men not able to father a child, but they must have 
an evidence of such at screening.
4. Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 1
5. Patients with a confirmed diagnosis of advanced, unresectable and/or metastatic solid 
tumours, who have failed standard treatment, or for whom no therapy of proven efficacy 
exists, or who are not amenable to standard therapies. 
6. Presence of at least one measureable lesion according to RECIST 1.1.
7. Life expectancy of at least 12 weeks after the start of the treatment according to the 
Investigator’s judgement
8. For Part B: Patients must have at least 1 tumour lesion amenable to biopsy, and must be 
willing to undergo a biopsy prior to first treatment and after 3 weeks while on therapy.
9. For Part B: Patients with following cancer types: bladder, colon, breast, NSCLC, ovarian, 
pancreatic, renal, esophagogastric, sarcoma, prostate, and melanoma.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3.3.3
Exclusion criteria
1. Major surgeries (major according to the Investigator’s assessment) performed within 
12 weeks prior to the first administration or planned within 12 months after screening 
(e.g., hip replacement), or moderate surgeries (moderate according to the Investigator's 
assessment) performed within 4 weeks prior to the first administration.
2.
Presence of active invasive cancers other than the one treated in this trial within 5 years 
prior to screening, except for appropriately treated basal cell carcinoma of the skin, or in 
situ carcinoma of uterine cervix, or other local tumours considered cured by local
treatment
3.
Patients who must or wish to continue the intake of restricted medications or any drug 
considered likely to interfere with the safe conduct of the trial
4.
Previous administration of BI 891065 or other SMAC mimetic/IAP inhibitor
5.
Patients who have been treated with any other anticancer drug or investigational drug, 
within 4 weeks or within 5 half-life periods (whichever is shorter) prior to first 
administration of BI 891065
6.
Persistent toxicity from previous treatments that has not resolved to ≤ Grade 1 (except 
for alopecia and Grade 2 neuropathy due to previous treatments)
7.
Active, known or suspected autoimmune disease except vitiligo or resolved asthma/atopy
8.
(Part B only) Patients removed from previous anti-PD-1 or anti-PD-L1 therapy because 
of a severe immune-related adverse event (irAE)
9.
History (including current) of interstitial lung disease or pneumonitis within 5 years
10. Any of the following cardiac criteria:
 Mean resting corrected QT interval (QTcF) >480 msec

Any clinically important abnormalities (as assessed by the investigator) in rhythm, 
conduction, or morphology of resting Electrocardiograms (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 with known or possible risk of QT interval prolongation

Patients with an ejection fraction (EF) of either <50% or less than the lower limit of 
normal of the institutional standard will be excluded, whichever is lower. 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.
11. Inadequate organ function or bone marrow reserve as demonstrated by the following 
laboratory values:

Absolute neutrophil count (ANC) <1.5 x 109/L (<1500/mm3)

Platelet count <100 x 109/L (<100,000/mm3)

Haemoglobin <9.0 g/dL


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 Alanine transaminase (ALT) >3 times the upper limit of normal (ULN) if no 
demonstrable liver lesion(s) (primary or metastases) or >5 times ULN in the 
presence of liver lesion(s)
 Aspartate aminotransferase (AST) >3 times the ULN if no demonstrable liver 
lesion(s) or >5 times ULN in the presence of liver lesion(s)

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

Serum creatinine > 1.5 x ULN (measured by enzymatic assay, Isotope dilution mass 
spectroscopy [IDMS] standardised Jaffe assay, or non-IDMS Jaffe assay). If serum 
creatinine is > 1.5 x ULN, patient is eligible if concurrent estimated glomerular 
filtration rate (eGFR) is ≥ 30 mL/min/1.73m3 (measured or calculated by Chronic 
Kidney Disease Epidemiology [CKD-EPI] formula)
12. Human immunodeficiency virus (HIV) infection. Test results obtained in routine 
diagnostics are acceptable if done within 6 months before the informed consent date.
13. Any of the following laboratory evidence of hepatitis virus infection. 

Positive results of hepatitis B surface (HBs) antigen

Presence of hepatitis B core (HBc) antibody together with hepatitis virus B (HBV) 
Deoxyribonucleic acid (DNA)

Presence of hepatitis virus C (HCV) antibody together with HCV Ribonucleic acid 
(RNA)
In Part A, test results obtained in routine clinical practice are acceptable if done within 6 
months before the informed consent date.
14. Known relevant hypersensitivity to the trial drugs or their excipients based on the 
investigator's assessment
15. Serious concomitant disease or medical condition affecting compliance with trial 
requirements or which are considered relevant for the evaluation of the efficacy or safety 
of the trial drug, such as cardiac, neurologic, psychiatric, infectious disease or active 
ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug administration, and in the judgment of the 
Investigator would make the patient inappropriate for entry into the trial.
16. Chronic alcohol or drug abuse or any condition that, in the Investigator’s opinion, makes 
them an unreliable trial patients, unlikely to complete the trial, or unable to comply with 
the protocol procedures
17. Women who are pregnant, nursing, or who plan to become pregnant during the trial. 
Women who are nursing can be enrolled if they stop nursing. In this case, the patient 
cannot resume nursing even after discontinuation of study treatment.
18. 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
19. Patients with known leptomeningeal disease
20. Patients receiving systemic treatment with any immunosuppressive medication within 
1 week prior to treatment start (steroids of max. 10 mg/day prednisolone equivalent per 
day are allowed, topical and inhaled steroids are not considered as immunosuppressive).


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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; please see sections 3.3.4.1 and 
3.3.4.2 below.
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 case report form (CRF). If applicable, 
consider the requirements for Adverse Event collection reporting (please see sections 
5.2.6.2.1 and 5.2.6.2).
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 trial assessments. Refer to section 4.2.2.1 for prohibited concomitant 
medications.
∀
Progressive disease according to RECIST v1.1 and/or iRECIST. Refer to section 5.1.1 for 
details and exceptions.
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
other diseases, or pregnancy).
∀
The patient experiences an AE requiring treatment discontinuation as listed in section
4.1.6.
Even if the trial treatment is discontinued, the patient remains in the trial and will undergo the 
procedures for the end of treatment visit and follow-up visits as outlined in the Flow Chart
and section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported.
Patients meeting the following criteria will be considered non-evaluable for DLT. If less than 
two patients are evaluable for DLT in a cohort, the non-evaluable patients will be replaced;
∀
Patient withdrawal for a reason other than DLT before completing the first treatment 
cycle
∀
Patients who have reduced BI 891065 dose level during the first treatment cycle, unless 
they develop a DLT


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∀
Patient who can’t be assessed for safety due to missed visits in the first cycle of treatment 
and who does not experience DLTs
∀
Patient who misses >5 doses of BI 891065 during the first treatment cycle for reasons 
other than treatment-related AEs and who does not experience DLTs
∀
(Part B only) Patients who have received less than 50% of the BI 754091 initial dose, 
unless they develop a DLT
Patients who miss one visit during the first treatment cycle may be replaced after discussion 
between the sponsor and the investigator if the information that needs to be collected during 
this visit is not available and makes the patient non-evaluable for determining DLT. All other 
patients who withdraw, including all patients who are withdrawn from the trial due to a DLT, 
and all patients who withdraw after the first treatment cycle, will not be replaced.
If a patient should become pregnant during the trial, the study treatment must be immediately 
stopped. The patient will be followed up until delivery or termination of pregnancy (see 
Section 5.2.6.2.3 for information on pregnancy forms). The data of the patient will be 
collected and reported in the electronic case report form (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, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk-assessment that could significantly affect the continuation of the trial.
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).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
BI 891065
Substance:
BI 891065
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
5 mg, 20 mg, 50 mg, 100 mg tablets
Posology:
Once daily (q.d.) or twice daily (b.i.d.), individual 
dose depending on dose escalation
Method and route of administration:
Oral
Table 4.1.1: 2
BI 754091
Substance:
BI 754091
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg/mL (vial with 15 mL filling volume)
Posology:
Infusion on day 1 of 21-day cycles
Method and route of administration:
Intravenous infusion
4.1.2
Selection of doses in the trial and dose modifications
4.1.2.1
Starting dose of BI 891065
In Part A, BI 891065 will be tested at a starting dose of 100 mg once daily. In case of DLTs 
in 100 mg cohort, a lower dose level may also be investigated. Twice daily dosing may also 
be investigated. 


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The starting dose was selected based on the data obtained in clinical trial 1379-0001
monotherapy dose-escalation part. As of the end of January 2019, BI 891065 was 
administered at dose range of 5 mg to 400 mg in 25 patients as single agent. In these patient 
cohorts, DLTs were not reported at any dose level tested, and the MTD was not reached. 
There was no treatment related SAE. There was an isolated increase in total bilirubin in 7 
patients (28%) which appears to be dose-dependent. All bilirubin increases were maximum 
Grade 2 and did not lead to dose-reduction or discontinuation of study drug. Twice daily 
dosing will be explored, aiming to reduce peak plasma concentrations compared to single
dosing of the same daily dose, which may reduce occurrences of bilirubin increase, and may 
allow for better tolerability of similar total daily doses compared to once daily dosing, and 
potentially higher daily doses. Etiology and clinical significance are currently under further 
investigation. Otherwise there were no abnormal lab trends identified which could not be 
explained by underlying disease. To obtain sufficient dose-PK relationship data in Asian 
patients, the starting dose of this trial is set at a lower dose than the highest dose in trial 
1379-0001.
In Part B, the starting dose of BI 891065 will be 200 mg per day, in combination with BI 
754091 240 mg once every three weeks. The SMC may recommend to start at a lower dose 
level depending on the MTD or occurrence of DLTs in Part A. In case of DLTs in the starting 
dose cohort of Part B, a lower dose level may also be investigated. Twice daily dosing will 
also be investigated.   
4.1.2.2
Dose of BI 754091
The dose of BI 754091 will be fixed at 240 mg once every three weeks. The dose of BI 
754091 was selected based on the data from preceding trials, including a first-in-human 
Phase I trial in Western patients (Trial 1381-0001) and a Phase I trial in Asian patients (Trial 
1381-0004). 
In the dose escalation part of trial 1381-0001, dose levels of 80 mg, 240 mg, and 400 mg 
every 3 weeks were investigated and three patients were assigned at each cohort. None of 
them experienced DLTs and the MTD was considered not reached. The RD for further 
development was determined to be 240 mg based on the results of in vitro binding testing, 
clinical safety data and the result of a receptor occupancy testing in trial 1381-0001. The 
preliminary data showed 100% PD-1 receptor occupancy in peripheral blood in all 
on-treatment patient samples compared to baseline throughout one treatment cycle, which 
also supports that the selected dose of 240mg administered every 3 weeks should be 
adequate.
The clinical safety is further supported by the data from trial 1381-0004 dose-finding part, 
where six Japanese patients received BI 754091 monotherapy 240 mg every 3 weeks and 
none of them experienced DLTs (Median number of treatment cycles: 4.5, range 2-8).


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4.1.3
Dose-finding scheme
The dose is planned to be tested in cohorts at pre-defined provisional dose levels. The 
provisional dose levels to be assigned to different cohorts of patients are listed in Tables 
4.1.3: 1 and 4.1.3: 2. Intermediate or lower dose levels may be investigated if agreed in the 
SMC, depending on the number of DLTs observed in the trial. The highest planned dose of 
BI 891065 is 400 mg per day.
Table 4.1.3: 1 Example of dose escalation in Part A
Dose level
Proposed daily dose of BI 
891065*
Participating countries
1
100 mg
Japan
2
200 mg**
Japan
3
400 mg**
Japan and Taiwan
*The total daily dose will be given in q.d. or b.i.d. dosing schedule.
**Actual dose level and dosing schedule for a cohort will be communicated separately as
determined by the SMC. Intermediate or lower dose level(s) may be investigated depending 
on the latest DLT rate estimate.
Table 4.1.3: 2 Example of dose escalation in Part B
Dose level
Proposed daily dose of 
BI 891065*
Proposed dose of 
BI 754091 (every three 
weeks)
Participating countries
1
200 mg**
240 mg
Japan and Taiwan
2
400 mg**
240 mg
Japan and Taiwan
* The total daily dose will be given in q.d. or b.i.d. dosing schedule.
**Actual dose level and dosing schedule for a cohort will be communicated separately as
determined by the SMC. Intermediate or lower dose level(s) may be investigated depending 
on the latest DLT rate estimate.
4.1.4
Method of assigning patients to treatment groups
There will be no randomisation in this trial, as it is a single-arm open-label trial. 
An interactive response technology (IRT) system is used to register participation of patients 
in the trial. Upon acquisition of informed consent, study sites access the IRT to register 
patients for screening. After assessment of all inclusion and exclusion criteria, study sites 
access the IRT to register each eligible patient for treatment, and the IRT system will assign 
the patient to the cohort which is open for recruitment.


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As soon as the planned number of patients in a cohort are registered for treatment, IRT will 
close the screening until the next cohort is opened for recruitment or until further treatment 
slots become available in the current cohort. Patients who are already in screening at the time
of the closure of the screening and who then meet all eligibility criteria can be registered for 
treatment. If more patients are eligible than planned number of patients for a cohort, it is 
exceptionally allowed to register more patients than planned for ethical reasons.
4.1.5
Drug assignment and administration of doses for each patient
4.1.5.1
Administration of BI 891065
BI 891065 tablets must be stored in the containers provided and handled according to the 
labelled storage instructions and shelf life. Labels will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.
Patients need to be instructed to return any unused BI 891065 in the dispensed bottles, in 
addition to returning any empty bottles.
All patients will be required to complete a Dosing Diary, which must be returned to the clinic 
for review at each clinic visit. The fasting status on the PK days should be recorded in the 
patient diary and collected in the eCRF (section 5.3.1). The diary should be given to patients 
before cycle 1 day 1.
Refer to Flow Chart and section 10.3 for information about sampling that is required prior to 
dose administration.
BI 891065 is taken either q.d. or b.i.d., depending on the assigned treatment regimen. Refer to 
Flow Chart for exceptions of dosing schedule where study drug is skipped.
Patients will be asked to fast overnight (minimum of 10 hours) prior to the morning dose on 
the following intensive PK days:
∀
Cycle 1 Day 1
∀
Cycle 1 Day 15
Refer to section 10.3 for details.
When BI 891065 and BI 754091 are to be administered on the same day, BI 891065 will be 
administered approximately 30 minutes following the end of infusion of BI 754091, based on 
the safety assessments made by the Investigator.
Whenever possible, all doses of BI 891065 should be taken with water, limited to a maximum 
of 240 mL. 
Missed doses of BI 891065 should not be made up if more than 6 hours have passed since 
scheduled dosing time. Missed doses must be recorded in the patient’s Dosing Diary, and 
then should be recorded in the eCRF.


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4.1.5.2
Administration of BI 754091
Vials of BI 754091 will be diluted and administered via i.v. infusion according to the details 
in the Instruction for Pharmacists.
4.1.6
Dose modifications (pause, delay, dose reduction, and discontinuation)
AEs that are immune related should be managed according to the Guidelines for irAE 
management (as outlined in Appendix 10.2). 
For Grade 4 AE/SAEs that are not immune related, study drug should be withdrawn. 
However, if it can be excluded with high certainty that the event was related to study 
medication, study drug should be paused, and resumption of study drug may be allowed after 
discussion with the Sponsor.
For Grade 3 AE/SAEs that are not immune related, study drug should be paused. 
For Grade 2 AEs/SAEs that are not immune related but are deemed intolerable by the patient 
or the treating physician and not responding to appropriate medical management, the 
physician should decide if a pause of treatment is warranted considering relevant variables 
such as perceived relatedness to study drug.  
If, after a treatment pause of ≤12 weeks, the non-immune related SAE/AE resolves to 
baseline or Grade 1 and the physician thinks it is clinically appropriate to restart study drug, 
then the physician may choose to restart BI 891065 at one dose lower than the dose 
administered before the pause (except for patients who are receiving the lowest dose allowed) 
according to Table 4.1.6: 1 and Table 4.1.6: 2, and BI 754091 at the same fixed dose of BI 
754091. Up to two dose reductions of BI 891065 are allowed per patient. If the AE/SAE 
prompting interruption has unequivocally been excluded to be drug related, reintroduction of 
BI 891065 at the same dose as prior to the pause may be considered.
There will be no dose reductions or escalations of BI 754091 in any one patient.  However, 
in the event of an infusion-related reaction ≤ Grade 2, the infusion rate of BI 754091 may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate. If an 
infusion-related reaction is Grade 3 or higher in severity at any point during the study, 
treatment with BI 891065 and BI 754091 will be permanently discontinued.
As a general rule for Part B, both drugs (BI 891065 and BI 754091) will be stopped, paused, 
or re-exposed together. Exemptions have to be justified and aligned with the Sponsor in 
writing. 
If exemption to the dose reduction and pause (e.g., to restart the treatment at the same dose 
level) is considered, it should be discussed and agreed with the sponsor in advance in writing.


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Table 4.1.6: 1
Dose reduction recommendations for BI 891065 in q.d. dosing (up to 
two dose reductions are allowed per patient)
BI 891065 dose before the pause
BI 891065 dose at restart
400 mg
200 mg
200 mg
100 mg
100 mg
50 mg (lowest dose allowed)
Table 4.1.6: 2
Dose reduction recommendations for BI 891065 in b.i.d. dosing
BI 891065 dose before the pause
BI 891065 dose at restart
200 mg x 2
100 mg x 2
100 mg x 2
50 mg x 2 (lowest dose allowed)
If an intermediate dose which is not listed in the table is investigated, a dose reduction 
guideline for that dose will be provided separately
There will be no dose reductions or escalations of BI 754091. Modifications of infusion rate 
are described in section 5.2.6.1.4.
The study treatment should be permanently discontinued if any of the following adverse 
events occur:
∀
A pause of treatment or delayed start of treatment of more than 12 weeks due to AEs
∀
Grade 3 or 4 CRS
∀
Interstitial lung disease (ILD) of any grade
∀
(For Part B only) Immune related AEs requiring permanent study drug discontinuation as 
described in Guidelines for Management of Immune-Related AEs (section 10.2):
-
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 total bilirubin >3 times 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


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-
autoimmune-hemolytic anemia 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. 
∀
Grade ≥3 infusion related reactions
∀
AEs of Grade ≥2 deemed intolerable by the patient or the treating physician and not 
responding to medical management within 12 weeks
∀
Grade 3 to 4 AEs that are classified as immune-related by the Investigator but are not 
listed in section 10.1 if they do not resolve to Grade ≤ 1 or baseline with 
immunosuppressive therapy within 2 weeks.
∀
≥Grade 4 drug-related AEs.
Other criteria leading to permanent discontinuation of study treatment are presented in 
Section 3.3.4.1.
4.1.7
Dose limiting toxicities
Dose-limiting toxicities (DLTs) will be recorded throughout the trial. Any DLT must be 
reported to the sponsor within 24 hours of first knowledge. Only DLTs occurring during 
cycle 1 will be used for MTD determination. All relevant safety information (including DLTs
occurring at any time) will be considered when selecting the RD.
Severity of AEs will be graded according to CTCAE Version 5.0. Any of the following AEs 
will be classified as DLTs following review by the Investigators and the sponsor, unless 
unequivocally due to underlying malignancy or an extraneous cause.
Haematologic toxicities:
∀
Any Grade 5 toxicity
∀
Neutropenia ≥ Grade 4 lasting for >7 days
∀
Febrile neutropenia of any duration (ANC <1.0 X 109 cells/L and fever ≥38.5°C)
∀
Neutropenia ≥ Grade 3 with documented infection
∀
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding
∀
Thrombocytopenia of any Grade which requires platelet transfusions
∀
Grade 4 anaemia unexplained by underlying disease
∀
Anaemia of any Grade which requires blood transfusions
Non-haematological toxicities:
∀
AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without initial 
findings of cholestasis (e.g., findings consistent with Hy's law or the FDA definition of 
potential DILI, see section 5.2.6.1.4)
∀
≥Grade 4 AST or ALT of any duration
∀
Any ≥Grade 3 non-haematologic toxicity with the following exceptions:


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-
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with immunosuppressive 
therapy within 2 weeks
-
Grade 3 fatigue that persists ≤7 days
-
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
-
Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated with 
clinical or radiographic evidence of pancreatitis
-
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical intervention
-
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention
-
Alopecia
-
Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that 
are managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy, and the patient is asymptomatic.
-
Grade 3 tumour flare syndrome
∀
Grade 2 pneumonitis of any duration
∀
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
∀
Treatment pause of BI 891065 for ≥7 days in Cycle 1 due to treatment-related AEs
∀
Any treatment-related ≥ Grade 2 toxicity that persists and results in a more than 2 weeks 
delay of administration of BI 754091 on Cycle 2 Day 1
∀
Any AEs that require dose reduction will be assessed by SMC and may be considered as 
DLTs unless the SMC considers the dose reduction as not strictly medically warranted
∀
Permanent treatment discontinuation according to section 4.1.6
The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays, will be analysed to determine if a 
given toxicity should be considered a DLT for dose escalation purposes.
Late DLTs are AEs that meet the same grading criteria as DLT criteria but occur after the 
first cycle of study treatment. In order to assess the recommended dose, the BLRM will be 
rerun using all DLTs up until 90 days after the first administration of the last patient.
4.1.8
Blinding and procedures for unblinding
Not applicable, as this is an open-label, single-arm trial.
4.1.9
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated contract 
research organisation (CRO). They will be packaged and labelled in accordance with the 
principles of 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.


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For details of packaging and the description of the label, refer to the ISF.
4.1.10
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) must be contacted immediately.
4.1.11
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled:
∀
Approval of the CTP by the Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC),
∀
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 CTP,
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the CTP and reconcile all investigational 
medicinal products received from the sponsor. At the time of return to the sponsor, the 
investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used in this trial or special emergency 
procedures to be followed. Recommendations for the management of immune-related AEs 
can be found in section 10.2.
Rescue medications to reverse the actions of BI 891065 or BI 754091 are not available.
Therefore, potential side effects of BI 891065 or BI 754091 have to be treated 
symptomatically (relevant information is available in section 5.2.6.1.4).
Concomitant therapy, with reasons for the treatment, must be recorded in the CRF 
during the screening and treatment periods, starting at the date of signature of informed 
consent and ending after the residual effect period (REP). After REP, only concomitant 
therapy indicated for treatment of a related AE has to be reported. If a new anti-cancer 
treatment is started, it will be documented in the CRF, on a separate page of follow-up 
therapy, different from the concomitant therapies pages.
4.2.1.1
Permitted concomitant medications
∀
If medically feasible, patients taking regular medication should be maintained on it
throughout the trial.
∀
Pre-medication is not required, but may be utilised following the first dose of study 
medication. This includes medications for the management of nausea, diarrhoea, and 
vomiting for which the patient must be treated according to institutional standards.
∀
Supportive care and other medications that are considered necessary for the patient’s
well-being may be given at the discretion of the Investigator.
∀
Blood transfusions are allowed at any time during the trial, except to meet inclusion
criteria. There must be at least 4 weeks between a patient’s last transfusion and the 
screening laboratory assessment. Exceptions to this will be considered by the Sponsor on 
a case-by-case basis.
4.2.1.2
Caution for concomitant medication and/or food
BI 891065 is a substrate of CYP3A4. In ongoing overseas trial of 1379-0001, the exposure 
(Cmax, AUC) tended to increase in two patients who took moderate CYP3A4 inhibitor from 
25 patients at 5 to 400 mg dose cohort. Caution is necessary for the intake of CYP3A4 
inhibitor (ex. clarithromycin, erythromycin, fluconazole, itraconazole, verapamil, 
ketoconazole, and diltiazem) or grapefruits and their juices, because the possibility cannot be 
excluded for the increase of plasma concentration.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
∀
No other investigational therapy or anticancer agent should be given to patients. If such
agents are required for a patient, then the patient must first be withdrawn from the trial.
∀
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. For the treatment of CRS, supportive 
therapy including steroids and/or interleukin 6 receptor (IL6R) antagonists (R15-0031)
may be used as clinically indicated.
∀
Pre-medications should not be given in cycle 1 to avoid masking the emergence of DLTs.
∀
Live attenuated vaccines are prohibited from informed consent until 30 days after the last 
dose of investigational product.
∀
Herbal preparations/medications are not allowed throughout the trial. 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. 
Patients should stop using these herbal medications at least 7 days prior to first dose of 
study treatment.
∀
Patients already receiving erythropoietin at the time of screening for the trial may
continue it, provided they have been receiving it for more than one month at the time trial
treatment is started. Prophylactic erythropoietin should not be started during the first 3 
weeks of treatment, but may be started thereafter. In Japan, no erythropoietin product is 
approved for anaemia associated with cancer chemotherapy.
∀
Prophylactic granulocyte colony stimulating factors are not allowed during the first 3 
weeks of treatment.
∀
For symptom control, palliative radiotherapy is permitted for any lesion, except during 
the first 3 weeks as it could interfere with the DLT evaluation for MTD/RD 
determination. If a patient need palliative radiotherapy during the first 3 weeks a 
case-by-case decision will be made together with the sponsor. Lesions that have been 
exposed to radiotherapy are no longer evaluable, and may not be included in the
assessment of the non-target lesions and the overall assessment. 
BI 891065 was found to be an inhibitor of various CYP450 enzymes in vitro. A drug-drug 
interaction with other medications metabolized by these enzymes cannot be excluded. 
Caution should be exercised when combining BI 891065 with substrate drugs of CYP450 
enzymes (1A2, 2C8, 2C9, 2C19, 2D6, 3A4). Alternatives with less potential for CYP450 
based interactions should be considered, where available. Close monitoring for potential
adverse reactions is warranted and patients should be informed about potential signs and 
symptoms of such adverse reactions (e.g., muscle pain from statins). BI 891065 was also 


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found to be an inhibitor of the drug transporters P-gp and BCRP in vitro. Caution should be 
exercised when combining BI 891065 with P-gp and BCRP substrates. 
Table 4.2.2.1: 1 provides the restrictions information for substrate drugs of CYP450 enzymes, 
P-gp and BCRP.


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Table 4.2.2.1: 1
Restrictions on concomitant treatment with substrate drugs of 
CYT450 enzymes, P-gp and BCRP
Type of medication
Instruction
Example of medication
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19, 
CYP2D6, CYP3A4 substrates 
with a high probability of exposure 
increase in combination with 
BI 891065
Permitted if strictly indicated and 
with judicious dosing
Buspirone, Lovastatin, 
Simvastatin and Nisoldipine
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19, 
CYP2D6, CYP3A4 substrates 
with a medium probability of 
exposure increase in combination 
with BI 891065
Permitted if strictly indicated and 
with judicious dosing
Atorvastatin, Tacrolimus, 
Cisapride, Terfenadine, 
Midazolam, Saquinavir, Rifabutin, 
and Sertraline
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19, 
CYP2D6, CYP3A4 substrates
with a low probability of exposure 
increase in combination with 
BI 891065
Permitted if strictly indicated and 
with judicious dosing
Alfentanil, Amodiaquine, 
Felodipine, Loperamide, 
Maraviroc, Methadone, 
Montelukast, Nifedipine, 
Nimodipine, Pioglitazone, 
Repaglinide, Trazodone, 
Triazolam, Verapamil and 
Zolpidem.
P-gp substrates (partly with 
narrow therapeutic margin)
Not Permitted 
Dabigatran etexilate
Digoxin
P-gp substrates and in addition 
involvement of CYP3A4 with 
narrow therapeutic margin
Permitted if strictly indicated and 
with judicious dosing
Apixaban
Rivaroxaban
P-gp and BCRP substrates with a 
probability of exposure increase in 
combination with BI 891065
Permitted if strictly indicated and 
with judicious dosing
Fexofenadine, Verapamil and 
Rosuvastatin
4.2.2.2
Restrictions on diet and life style
Patients should be instructed to avoid exposure to direct sunlight (including sunlamps), to use 
a sunblock (minimum sun-protection factor 30), and to wear clothing and sunglasses that 
protect against sun exposure during treatment and for 4 weeks after the last administration of 
BI 891065.
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, if 
feasible with the following caveats:
∀
Fasting requirements on PK days are described in section 4.1.5.1


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4.2.2.3
Contraception requirements
Women of childbearing potential and men able to father a child must use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly. A list of contraception methods meeting these 
criteria is provided in the patient information.
4.3
TREATMENT COMPLIANCE
The investigational products should only be used as directed in this protocol.
4.3.1
BI 891065
Patients are requested to bring all remaining BI 891065 including empty package material 
with them when attending visits. Details of treatment with investigational product for each 
patient will be recorded in the eCRF.
The trial personnel at the investigational site will account for all drugs dispensed and for 
appropriate destruction. 
Based on counts, treatment compliance will be calculated as shown in the formula below. 
Compliance will be verified by the CRA authorised by the Sponsor.
Treatment compliance (%) =
Number of tablets actually taken # 100
     Number of tablets that should have been taken
If the number of doses taken is not between 80% to 100%, site staff will explain to the patient
the importance of treatment compliance.
4.3.2
BI 754091
BI 754091 will be administered by i.v. infusion at the sites by the Investigator and/or trained 
site personnel, and dosing will be recorded in the eCRF. Therefore, actual dosing is expected 
to precisely follow the prescribed drug regimen. Missed or interrupted doses will be recorded 
in the eCRF with the associated reasons. The method of collecting dosing information assures
that total exposure can be calculated programmatically taking into account any missing doses.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Tumour assessments
Tumour response will be evaluated at the site according to RECIST Version 1.1 (R09-0262) 
and/or iRECIST (R17-0923). 
The assessment by the Investigator and/or the local radiologist will be the basis for 
continuation or discontinuation of the trial in an individual patient (in addition to safety).
The baseline scan(s) (CT scan and/or magnetic resonance imaging [MRI] according to 
Investigator’s decision) from screening must have been performed within 4 weeks prior to 
treatment with the trial drug(s) and the Investigator will record the target (5 target lesions in 
total and maximum 2 per organ) and non-target lesions at baseline in the patient’s medical 
records and in the CRF before the start of treatment. The patients will be re-evaluated every 6 
weeks for the first 24 weeks, then every 9 weeks thereafter, and at the end of treatment (EOT)
visit (if not performed within the previous 4 weeks). The same method of assessment and the 
same technique must be used to characterise each reported lesion at baseline and during 
treatment. Lesions in previously irradiated areas may not be considered measurable at 
baseline unless the lesions appeared for the first time or have re-grown after irradiation.
If the patient stops treatment with the trial medication for a reason other than progression, the 
tumour assessment according to RECIST v1.1 and iRECIST will be performed with a 
frequency according to local standard and the information will be collected at the follow-up 
visits for PD (section 6.2.3.3).
Patients will be allowed to stay on treatment in the case of initial PD according to RECIST 
version 1.1, if the Investigator feels that the patient is clinically stable. As a rule, the 
treatment will be discontinued when a patient is considered to be confirmed progressive 
disease according to iRECIST (iCPD). However, the patient may still continue to receive 
treatment if the Investigator and sponsor agree that the patient is deriving clinical benefit. In 
this case, the rationale to continue the treatment beyond iCPD should be provided in the CRF.
Duplicates of the images will be collected and stored by a BI-appointed representative, and 
may be used for further review, if deemed appropriate, e.g., the images may be used for 
further analysis to explore the potential for enhanced and improved baseline and on-treatment 
markers/patterns of early efficacy based on comprehensive quantitative CT metrics (i.e., 
radiomics features, assessed in standard-of-care medical imaging data).


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling, or after a sufficient period of rest (usually 5 minutes is sufficient, but a longer rest 
may be required if there are any problems at the blood sampling).
This includes systolic and diastolic blood pressure, pulse rate (electronically or by palpation 
count for 1 minute), body temperature, and arterial oxygen saturation (SpO2) by non-invasive 
pulse oximetry. SpO2 is required in Part B only. The results must be included in the source 
documents available at the site.
5.2.3
Safety laboratory parameters
For the sampling time points please see the Flow Chart. All analyses will be performed 
locally and the respective reference ranges will be provided in the ISF. Patients do not have 
to be fasted for the blood sampling for the safety laboratory tests.
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (please refer to section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.2.6.1.4 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
5.2.3.1
Haematology
The standard haematology panel will consist of: haemoglobin, red blood cell count, 
haematocrit, mean corpuscular volume, reticulocytes, white blood cell count, and differential 
blood count (preferably expressed in absolute values), and platelets.


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5.2.3.2
Biochemistry
The standard biochemistry panel will consist of glucose (serum or plasma), sodium, 
potassium, chloride, calcium, phosphate, serum creatinine (measured by enzymatic assay, 
Isotope dilution mass spectroscopy [IDMS] standardised Jaffe assay, or non-IDMS Jaffe 
assay), AST, ALT, alkaline phosphatase, lactate dehydrogenase, gamma glutamyl transferase, 
bilirubin (total, direct, and indirect bilirubin), haptoglobin, total protein, albumin, urea or urea 
nitrogen, uric acid and creatine kinase (CK). If CK is elevated, then CK-MB [cardiac], 
Troponin (either I or T), and myoglobin should be reactively tested.
A thyroid panel (Thyroid Stimulating Hormone [TSH], free T4, and free T3) will be done in
Part B at the time of each standard biochemistry panel.
If symptoms of pancreatitis are observed, amylase and lipase should be tested at the 
discretion of the Investigator.
5.2.3.3
Coagulation
Activated partial thromboplastin time (aPTT) or prothrombin time (PT) (expressed either in 
seconds or as percentage) will be tested.
5.2.3.4
Urinalysis
Urine (pH, glucose, erythrocytes, leukocytes, protein, and nitrite) will be analysed by dipstick 
(semi-quantitative measurements).
5.2.3.5
Pregnancy test
A beta human chorionic gonadotropin (β-HCG) pregnancy test in serum (or plasma) will be 
performed for women of childbearing potential at screening. Thereafter, this test may be done 
in serum (or plasma) or urine.
5.2.3.6
Virology
HBV, HCV, and HIV testing should be performed at screening. In Part A these tests are 
exempted if test results obtained in routine clinical practice within 6 months before the 
informed consent date are available. In part B, HBV and HCV tests are mandatory but HIV 
testing is not mandatory if test results obtained in routine clinical practice within 6 months 
before the informed consent date are available.
The required test items are as follows:
For HBV: HBs antigen and HBc antibody tests are performed. HBV-DNA test is required 
only for patients with HBc antibody positive results. 


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For HCV: HCV antibody test is performed. HCV-RNA test is required only for patients with 
HCV antibody positive results. 
5.2.3.7
Alpha-1 acid glycoprotein
One plasma sample will be taken for alpha-1 acid glycoprotein (AGP) analysis at the 
beginning of Cycles 1 and 2 at the time of the safety laboratory tests (prior to BI 891065 
administration).
5.2.4
Electrocardiogram
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting ECGs will be digitally recorded 
at various time points throughout the trial. The Flow Chart outlines which visits will require 
ECGs, and section 10.3 outlines which time points require triplicate ECGs to be done along 
with certain PK samples.
All ECGs will be obtained after the patient has been resting supine for at least 10 minutes 
prior to the indicated times. All ECGs should be recorded with the patient in the same 
physical position.
Electrocardiogram machines will be provided 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 outlined in section 10.3 will be transmitted to the 
central vendor.
ECGs may be repeated for quality reasons and the repeated recording 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, and all 
treatment related decisions should be based on the investigator's assessment. Clinically 
relevant abnormal findings will be reported either as baseline condition (if identified at the 
screening visit) or otherwise as adverse events and will be followed up and/or treated as 
medically appropriate. CTCAE Version 5.0 will be used for the grading of prolonged QTcF 
intervals.
In case of related ECG changes and whenever the Investigator deems necessary, additional 
ECG monitoring will be performed in the respective and later courses of treatment. 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 
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).


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In case of QTcF prolongation to >500 ms (mean of 3 ECGs for triplicate 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.
In order not to confuse an ECG recording, PK samples should be taken after performing the
ECG.
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.
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
Other safety parameters
5.2.5.1
ECOG performance status
The ECOG performance status will be assessed at the times indicated in the Flow Chart.
5.2.5.2
Ejection fraction
The ejection fraction should be measured only if clinically indicated using echocardiogram 
(ECHO) or multi-gated acquisition (MUGA) scan. Refer to section 3.3.3 for details on which 
patients require an ejection fraction assessment.
5.2.5.3
Chest X-ray (Part B only)
A chest X-ray must be performed in Part B only at the time points specified in the Flow
Chart.


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of pre-existing conditions other than the underlying disease
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
∀
results in death,
∀
is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe,
∀
requires inpatient hospitalisation or prolongation of existing hospitalisation
∀
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. 
For Japan only: AEs which possibly lead to disability will be handled as “deemed serious for 
any other reason” and be reported as SAEs.
Patients may be hospitalized for administrative reasons during the trial, including 
hospitalization for respite care. These as well as hospitalizations/surgical procedures which 


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were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalization/surgical procedure has not 
changed/worsened after signing informed consent)
5.2.6.1.3
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since the discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC)
system. These events should always be reported as SAEs as described above.
5.2.6.1.4
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.6.2.2.
In this trial, DLTs, the following events are defined as AESIs.
Dose limiting toxicities
DLTs are considered to be AESIs, and must be reported as such. The definition of DLTs is 
presented in section 4.1.7.
BI 754091 infusion related reactions (Part B only)
Infusion-related reactions CTCAE Version 5.0 Grade ≥2 are defined as AESIs.
The following terms describe those events that are to be considered potential infusion-related 
AEs. These events are considered as AESIs and must be reported to the sponsor within 24 
hours of the event:
∀
Allergic reaction
∀
Anaphylaxis
∀
CRS
∀
Serum sickness
∀
Infusion reactions


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∀
Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential 
infusion-related AE, the Investigator may also report that event as an AESI.
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of BI 754091 may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate.
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional 
standard may be administered prior to subsequent infusions at the discretion of the 
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the trial, treatment with 
BI 754091 will be permanently discontinued.
As with any mAb, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and trial personnel must be trained to recognise and treat anaphylaxis. All trial sites will have 
emergency resuscitation services and access to intensive care available.
Cytokine release syndrome
Events of Grade ≥2 CRS are defined as AESIs. Patients will be closely monitored for CRS 
and, in case of suspected or confirmed CRS, appropriate treated according to best medical 
judgement based on institutional standards and/or publications (e.g., Lee at al. 2016 
[R16-2323]). For the treatment of CRS, supportive therapy including steroids and / or 
interleukin 6 receptor (IL6R) antagonists (R15-0031) may be used as clinically indicated.
Patients will remain hospitalised for at least three days after the first administration of BI 
891065. On day four or later, the investigator will then evaluate whether it is appropriate to
discharge the patient based on the patient's condition. Thereafter, patients will be monitored 
with regular safety visits. All trial sites will have emergency resuscitation services and access 
to intensive care available. Hospitalisations for routine monitoring is not considered as an 
SAE.
Monitoring will include measurement of body temperature, heart rate, and blood pressure at 
regular intervals as presented in the Flow Chart. Patients will be assessed for signs or 
symptoms of CRS (e.g., hypotension, hypoxia, tachycardia, fever, 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.
The following recommendations for the management of CRS regarding administration of 
BI 754091 and BI 891065 should be considered by the Investigator as guidance:


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∀
In case of Grade 2 CRS, the intake of BI 891065 and infusion of BI 754091 should be 
temporarily interrupted. BI 891065 maybe resumed as soon as symptoms of CRS 
have completely resolved to baseline for at least 48 hours.
In case less than 50% of a BI 754091 dose was administered due to CRS, a dose of 50% 
of the intended dose may be administered on the day when BI 891065 is re-started to 
ensure the patient receives an adequate dose of BI 754091. Please see section 3.3.4.1
regarding replacement of patients.
∀
In case of Grade 2 CRS, patients should be under close surveillance during the first 2 
re-exposure administrations of BI 891065 and (if the CRS occurred during the or 
shortly after the infusion of BI 754091) during the first re-exposure administration of 
BI 754091 to ensure appropriate surveillance.
In the case of Grade 3 or 4 CRS, the study treatment should be permanently discontinued 
(section 4.1.6). 
Immune-related adverse event (irAE) (Part B only)
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. The Sponsor has defined a list of potential irAEs which need to be 
reported as AESI in section 10.1. If an Investigator determines another event (not on the list) 
should be a potential irAE, the Investigator may also report that event as an AESI.
Recommendations for the management of irAEs are presented in section 10.2.
Hepatic injury and potential drug-induced liver injury (DILI)
A potential hepatic injury is defined by the following alterations of hepatic laboratory 
parameters in patients with normal aminotransferase levels at baseline: 
∀
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
A potential hepatic injury is defined by the following alterations of hepatic laboratory 
parameters in patients with abnormal aminotransferase levels of >ULN and ≤3 fold ULN at 
baseline: 
∀
an elevation of AST and/or ALT ≥3 fold the baseline value combined with an elevation of 
bilirubin ≥2 fold the baseline value measured in the same blood draw sample, or
∀
aminotransferase (ALT, and/or AST) elevations ≥5 fold the baseline value.
A potential hepatic injury is defined by the following alterations of hepatic laboratory 
parameters in patients with abnormal aminotransferase levels of >3 fold and ≤5 fold ULN at 
baseline (patients with liver metastases only):
∀
an elevation of AST and/or ALT ≥2 fold the baseline value combined with an elevation of 
bilirubin ≥2 fold the baseline value measured in the same blood draw sample, or
∀
aminotransferase (ALT, and/or AST) elevations ≥3 fold the baseline value.


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be reported according to Figure 5.2.6.1.4: 1, and be followed up 
according to the “potential DILI checklist” provided in the eDC system.
Figure 5.2.6.1.4: 1
Processing potential DILI cases
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the potential DILI checklist should be 
followed
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law, and is described in the FDA's guidance on drug induced liver injury.
Hy’s Law cases have the following 3 components:
∀
The drug causes hepatocellular injury, generally shown by a higher incidence of 
3-fold or greater elevations above the ULN of ALT or AST
∀
Among trial subjects showing such aminotransferase elevations, often with elevations
much greater than 3 times ULN, one or more also show elevation of serum total 
bilirubin to >2 times ULN, without initial findings of cholestasis (elevated serum 
ALP)
∀
No other reason can be found to explain the combination of increased 
aminotransferase and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or 
acute liver disease; or another drug capable of causing the observed injury.


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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5
(R18-1357).
5.2.6.1.6
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).
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.


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5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
∀
From signing the informed consent onwards until the 30-day follow-up-visit:
all AEs (non-serious and serious) and all AESIs.
∀
After the 30-day follow-up-visit until the individual patient’s end of trial: 
all related SAEs and all related AESIs.
∀
After the individual patient’s end of the trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
report any new occurrence of cancer of new histology 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 5.2.6.2.2), but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see section 5.2.6.2.4.
5.2.6.2.2
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 via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
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. <for Japan only> 
Pregnancy until 6 months after the last dose of study medication should be reported as a drug 
exposure during pregnancy.


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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. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.6.2.4
Exemptions to SAE reporting
Collection and reporting of PD
The outcome “disease progression” / “progressive disease (PD)” is used to assess trial 
endpoints for the analysis of efficacy and as such is exempted from AE/SAE reporting. 
“Disease progression” / “progressive disease (PD)”, and signs/symptoms thereof which can 
exclusively be determined to be due to the progression of the underlying malignancy and 
meet the expected pattern of disease progression for the disease under study will be recorded 
on the appropriate pages of the eCRF as part of efficacy data collection only. It will not be 
recorded on the AE page in the eCRF and will not be reported on the SAE Form even when it 
meets standard seriousness criteria. 
However, when there is evidence suggesting a causal relationship between the trial drug(s) 
and the progression of the underlying malignancy (progressive disease, PD), the event must 
be recorded on the AE page in the eCRF and reported as an SAE on the SAE Form.
Exempted events are monitored at appropriate intervals.
Lab values meeting the hepatic injury definition as defined in section 5.2.6.1.4 will need to be 
reported as AESI. PD reporting exemption does not apply to hepatic injury. Please follow 
Figure 5.2.6.1.4: 1 for reporting hepatic injury / potential DILI cases.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood and urine samples will be collected for the purpose of PK analysis. Further information 
about sampling is provided in section 5.3.2.


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Date and clock times of PK sampling will be recorded in the CRFs, and the following information 
should be collected in the eCRF for the last 4 administrations prior to PK sampling and on the 
day of PK sampling for BI 891065:
1.
Date and clock times of drug administration
2.
Information with respect to food intake (date and time) in case the patient takes the drug after 
meals
3.
If vomiting or diarrhoea occurs within 3 hours after drug administration, the time of the onset 
of the episode(s)
The potential of BI 891065 to inhibit OATP1B1/B3 will be assessed by using an exploratory 
plasma biomarker: Coproporphyrin. Plasma samples are taken from patients in Part A at time 
points given in Table 10.3: 1. Assays are under development. Measurement will be done when 
feasible assays have been developed and validated.
5.3.2
Methods of sample collection
The planned PK analyses will require blood and urine sampling at the time points indicated in
the Flow Chart. Correct, complete and legible documentation of drug administrations and
blood sampling times, as well as adequate handling and identification of PK samples, are
mandatory to obtain data of adequate quality for the PK analysis.
Details on sample characteristics, collection, processing, handling, and shipment are provided
in the Laboratory Manual.
5.3.2.1
Plasma sampling for 
 pharmacokinetics and 
, blood will be 
taken from an antecubital or forearm vein at the time points listed in the flow charts and 
specified in PK time schedules in section 10.3. Blood will be withdrawn by means of either 
an indwelling venous catheter or by venipuncture.
After completion of the trial, the plasma samples may be used for further methodological
investigations, e.g., for stability testing, assessment of metabolites. However, only data
related to the analyte and/or its metabolites will be generated by these additional
investigations. The trial samples will be discarded after completion of the additional
investigations, but not later than 5 years following signature of the final trial report.
5.3.2.2
Plasma sampling for 
 pharmacokinetics
, samples will be drawn at the time 
points listed in the flow charts and specified in PK time schedules in section 10.3.
For Part B, if collected from an arm, it is essential to collect blood from the arm that is
opposite to the arm used for infusion in order to avoid artificially high or low drug
concentration determinations.


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After completion of the trial, plasma samples may be used for further methodological
investigations (e.g., stability testing). However, only data related to the analyte or
bioanalytical assay will be generated by these additional investigations. The trial samples will
be discarded after completion of the additional investigations, but not later than 5 years after
the final trial report has been signed.
5.3.2.3
Urine sampling and analysis for pharmacokinetics of 
A background urine sample will be collected before administration of trial medication (within
2 hours before drug dosing) and aliquots will be retained to check for analytical interference.
All urine voided during the sampling intervals is indicated in section 10.3: An aliquot will be 
collected and stored. Patients will be told to empty their bladders at the end of each sampling 
interval.
In order to facilitate urine sampling, patients will be advised to drink at least 100 mL water
before the end of each urine sampling interval. Details on urine sample characteristics,
processing, handling, and shipment are provided in the Laboratory Manual.
After completion of the trial, the urine samples may be used for further methodological
investigations, e.g., for stability testing, assessment of metabolites. However, only data
related to the analyte and/or its metabolite(s) will be generated by these additional
investigations. The trial samples will be discarded after completion of the additional
investigations but not later than 5 years upon the final trial report has been signed.


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5.4
ASSESSMENT OF BIOMARKER(S)
SMAC mimetics induce rapid degradation of cIAP1 (by activating the auto ubiquitin ligase
activity and targeting the protein to proteasome degradation). The degradation of cIAP1 
leads, amongst others, to the activation of the alternative NF-Kb pathway, and activation of 
subsets of immune cells and secretion of cytokines. Cytokine secretion will be monitored, 
therefore, also in the combination with the PD-1 checkpoint inhibitor. These include 
mechanism-related cytokines (e.g., IL-2, IL-6, IL-10, IFN-γ, and TNFα), as well as 
exploratory immune-related cytokines.
The biomarkers in this clinical trial are exploratory. Most of these assessments are hypothesis 
generating and will be used to expand our understanding of the disease and trial drugs.
As medical knowledge in this field is constantly evolving, other tissue/blood biomarkers that
may become relevant as predictive markers of treatment response may also be explored via 
available blood or acquisition of additional tumour tissues/blood. The list of biomarkers 
planned to be studied during the trial may change based on new information in the literature 
or early analyses.
5.4.1
Methods of sample collection
Details about blood sample collection, plasma/serum preparation, required tubes, labelling of 
tubes, storage and shipment (frequency and addresses) will be provided in the Laboratory 
Manual.


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5.4.3
Storage period of samples
Remaining blood samples from the biomarker analysis will be destroyed no later than 3 years 
after the finalisation of the CTR.
5.4.4
Pharmacogenomic biomarkers
Pharmacogenetics (PGx) investigates genetic variations in patients to explain and to predict 
their individual response to drugs. 
To perform the pharmacogenetic analysis, all patients will provide a blood sample for DNA 
isolation at Visit 1 of Cycle 1 (C1V1) or at a later visit during treatment. DNA will be 
extracted from the blood sample to explore the relationship of potential bilirubin increase and 
OATP 1B1, 1B3 and UGT1A polymorphism.
The results of pharmacogenetic tests will not be disclosed to patients because they are 
exploratory analyses. All data and samples that had already been collected up to the time of 
withdrawal of consent will still be used. The pharmacogenetic samples will not be stored 
upon completion of the genotype analysis and will be destroyed before the end of the clinical 
trial.
Detailed instructions for handling, storage, and shipment of the biomarker samples will be 
provided in the laboratory manual included in the ISF.
As of November 2020, the sponsor came to the conclusion that the genotyping analysis 
would not result in gaining additional supportive information and the analysis was cancelled.
5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTS
5.6.1
Immunogenicity testing
All patients in Part B: for anti-drug antibodies (ADA) assessment, blood samples will be 
drawn at the time points listed in the Flow Chart and section 10.3. Details on sample
collection, characteristics, processing, handling, and shipment are provided in the Laboratory
Manual.
Plasma samples may be used for further methodological investigations, (e.g., stability 
testing), however, only data related to the ADAs will be generated by these additional 
investigations. The trial samples will be discarded after completion of the additional 
investigations, but not later than 5 years after the final trial report has been signed.
The presence of ADA in relation to BI 754091 will be assessed using a validated
immunoassay in a tiered approach (screening, confirmatory, and titration analysis as
appropriate).
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are in accordance with measurements in Phase I 
oncology trials and will be performed in order to monitor safety aspects and to determine 
efficacy and PK parameters in an appropriate way.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and exclusion criteria for the part they are participating in and 
who have signed a written ICF, are eligible for participation in the trial. Patients will visit the 
clinical site at the time points specified in the Flow Chart. The allowed windows for each 
visit are also specified in the Flow Chart. Additional flexibility (e.g., to allow for public 
holidays and patient unavailability) may be allowed if agreed between the investigator and 
the sponsor. If a patient misses a scheduled visit, and reports to the Investigator between the 
missed visit and the next scheduled visit, the assessments for the missed visit must be done 
with the actual date and the reason must be given for the delayed visit. The next visit should 
still take place at the time it was originally scheduled in this treatment cycle. In case the day 
of treatment administration (visit 1 of a cycle) is delayed, all subsequent visits of a cycle will 
be recalculated based on the actual date of treatment of the delayed cycle.
Once the decision for any reason is made for a patient to stop the treatment with BI 891065 or 
the combination of BI 891065 plus BI 754091, an EOT visit must occur as soon as possible 
(preferably within 7 days and no later than 14 days after the decision to discontinue the 
treatment). After the EOT visit, the patient must undergo a follow-up safety evaluation
30 (+7) days after the last administration of trial therapy.
Additional follow-up visits for PD after the 30-day safety follow-up visit will only be 
performed for patients who did not progress on treatment (see section 6.2.3.3). The follow-up 
visits for PD will be performed once every 12 weeks at least (in person or by telephone) until 
PD, introduction of a new anti-cancer treatment, death, loss to follow-up, withdrawal of 
consent, or end of the whole trial.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow Chart will be performed at the respective visits.
Specific details to conduct of physical examination, collection of vital signs (including blood 
pressure measurement), laboratory investigations, assessment of ECG, and other safety 
parameters can be found in the subsections of Section 5.2.
Procedure for collection of blood samples for PK, ADA and biomarkers are given in sections 
5.3, 5.6.1, and 5.4, and detailed sampling time point information is given in section 10.3.
6.2.1
Screening
At enrolment, each potential patient will provide written informed consent prior to starting 
any trial specific procedures. Upon signature of the informed consent, patients will be 
assigned a unique patient number as enrolment (screening) occurs.


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6.2.1.1
Screening Period
Screening (Visit 1) will take place 1 to 14 days prior to first administration of trial medication
(except for tumour assessment, for which scans up to 28 days prior to the first administration 
is accepted).
If an extension of screening period is required, this should be discussed and agreed with the
sponsor. A repeat testing during the screening period for items not meeting the eligibility 
criteria is basically not allowed. The exemption to this should be discussed and agreed with 
the sponsor.
6.2.1.2
Baseline Conditions
Demographics (sex, birth year, race, and ethnicity where allowed), information on tobacco 
use, and baseline conditions will be collected during the screening visit.
6.2.1.3
Medical History
6.2.1.3.1
Medical history of cancer
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumour site will 
be reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumour, (lymph) 
node, and metastasis (TNM) classification will be provided as obtained at diagnosis and at 
trial screening. Previous surgeries will be reported.
Previously administered anti-cancer therapies will be reported, including start and end dates 
(month and year may be sufficient), as well as whether therapy was given as neoadjuvant, 
adjuvant, or palliative therapy. The date of tumour progression after previous lines of 
treatment will be recorded, if known.
Baseline information relevant to the disease history such as PD-L1 expression level, 
microsatellite instability (MSI), and tumour mutation burden (TMB) information will be 
collected in eCRF where available.
6.2.1.3.2
Other medical history
Past diseases and/or concomitant diagnoses relevant to patient's safety during the trial as 
judged by the Investigator will be recorded in eCRF.


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6.2.1.4
Concomitant medications
Past medications relevant to patient's safety during the trial as judged by the Investigator will 
be recorded in eCRF. From the date of signature of the ICF, all concomitant medications will 
be recorded. Post-trial therapy for advanced or metastatic disease will also be documented.
6.2.2
Treatment period(s)
Please refer to the Flow Chart for a detailed presentation of each visit during the treatment
period.
6.2.3
Follow-up period and trial completion
6.2.3.1
End-of-treatment (EOT) visit
The EOT visit will be performed after permanent discontinuation of trial treatment for any 
reason, preferably within 7 days but no later than 14 days after Investigator has decided to
discontinue the trial medication or became aware that the trial medication had been 
terminated.
The assessments of the EOT visit will then be performed instead of at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of treatment discontinuation, unless it has been done within the past 
4 weeks.
6.2.3.2
30-day safety follow-up visit (end of residual-effect period)
The Residual Effect Period (REP) of BI 891065 monotherapy and combination therapy of BI 
891065 and BI 754091 are defined as 30 days. The safety follow-up visit is performed 30 
(+7) days after permanent discontinuation of the trial medication. The information collected 
at this visit must include all new AEs that occurred after the EOT visit, and a follow-up of 
AEs ongoing at EOT.
6.2.3.3
Follow-up visits for PD (extended follow-up period)
Additional follow-up visits for progression after the 30-day safety follow-up visit will only be 
performed for patients who did not progress on treatment. These will be performed once 
every 12 weeks at least (preferably in person, but if the patient cannot visit the study sites, 
collecting information by telephone is accepted).
The follow-up period for progression will end at the earliest if one of the following events is 
met:
∀
Disease progression
∀
Start of a new anti–cancer therapy


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∀
Death
∀
Withdrawal of consent
∀
Lost to follow-up
∀
6 months after the last patient completed the 30-day safety follow-up visit
∀
End of whole trial as specified in section 8.6
The following will be obtained and/or performed during the follow-up visits for progression.
∀
Date of contact
∀
For each reportable serious adverse event / AESI, the investigator should provide the 
information with regard to concomitant medication and the medication administered 
to treat the adverse events on the appropriate CRF pages and the SAE form including 
trade name, indication and dates of administration
∀
Treatment and date with any subsequent anti-cancer therapy (including surgery and 
radiotherapy) including the name and type of the anti-cancer drug and/or best 
supportive care (if applicable)
∀
Outcome (date of and reason for death [if applicable], in case the patient had PD the 
actual date of PD shall be recorded)
6.2.3.4
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:
∀
Completion of planned follow-up period
∀
Lost to follow-up
∀
Refusal to be followed-up
∀
Death
6.2.3.5
Study procedures modification after implementation of protocol version 5
After implementation of protocol version 05, the patient will have assessments as medically 
indicated to monitor the safety at the discretion of the investigator.
These assessments may include: ECG, safety lab, and vital signs at a frequency decided by 
the investigator. 
The study treatment is administered as continuous daily dosing and the administration 
information will be documented in the eCRF. Tumour assessment will be performed 
according to standard of care based on medical opinion of the investigator. The results of any 
assessments will be documented in the source data, but will not be collected in the eCRF. The 
blood sampling for cytokine at the EOT visit is not required. Findings which qualify as an 
(S)AE will be reported in the eCRF and in case of an SAE, on the SAE form (timelines and 
distribution requirements for SAEs apply).
The data collection is required only for the following items:
-
Adverse events


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-
Concomitant medications that are used to treat adverse events
-
Drug dispensing
-
Dose changes
-
At each cycle visit: visit date and medication compliance to BI 891065
-
At EOT visit: visit date, end of treatment – BI 891065, and subject retention
-
At safety follow-up visit: visit date and end of study page
-
Death details (if applicable)


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Part A
The trial will be performed as an open-label trial. The objective of the design is to determine 
the MTD defined as the highest dose with less than 25% risk of the true DLT rate being 
above 0.33 (EWOC criterion). The dose-finding of Part A will be guided by a Bayesian 
2-parameter logistic regression model with overdose control (R13-4806; R13-4803).
The model is given as follows:
logit(πd) = log(α) + β*log(d/d*), 
where logit(π) = log(π/(1-π)).
πd represents the probability of having a DLT in the MTD evaluation period at dose d, d* = 
200 mg is the reference dose, allowing for the interpretation of α as the odds of a DLT at dose 
d*, and θ = (log(α), log(β)) with α, β > 0 is the parameter vector of the model.
The estimated probability of a DLT at each dose level from the model will be summarized 
using the following intervals:
Under toxicity: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM-recommended dose for the next cohort is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the doses 
fulfilling EWOC. Applying the EWOC criterion, it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will exceed 0.33. However, the maximum 
allowable dose increment for the subsequent cohort will be no more than 100 %.
The MTD may be considered reached if 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 0.5, OR
•
At least 12 patients have been treated in the dose escalation phase of the trial, of which at 
least 6 at the MTD.
The SMC may decide stopping the dose escalation phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm this MTD estimate. If no DLT is 
observed at a dose of which the efficacy is considered sufficient, the SMC may decide to 
include an additional number of patients at this dose level and to declare this dose as the dose 
recommended for further testing.
The BLRM is set up for a fixed dosing schedule of once daily (q.d.) across dose levels of 
BI 891065. For the purpose of dose-toxicity modelling, a b.i.d. regimen will be converted in 


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the BLRM to an equivalent q.d. regimen that has a similar Cmax at steady state, based on the 
assumption that safety events are triggered by Cmax at steady state. For example, the 200 mg 
b.i.d. regimen will be modelled as equivalent to a 300 mg q.d regimen in reference to the 
simulation results from trial 1379-0001. For any other b.i.d. doses considered, their 
conversions will be specified in the TSAP. If multiple b.i.d. doses are tested, appropriate 
modifications to the BLRM to account for the heterogeneity of different dosing schedules 
might be considered. Details will be specified in the TSAP if needed.
Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified.
The prior distribution for θ will be specified as a mixture of two bivariate normal 
distributions, 
f(θ) = a1f1(θ) + a2f2(θ)
with
ai, i = 1, 2 the prior mixture weights (a1+ a2 = 1)
and
fi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Prior derivation:
To determine the prior distribution for θ, a meta-analytic predictive (MAP) approach will be 
used. Toxicity information on BI 891065 from the 1379-0001 Phase I study will be 
incorporated. Exact details on the derivation of the prior distributions and on the evaluation 
of the model using hypothetical data scenarios and operating characteristics are provided in
Appendix 10.4.1, a brief description is given here. 
The historical data for BI 891065 can be found in Table 7.1.1: 1.


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Table 7.1.1: 1 Historical data for BI 891065
Trial
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
1379-0001
5 mg q.d.
0/2
15 mg q.d.
0/1
25 mg q.d.
0/2
50 mg q.d.
0/4
100 mg q.d.
0/3
200 mg q.d.
0/3
400 mg q.d.
0/6
The following steps were performed to derive the prior distribution for θ:
∀
The MAP prior was derived using the information in Table 7.1.1: 1 allowing for 
moderate to substantial between-trial heterogeneity. This mixture component was 
assigned 90% mixture weight.
∀
A second, weakly informative component was added with 10% mixture weight.
The prior distributions are given in Table 7.1.1: 2. The corresponding prior probabilities of a 
DLT at different doses and the corresponding probability of undertoxicity, targeted toxicity, 
and overtoxicity are shown in Table 7.1.1: 3. As can be seen from Table 7.1.1: 3, all dose 
levels of BI 891065 have prior probability of overtoxicity below 25%. Therefore, they fulfil
the overdose criterion and are suitable starting dose levels.
Table 7.1.1: 2 Prior distribution
Parameter
Means, standard deviations, 
correlation
Mixture weight
θ: component 1
(-3.66, -0.28), (1.20, 0.83), 
-0.10
0.9
θ: component 2
(-3, 0), (2, 1), 0
0.1


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Table 7.1.1: 3 Prior probabilities of DLTs
Dose
Probability of true DLT rate in
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
50 mg q.d.
0.981
0.014
0.005
0.022
0.050
0.000
0.007
0.137
100 mg q.d.
0.968
0.024
0.008
0.032
0.062
0.000
0.013
0.186
200 mg q.d.
0.932
0.050
0.018
0.053
0.085
0.002
0.026
0.282
200 mg b.i.d*
0.873
0.086
0.041
0.08
0.12
0.003
0.039
0.436
400 mg q.d.
0.813    0.115
0.072
0.107
0.155
0.004
0.051
0.606
*: The 200 mg b.i.d. dose is modelled as equivalent to a 300 mg q.d. dose in terms of dose-toxicity relationship in the BLRM.
The prior may be updated once the trial has started in case new data that can be used will be 
available. The prior that is used for each BLRM analysis for the SMC meetings will be 
documented in the SMC minutes, the prior used for the final analysis will be documented in 
the Trial Statistical Analysis Plan (TSAP).
7.1.2
Part B
Part B of the trial will be performed as an open-label single-arm trial. The primary objective 
of this part is to determine the MTD of BI 891065 in combination with BI 754091 at fixed 
dose of 240 mg. To determine the MTD, patients are entered sequentially into escalating dose 
cohorts. The dose escalation will be guided by a Bayesian 5-parameter logistic regression 
model with overdose control (R15-4233).
This logistic regression model is defined as follows. Let π1,d1 be the probability of having a 
DLT when giving dose d1 of BI 891065 as monotherapy, and π2,d2 the probability of having a 
DLT when giving dose d2 of the combination partner BI 754091 as monotherapy, 
respectively. A logistic regression is used to model the dose-toxicity relationship for each of 
these drugs individually:
BI 891065: logit(π1,d1) =log(α1) + β1log(d1/d1*)
BI 754091: logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses d1* = 200 mg and d2* = 240 mg represent the reference doses for BI 891065
and 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 891065 and BI 754091, a dose-dependent interaction term -∞<η<∞ is introduced 
in the model by the following definition:


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odds(π12,d1,d2) = odds(π012,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the random variable describing the observed number of DLTs in nd1,d2
patients at the dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
The prior distributions for θk will be specified as a mixture of two bivariate normal 
distributions, 
f(θk) = a1,k f1(θk) + a2,k f2(θk)
with 
a1,k, a2,k the prior mixture weights (a1,k + a2,k = 1), k = 1,2 and
fi(θk) = MVN(μik, ∑ik) a bivariate normal distribution with mean vector μik and covariance 
matrix ∑ik where
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
A weakly informative normal prior distribution will be used for η.
The estimated probability of DLT π12,d1,d2 at each dose combination d1, d2 from the model-
will be summarized using the following intervals:
Under toxicity: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM recommended the starting dose of Part B is the combination with the highest 
posterior probability of the DLT rate falling in the target interval [0.16, 0.33) among the dose 
combinations fulfilling the EWOC principle. Per EWOC it should be unlikely (<25% 
posterior probability) that the DLT rate at the dose combination will exceed 0.33. However, 
the maximum allowable dose increment for the subsequent cohort will be no more than 100% 
for each drug.
The MTD may be considered reached if 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 9 patients have been treated in the dose escalation phase of the trial, of which at 
least 6 at the MTD
The BLRM is set up for a fixed dosing schedule of once daily (q.d.) across dose levels of 
BI 891065. For the purpose of dose-toxicity modelling, a b.i.d. regimen will be converted in 
the BLRM to an equivalent q.d. regimen that has a similar Cmax at steady state, based on the 


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assumption that safety events are triggered by Cmax at steady state. For example, the 200 mg 
b.i.d. regimen will be modelled as equivalent to a 300 mg q.d regimen in reference to the 
simulation results from trial 1379-0001. For any other b.i.d. doses considered, their 
conversions will be specified in the TSAP. If multiple b.i.d. doses are tested, appropriate 
modifications to the BLRM to account for the heterogeneity of different dosing schedules 
might be considered. Details will be specified in the TSAP if needed.
Prior derivation:
To determine the prior distributions for θ1 and θ2, a MAP approach will be used. Toxicity 
information on BI 891065 from Part A of this trial, Part A and Part B from trial 1379-0001, 
and toxicity information on BI 754091 from trials 1381-0001, 1381-0004 will be
incorporated. Exact details on the evaluation of model using hypothetical data scenarios and 
operating characteristics are provided in the statistical Appendix 10.4.2; a brief description is 
given here.
The historical data for BI 891065 can be found in Table 7.1.2: 1. For BI 754091, the
historical data can be found in Table 7.1.2: 2. The historical data for the combination of BI 
891065 and BI 754091 can be found in Table 7.1.2: 3. 
Table 7.1.2: 1 Historical data for BI 891065 monotherapy (status as of 14 Feb 2020)
Trial
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
1379-0001 Part A
5 mg q.d.
0 / 2
15 mg q.d.
0 / 1
25 mg q.d.
0 / 2
50 mg q.d.
0 / 4
100 mg q.d.
0 / 3
200 mg q.d.
0 / 3
400 mg q.d.
0 / 6
1379-0006 Part A
100 mg q.d.
1 / 3


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Table 7.1.2: 2 Historical data for BI 754091 monotherapy (status as of04 Feb 2020)
Trial
Dose (mg)
N of patients with DLTs / N 
of patients
1381-0001
80
0 / 3
240
0 / 86
400
0 / 3
1381-0004
240
0 / 6
Table 7.1.2: 3 Historical data for dose combination of BI 891065 and BI 754091 from BI trial 
1379-0001 (status as of 13 Nov 2019)
Dose BI 891065
Dose  BI 754091
N of patients with DLTs during MTD 
evaluation period / N of evaluable patients
50 mg q.d.
240 mg
0/6
200 mg q.d.
240 mg
0/8
400 mg q.d.
240 mg
1/5
The following steps were used to derive the prior distributions for all parameters:
•
θ1: 

The meta-analytic-predictive prior was derived using the information in Table 7.1.2:
1, allowing for moderate to substantial between-trial heterogeneity. This mixture 
component was assigned 90% mixture weight.

A second, weakly-informative component was added with 10% mixture weight.
•
θ2: 

The meta-analytic-predictive prior was derived using the information in Table 7.1.2:
2, allowing for moderate to substantial between-trial heterogeneity. This mixture 
component was assigned 90% mixture weight.

A second, weakly-informative component was added with 10% mixture weight.
•
η: based on the a priori assumption of no interaction between the two compounds, a 
normal distribution with mean 0 and standard deviation 0.56 was chosen. At the starting 
dose combination, the corresponding 95% prior interval covers an up to 1.4 fold increase 
(or decrease) in the odds of a DLT over no interaction.
The prior distributions are given in Table 7.1.2: 4. The corresponding prior probabilities of a 
DLT at different dose combinations and the corresponding probabilities of under toxicity, 
targeted toxicity and over toxicity are shown in Table 7.1.2: 5. As can be seen from Table 
7.1.2: 5, the dose combinations 25 mg q.d. BI 891065 and 240 mg BI 754091, 50 mg q.d. BI 
891065 and 240 mg BI 754091, 100 q.d. mg BI 891065 and 240 mg BI 754091, and 200 mg 
q.d. BI 890165 and 240 mg BI 754091 have prior probabilities of over toxicity below 25% in 
both scenarios. They all fulfil the overdose criterion and are therefore suitable starting dose 
combinations.


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Table 7.1.2: 4 Prior distributions
Parameter
means, standard deviations, correlation
mixture weight
log(α1), log(β1): component 1
(-1.847, -0.404), (0.568, 0.689), 0.071
0.9
log(α1), log(β1): component 2
(-1.847, -0.404), (2, 1), 0
0.1
log(α2), log(β2): component 1
(-2.932, -0.177), (0.568, 0.883), -0.017
0.9
log(α2), log(β2): component 2
(-2.932, -0.177), (2, 1), 0
0.1
η
0, 0.56
N/A
Table 7.1.2: 5 Prior probabilities of DLTs
Dose BI 
891065
Dose BI 
754091
Probability of true DLT rate 
in 
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
25 mg q.d.
240 mg
0.84
0.131
0.029
0.114
0.096
0.027
0.093
0.357
50 mg q.d.
240 mg
0.759
0.205
0.036
0.133
0.103
0.034
0.111
0.397
100 mg q.d.
240 mg
0.603
0.338
0.059
0.165
0.114
0.044
0.14
0.475
200 mg q.d.
240 mg
0.387
0.427
0.186
0.227
0.147
0.048
0.193
0.616
200 mg b.i.d*
240 mg
0.315
0.352
0.333
0.284
0.195
0.038
0.237
0.771
400 mg q.d.
240 mg
0.296
0.282
0.422
0.332
0.239
0.028
0.275
0.881
*: The 200 mg b.i.d. dose is modelled as equivalent to a 300 mg q.d. dose in terms of dose-toxicity relationship 
in the BLRM.
The prior may be updated once the trial has started in case new data that can be used will be 
available. The prior that is used for each BLRM analysis for the SMC meetings will be 
documented in the SMC minutes, the prior used for the final analysis will be documented in 
the TSAP.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical test will be
performed.
7.3
PLANNED ANALYSES
For the determination of the MTD, only MTD evaluable patients will be considered. For the
analysis of secondary and further endpoints, all patients in the treated set (i.e. patients treated
with at least one dose of trial medication) will be included in the analysis. Any other analysis
sets will be defined in the TSAP.


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No per protocol set will be used in the analysis. However, important protocol deviations will 
be summarised. The IQRMP will specify the important protocol deviations in detail.
7.3.1
General considerations
7.3.1.1
Patient analysis sets
Treated set (TS): 
This patient set includes all patients who were documented to have received at least one dose 
of any trial medication. The TS is used for safety analyses and in efficacy analyses.
MTD evaluation set:
This patient set includes all patients who were documented to have received at least one dose 
of any trial medication and were considered evaluable for DLT assessment (see section 
3.3.4.1). The MTD evaluation set will be used for the primary analyses of DLTs and MTD 
determination.
Rules for replacement of patients are defined in the section 3.3.4.1. The list of replaced 
patients will be stored in the trial master file.
Pharmacokinetic parameter analysis set (PKS): 
This set includes all patients in the treated set (TS) who provide at least one PK endpoint that 
was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK 
non-evaluability (as specified in the following subsection ’Pharmacokinetics’). Thus, a 
patients will be included in the PKS, even if he/she contributes only one PK parameter value 
for one period to the statistical assessment. Descriptive and model based analyses of PK
parameters will be based on the PKS.
ECG Set:
This set includes all patients in the treated set who do not have an artificial pacemaker and 
have at least one on-treatment value for at least one ECG variable.
ECG Pharmacokinetic Concentration Set (ECGPCS):
This set includes all patients from the ECG Set who provide at least one time-matched pair of 
valid BI 891065 plasma concentration and corresponding ECG variable to be used in the 
exposure-response analysis.
The decision about concentration value validity needs to be made within the Clinical 
Pharmacology group.
The analysis of ECG data will be based on the ECG Set, except those analyses concerning the 
relationship between plasma concentrations and ECG variables which will be based on the 
ECGPCS. Listings for patients with artificial pacemakers will be based on the TS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(IPD) categories will be specified in the IQRMP, IPDs will be identified no later than in the


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Report Planning Meeting, and the IPD categories will be updated as needed.
7.3.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in section 2.1 and 2.2 for BI 891065 and BI 754091
will be calculated according to the relevant Standard Operating Procedure (SOP) of the
Sponsor (001-MCS-36-472). Pharmacokinetic analyses will be performed using validated
software programs, normally. Phoenix Winnonlin (Pharsight®) with applications validated for
the respective purpose. Graphs and tables will be generated using validated customised SAS®
macros or appropriate graphic software. A reference to the software used, e.g., name, will be
indicated in the CTR.
Only concentration values within the validated concentration range and actual sampling times
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is
to the same number of decimal places provided in the bioanalytical report).
7.3.2
Primary endpoint analyses
7.3.2.1
Part A
In order to identify the MTD and/or RD of BI 891065, the number of evaluable patients with 
DLTs during the MTD evaluation period at each dose level must be presented. 
For the analysis of tolerability and safety, please refer to section 7.3.5.
7.3.2.2
Part B
In order to identify the MTD and/or RD of the combination therapy of BI 891065 and 
BI 754091, the number of evaluable patients with DLTs during the MTD evaluation period at 
each dose level must be presented. 
For the analysis of tolerability and safety, please refer to section 7.3.5.
7.3.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively.


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7.3.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 30 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.6
Interim Analyses
The sponsor will continuously monitor the safety. The dose escalation design foresees that 
the sponsor and the SMC perform regular safety evaluations. These evaluations will be 
unblinded to dose.
No formal interim analysis of efficacy data is foreseen, although efficacy data when available 
may be considered as part of the safety evaluations.
If considered necessary, as soon as the MTD is determined, an evaluation of the safety 
aspects will be performed. Results of this evaluation will be documented and archived. If 
applicable, such an analysis will be defined in more detail in the Statistical Analysis Plan.


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For pharmacokinetics, no interim analysis is planned. Exploratory pharmacokinetic 
evaluations can be done during the trial on an ad-hoc basis. 
7.4
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory 
values will be imputed by the respective values from the screening visit. No other 
imputations will be performed on missing data although every effort will be made to obtain 
complete information on all adverse events, with particular emphasis on potential DLTs.
Handling of missing PK data will be performed according to the relevant Corporate
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug
concentration-time data will not be imputed.
7.5
RANDOMISATION
No randomisation will be performed. Patients will be assigned to escalating dose groups by 
order of admission into the trial.
7.6
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for this
trial. Approximately 12 patients are expected for Part A, and approximately 9 patients 
expected for Part B. Fewer or more patients might be needed based on the recommendation 
of the SMC and the criteria specified. However, the actual number of patients will depend on 
the number of dose cohorts tested. Detailed information of simulation study to evaluate 
operating characteristics of the BLRM will be provided in section 10.4.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
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 Japanese 
GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) 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 Clinical Trial Report.
In exceptional cases, data may be published before the clinical trial report as long as this is 
discussed and agreed to by the investigators and the sponsor.
The certificate of insurance cover is made available to the investigator and the patients, and is 
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 
patient-information form retained by the investigator as part of the trial records. A signed 


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copy of the informed consent and any additional patient information must be given to each 
patient or the patient’s legally accepted representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or
delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial patient 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 4.1.11.


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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 source documents necessary for tumour assessment will be provided to an 
authorised vendor. Before sending or uploading those copies, the investigator must ensure 
that all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.


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8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
Exemptions from expedited reporting are described in section 5.2.6.2.4.
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:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.


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8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection and future use of 
biological samples and clinical data, in particular
∀
The facilities storing biological samples from clinical trial participants are qualified 
for the storage of biological samples collected in clinical trials
∀
A fit for purpose documentation (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/PK data
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). 
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of suspected unexpected 
serious adverse reactions (SUSARs) occurring with the trial medication until 30 days after 
LPLT at their site. Early termination of the trial is defined as the premature termination of 
the trial due to any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A SMC composed of participating investigators and members of the BI trial team will be 
established to review individual and aggregated safety and efficacy data to determine the 
safety profile and risk/benefit ratio and recommend next dose level/does 
escalation/de-escalation/modification/next cohort size, and appropriateness of further 
enrolment. Details of the SMC responsibilities and procedures are described in the SMC 
charter. Regarding SMC please see also sections 2.1, 3.1, 3.2, 4.1, and 7.1 of the clinical trial 
protocol.
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. 


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BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
1. manage the trial in accordance with applicable regulations and internal SOPs,
2. direct the clinical trial team in the preparation, conduct, and reporting of the trial,
3. ensure appropriate training and information of Clinical Trial Managers (CT Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Data management will be done by BI or a vendor according to BI SOPs. 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.
A central laboratory service, a central imaging collection service, and an IRT vendor will be 
used in this trial. Details will be provided in the IRT Manual and Central Laboratory Manual, 
available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et 
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Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER) 2012
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European Medicines Agency (EMA). Committee for Medicinal Products 
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Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
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Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose 
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Maude SL, Barrett D, Teachey DT, Grupp SA:Managing cytokine release 
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Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott 
DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in 
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Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poodubskaya 
E,et al. Nivolumab versus docetaxel in advanced squamous-cell 
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ipilimumab in advanced melanoma. N Engl J Med 2015. 372(26):2521-32.
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Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. 
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ipilimumab-refractory advanced melanoma: a randomised dose-comparison 
cohort of a phase 1 trial. Lancet. 2014;384(9948):1109-17.
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Zhao W, Yang H, editors. Statistical methods in drug combination studies. 
(CRC Biostatistics Series) Boca Raton: CRC Press 2015.
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Garon EB, Rizvi NA, Hui R, Leigh N, Balmanoukian AS, Eder JP, et al, 
KEYNOTE-001 Investigators. Pembrolizumab for the treatment of 
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Mazieres J, et al, POPLAR Study Group. Atezolizumab versus docetaxel 
for patients with previously treated non-small-cell lung cancer (POPLAR): 
a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 
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AV, Necchi A, et al. Atezolizumab in patients with locally advanced and 
metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. 
Lancet. 2016 May 7;387:1909-20.
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therapeutics. Pharmacol Ther 2014; 144(1):82-95.
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Current concepts in the diagnosis and management of cytokine release 
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Fairbrother WJ, et al. A phase I dose-escalation study evaluating the safety 
tolerability and pharmacokinetics of CUDC-427, a potent, oral, monovalent 
IAP antagonist, in patients with refractory solid tumors. Clin Cancer Res. 
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refractory solid tumors or lymphoma. Mol Cancer Ther. 
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without LCL161 in patients with triple negative breast cancer (this study 
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30, 2016). Available from: 
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al. RECIST Working Group. iRECIST: guidelines for response criteria for 
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Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino 
JM, et al, National Comprehensive Cancer Network Management of 
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9.2
UNPUBLISHED REFERENCES
c07895879
Investigator’s Brochure: BI 754091; Indication: Solid tumors 
1381.P1. Version 3, 29 January 2019.


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c14463420
Investigator’s Brochure: BI 891065; Indication: Various 
malignancies 1379.P1. Version 4, 12 September 2018.
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics


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


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Table 10.1: 1 Immune-related adverse events of special interest (continued)
Endocrine (report as AESI for any grade)
∀Type 1 diabetes mellitus (if new onset)
Hematologic (report as AESI if an irAE is ≥Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)
∀Autoimmune haemolytic anaemia
∀Aplastic anaemia
∀Thrombotic thrombocytopenic purpura
∀Idiopathic (or immune) thrombocytopenia purpura
∀Disseminated intravascular coagulation
∀Haemolytic-uraemic syndrome
∀Any Grade 4 anaemia regardless of underlying mechanism
Hepatic (report as AESI if an irAE is ≥Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)
∀Hepatitis
∀Autoimmune hepatitis
∀Transaminase elevations (ALT and/or AST)
Infusion Reactions (report as AESI for any grade)
∀Allergic reaction
∀Anaphylaxis
∀Cytokine release syndrome
∀Serum sickness
∀Infusion reactions
∀Infusion-like reactions
Neurologic (report as AESI for any grade)
∀Autoimmune neuropathy
∀Guillain-Barre syndrome
∀Demyelinating polyneuropathy
∀Myasthenic syndrome


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Table 10.1: 1 Immune-related adverse events of special interest (continued)
Ocular (report as AESI if an irAE is ≥ Grade 2 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)
∀Uveitis
∀Iritis
Renal (report as AESI if an irAE is ≥ Grade 2)
∀Nephritis
∀Nephritis autoimmune
∀Renal failure
∀Renal failure acute
∀Creatinine elevations (report as an AESI if ≥ Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)
Skin (report as AESI for any grade)
∀Dermatitis exfoliative
∀Erythema multiforme
∀Stevens-Johnson syndrome
∀Toxic epidermal necrolysis
Skin (report as AESI if an irAE is ≥ Grade 3)
∀Pruritus
∀Rash
∀Rash generalized
∀Rash maculopapular
∀Any rash considered clinically significant in the physician’s judgment
Other (report as AESI for any grade)
∀Myocarditis
∀Pancreatitis
∀Pericarditis
∀Any other Grade 3 event that is considered immune-related by the physician


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10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS
Regarding diagnosis, grading and therapeutic 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, 
∀
BI 754091 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).
∀
For most Grade 2 irAEs, BI 754091 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. 
∀
For Grade 3 irAEs, BI 754091 has to be withheld, and treatment with high-dose 
corticosteroids (1-2mg/kg/day 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  
BI 754091 may be considered for selected irAEs, but caution is advised, in particular in 
patients with early-onset irAEs. Expert consultancy and agreement with the sponsor is 
recommended prior to restart of therapy.
∀
Most Grade 4 irAEs warrant permanent discontinuation of BI 754091. 
∀
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. 
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. 
The list of irAEs for which BI 754091 should be permanently discontinued are summarised in 
section 4.1.6
∀
encephalitis, aseptic meningitis, transverse myelitis, or Guillain-Barre syndrome of 
any grade 
∀
acquired thrombotic thrombocytopenic purpura of any grade


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∀
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 total bilirubin >3 times 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-hemolytic anemia 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. 
Dose adjustment of BI 754091 besides interrupting or permanently discontinuing BI 754091 
are not allowed. 
In rare situations when benefit and risk assessment is considered positive for a patient to 
continue BI 754091 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 BI 754091 
until improvement or resolution; BI 754091 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 BI 754091 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 BI 754091 and immediately initiate 
treatment according to available guidelines. 
Diarrhoea/Colitis:
∀
For Grade 1 diarrhoea/colitis, consider interruption of BI 754091 therapy.  
∀
For Grade 2 diarrhea/colitis, withhold BI 754091 until patient’s symptoms recovered to 
grade 1 or less. Consider initiating treatment with steroids. 
∀
For Grade 3 diarrhoea/colitis, withhold BI 754091 and immediately start treatment 
(steroids, non-steroidal immunosuppressents) as per available guidelines. 
∀
For Grade 4 diarrhoea/colitis, permanently discontinue BI 754091 and immediately 
commence adequate therapy (e.g. i.v. corticosteroids).   


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∀
For Grade 1-3 colitis, restart of BI 754091 may be considered once symptoms improve to 
Grade 1 or less without need for continued steroids. After careful benefit risk assessment, 
BI 754091 may also be restarted after recovery to grade 1 or less, and on corticosteroid ≤ 
10 mg per day  
∀
BI 754091 should be permanently discontinued for recurrent diarrhoea/colitis of any 
grade.  
Diabetes
∀
Consider withholding BI 754091 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
-
BI 754091 should be withheld until glucose level is controlled with insulin with no 
sign of ketoacidosis.  
∀
BI 754091 may be restarted once insulin therapy has established stable glycemic control 
Thyroid disorders:
For diagnosed thyroid disorders, thyroid hormone supplementation and monitoring should 
occur as per available guidelines
∀
Primary hypothyroidism:
-
For Grade 1 hypothyroidism, BI 754091 may be continued, with regular monitoring 
of thyroid values. 
-
For Grade 2 hypothyroidism, consider withholding BI 754091
-
For Grade 3-4 hypothyroidism, withhold BI 754091, consider admission and IV 
therapy, especially in case of myxedema 
-
BI 754091 may be restarted once symptoms resolve to baseline with appropriate 
thyroid hormone supplementation
∀
Primary hyperthyroidism
-
For Grade 1 hyperthyroidism, BI 754091 may be continued , with regular 
monitoring of thyroid values. 
-
For Grade 2 hyperthyroidism, consider withholding BI 754091, initiate therapy as per 
available guidelines. 
-
For Grade 3-4 hyperthyroidism, withhold BI 754091. Consider hospitalization, 
especially in case of thyreotoxicosis. 
-
BI 754091 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 BI 754091 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. 


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∀
Therapy with BI 754091 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 BI 754091 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.
∀
For Grade 1 hepatitis (elevated AST/ALT < 3x ULN and/or total bilirubin <1.5x ULN), 
BI 754091 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), BI 
754091 should be suspended. Monitoring of liver values every 3 days is recommended. 
Initiate treatment according to available guidelines. Restarting of BI 754091 may be 
considered upon recovery to grade 1 or less, and on corticosteroid ≤ 10 mg per day .
∀
For Grade 3 or higher hepatitis, BI 754091 has to be permanently discontinued. 
Nephritis:
∀
For Grade 1 nephritis, consider temporarily withholding BI 754091.
∀
For Grade 2 nephritis, withhold BI 754091. Consult nephrology. Initiate treatment 
according to guidelines. In case of no improvement or worsening, permanently 
discontinue BI 754091.BI 754091 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 BI 754091. 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.
∀
BI 754091 should also be permanently discontinued for recurrent nephritis grade 2 or 
higher.
Rash
∀
For Grade 1 rash, continue BI 754091. Initiate topical treatment.  
∀
For Grade 2 rash, BI 754091 may be continued, in case of no improvement upon weekly 
monitoring, consider interruption of BI 754091 therapy. Treat topically, add systemic 
corticosteroid therapies as clinically appropriate. 
∀
For Grade 3 rash, withhold BI 754091. Initiate topical and systemic therapy as per 
available guidelines. Upon improvement of event to grade 1 or less, and on corticosteroid 


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≤ 10 mg per day, consult with dermatology whether therapy with BI 754091 might be 
restarted, especially in case no alternative anti-neoplastic therapy is available. 
∀
For Grade 4 rash, BI 754091 should be permanently discontinued.
∀
BI 754091 should also be discontinued for recurrent rash grade 3 or higher.
Bullous dermatosis
∀
For Grade 1 bullous dermatosis, use local wound care and observation. BI 754091 can be 
continued. 
∀
For Grade 2 bullous dermatosis, withhold BI 754091. Administer topical therapy, add 
systemic therapy as clinically adequate. 
∀
For Grade 3 bullous dermatosis, withhold BI 754091, initiate topical and systemic 
therapy as per available guidelines. Restarting of BI 754091 may be considered after 
dermatology consultation. 
∀
For Grade 4 bullous dermatosis, permanently discontinue BI 754091.
Severe cutaneous adverse reaction (SCAR), Stevens Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN)
∀
For Grade 2 events, withhold BI 754091, initiate treatment as per available guidelines. 
Closely monitor for improvement or worsening. 
∀
For Grade 3 events, withhold BI 754091. 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 BI 754091, 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, BI 754091 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
∀
BI 754091 should be permanently discontinued for any grade.
  
Myasthenia gravis
∀
For Grade 2 myasthenia gravis, withhold BI 754091, 
∀
For Grade 3 or 4 myasthernia gravis, permanently discontinue BI 754091  
Guillain Barré Syndrome (GBS)
∀
Discontinue BI 754091 permanently for any grade GBS. 
Transverse Myelitis
∀
Discontinue BI 754091 permanently for any grade transverse myelitis. 
Peripheral neuropathy, autonomic neuropathy
∀
For Grade 1 events, may continue BI 754091, but with low threshold to discontinue 
while monitoring closely for worsening. 


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∀
For Grade 2 events, withhold BI 754091 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 BI 754091. 
Inflammatory Arthritis
∀
For Grade 1 arthritis, BI 754091 can be continued. Administer analgetic treatment 
(acetaminophen, nonsteroidal anti-inflammatory drug [NSAID]). 
∀
For Grade 2-4 arthritis, withhold BI 754091. Initiate treatment as per available 
guidelines, cave regarding reactivation of tuberculosis/opportunistic infections in case of 
prolonged immunosuppressive/DMARD therapy. 
BI 754091 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, BI 754091 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 BI 754091, discontinue permanently in patients with 
objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI or biopsy). 
Initiate therapy as per available guidelines. Resuming BI 754091 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 BI 754091. 
∀
BI 754091 should be permanently discontinued if there is any evidence of myocardial 
involvement.
Polymyalgia-like syndrome
∀
For Grade 1 event, BI 754091 can be continued.   
∀
For Grade 2 event, withhold BI 754091 and promptly initiate adequate therapy. If no 
improvement, treat as grade 3.
∀
For Grade 3 or G4 event, withhold BI 754091, promptly initiate adequate therapy 
Rheumatology consultancy is highly recommended. 
BI 754091 may be resumed after careful assessment of risks and benefits, rheumatology 
consultancy highly recommended prior to reinitiation. BI 754091 may only be re-started upon 
recovery to grade 1 or less and on corticosteroid ≤ 10 mg per day. 
Myocarditis
∀
Discontinue BI 754091 permanently for any grade of myocarditis. 
Uveitis/Iritis, Episcleritis
∀
For Grade 1 events, treatment with BI 754091 can continue. Treat topically as needed.
∀
For Gade 2 events, withhold therapy with BI 754091, urgent ophthalomology referral is 
recommended. Initiate topical treatment, consider systemic therapy if needed. Restart of 
BI 754091 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 


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are permitted). Continuation of topical/ocular steroids is permitted and does not prohibit 
resuming BI 754091 therapy. 
∀
For Grade 3 or 4 events, permanently discontinue BI 754091 therapy. Seek emergent 
ophthalmology consultation.. Initiate adequate local and systemic treatment.   
Autoimmune-hemolytic anemia (AIHA)
∀
For Grade 1 AIHA, continue treatment with BI 754091. Close follow-up of anemia and 
other lab values. 
∀
For Grade 2-4 AIHA, discontinue BI 754091 permanently. Initiate systemic therapy as 
per guideline. Consult Hermatology.
Acquired thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome. 
Timely recognition upon suggestive findings is essential, timely/immediate involvement of 
hematology consultancy may be beneficial. 
∀
For any grade TTP, permanently discontinue BI 754091. 
∀
For HUS (TTP excluded), withhold BI 754091 for grade 1 and grade 2, provide 
supportive care. Upon full recovery, BI 754091 may be restarted after carefuly weighing 
of risks and benefits. 
∀
For Grade 3 or Grade 4 HUS, discontinue BI 754091 permanently. 
Immune thrombocytopenia (ITP)
∀
In case of Grade 1 ITP, BI 754091 can be continued. 
∀
For Grade 2 or Grade 3 ITP, withhold BI 754091 and initiate systemic therapy. BI 
754091 may be restarted upon resolution to at least grade 1. 
∀
For Grade 4 ITP, permanently discontinue BI 754091. 










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10.4
STATISTICAL APPENDICES 
A Bayesian logistic regression model with overdose control will be used to guide dose 
escalation in this part of the trial. The BLRM is introduced in section 7.1, which also 
specifies the prior for the model. After patients in each cohort have completed at least one 
cycle of treatment, the prior distribution will be updated through Gibbs sampling procedures 
with the accumulated DLT data from the MTD evaluation period. Posterior probabilities for 
the rate of DLTs will be summarised from BLRM. Selection of the next dose will be based on 
these probabilities as well as on other safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD under various 
dose-toxicity relationships through computer simulation. These results are summarized in 
Table 10.4.1: 3 and Table 10.4.2: 3 for Part A and Part B respectively. In addition, 
recommendations of the next dose level by the BLRM with overdose control principle are 
also provided under various hypothetical outcome scenarios in early cohorts to show how it 
facilitates on-trial dose-escalation decisions (see Table 10.4.1: 1 for Part A and Table 
10.4.2: 1 for Part B). For simplicity reasons, a cohort size of 3 patients who are all evaluable 
is assumed.
10.4.1
Part A
Hypothetical data scenarios:
Hypothetical data scenarios are shown in Table 10.4.1: 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model and the 100%
escalation limit. It is assumed that each cohort has exactly three patients who are all evaluable. 
For each scenario, the probability of overdose for the current dose, as well as the next 
potential dose and related probabilities of under-dosing, target dose, and over-dosing are 
shown.
For example, scenario 1 represents the case that no DLT is observed in the first three patients 
at the starting dose of 100 mg. In this case, the next optimal dose, i.e. the dose with the 
highest probability of being in the target interval, is 400 mg. Since the escalation is restricted 
to a maximum of 100 % from the previous dose per protocol, the next dose to be tested in the 
trial would be 200 mg. Similarly, scenario 4 represents the case that 3 patients have been 
treated at 100 mg and 3 at 200 mg, none of them with a DLT. In this case, the model requires 
to escalate to 400 mg.
Scenario 3 shows the case that 2 DLTs are observed in the first three patients at the starting 
dose of 100 mg. The model then allows the next dose to be de-escalated to 50 mg.
Finally, scenario 8, 9 and 10 illustrate a case where escalation has proceeded up to the highest 
dose of 400 mg, where the MTD could be declared at 400 mg.


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Table 10.4.1: 1 
Hypothetical data scenarios
Scenario
Dose 
(q.d.
mg)
# 
Patients
# 
DLT
Current 
Dose: P 
(OD)
Next 
recommended 
dose
Next dose:
P 
(UD)
P 
(TD)
P 
(OD)
1
100
3
0
0.001
400*[200]
0.834
0.106
0.060
2
100
3
1
0.041
400*[200]
0.564
0.253
0.184
3
100
3
2
0.316
50
0.533
0.262
0.205
4
100
200
3
3
0
0
0.002
400
0.871
0.091
0.039
5
100
200
3
3
0
1
0.030
400
0.596
0.237
0.167
6
100
200
3
3
0
2
0.193
200
0.479
0.327
0.193
7
100
200
3
3
1
1
0.140
200
0.520
0.340
0.140
8
100
200
400
3
3
6
0
0
0
0.001
400
0.970
0.029
0.001
9
100
200
400
3
3
6
0
0
1
0.023
400
0.814
0.163
0.023
10
100
200
400
3
3
6
0
0
2
0.134
400
0.496
0.371
0.134
11
100
200
400
3
3
6
0
0
3
0.413
200
0.824
0.164
0.013
12
100
200
400
3
3
6
0
0
4
0.745
200
0.763
0.198
0.039
Operating characteristics:
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 


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metrics such as the probability of recommending a dose with true DLT rate in the target 
interval can be approximated via simulation. Table 10.4.1: 2 describes 6 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. 
These scenarios reflect a wide range of possible cases as follows:
∀
Scenario 1: aligned with prior means
∀
Scenario 2: high-toxicity scenario
∀
Scenario 3: low-toxicity scenario
∀
Scenario 4: non-logistic dose-toxicity scenario
∀
Scenario 5: low-toxicity followed by high-toxicity
∀
Scenario 6: super high-toxicity scenario
Table 10.4.1: 2 
Assumed true dose-toxicity scenarios
Scenario
Dose (mg q.d.)
40*
50
100
200
400
600*
1: Prior
P(DLT)
NA
0.022
0.032
0.053
0.107
0.181
2: High Tox
NA
0.194
0.253
0.425
0.527
NA
3: Low Tox
NA
0.008
0.028
0.054
0.143
0.181
4: 
Non-Logistic
NA
0.032
0.098
0.268
0.467
NA
5: Low-High
NA
0.008
0.052
0.241
0.335
NA
6: Super 
High Tox
0.260
0.450
0.578
0.660
0.737
NA
* To allow the model to implement the above scenarios and to evaluate the operating 
characteristics, 40 mg and 600 mg doses were included even if they will not be tested in the 
trial.
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rules:
∀
Escalate to the dose which maximises the probability of the targeted toxicity region 
and satisfies the overdose criterion if it is ≤ 100% increase from the current dose.
∀
If the recommended dose satisfying the overdose criterion is > 100% increase in dose, 
then escalate to the highest dose level which is ≤ 100% increase from the current 
dose.
The MTD was considered reached if at least 6 patients have been evaluated at a dose level 
which is the model’s recommendation for the next dose cohort and for which the posterior 
probability of targeted toxicity was at least 50%.
It was then assessed how often a dose was declared as MTD with true DLT rate in the under-, 
targeted or over-dose range.
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.4.1: 3.


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Table 10.4.1: 3 
Simulated operating characteristics
% of trials declaring a MTD with true DLT rate in
# Patients
# DLTs
underdose
target dose
overdose
Stopped
Mean 
(Min-Max)
Mean
(Min-Max)
1
17.7
82.3
0
0
16.5
(12-42)
1.9 (1-7)
2
0
45.4
37.8
16.8
12.9 (3-30)
4.5 (1-11)
3
22.2
77.6
0
0.2
16.4
(12-42)
1.9 (0-6)
4
18.8
52.8
27.1
1.3
13.7 (6-33)
3.7 (1-9)
5
7.4
42.8
49.5
0.3
13.4 (6-27)
3.0 (1-8)
6
0
0.1
11.6
88.3
8.1 (3-27)
4.5 (2-12)
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
82.3% of the simulated trials declared a dose as MTD with true DLT rate under the targeted 
dose range. 
Scenario 2 (high-toxicity scenario) shows, that when the true DLT rate is high, i.e. the 
majority dose levels with true DLT rate above the target interval, 45.4% of the simulated 
trials declared a dose as MTD with true DLT rate in the targeted dose range. 16.8% of the 
trials were stopped without declaring a MTD since all dose levels were too toxic. This is an 
expected situation for a high-toxicity scenario. 
Scenario 3 shows that when the true DLT rate is low, 77.6% of the simulated trials declared a 
dose as MTD with true DLT rate in the target dose range.
Scenario 4 represents a case where the assumed true dose-toxicity curve does not follow a 
logistic shape. In this scenario, 52.8% of trials declared MTDs with true DLT rate in the 
target interval.
Scenario 5 shows that when the true DLT rate is low-high, 42.8% of the simulated trials 
declared a dose as MTD with true DLT rate in the targeted dose range. 428 trials declared 
200 mg as the MTD, and 495 trials declared 400 mg as the MTD.
Scenario 6 shows that when the true DLT rate is super high, most of simulated trials stopped, 
since none of the doses is considered tolerable anymore. This is an expected situation for a 
super high-toxicity scenario.
The mean patient numbers range from 8.1 patients (Scenario 6) to 16.5 patients (Scenario 1) 
and the maximum number of patients was 42. Therefore, the patient numbers are as expected 
and increase when moving away from the high-toxicity scenario.


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By reviewing the metrics presented in Table 10.4.1: 3, it can be seen that the model is not 
sensitive to different scenarios of truth. In general, this model is conservative due to the 
overdose control criteria. In most 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.
On-study recommendations based on the model 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 3.5.1 and JAGS was used for data scenarios and simulations.
10.4.2
Part B
Hypothetical data scenarios:
Hypothetical data scenarios are shown in Table 10.4.2: 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model and the 100%
escalation limit. It is assumed that each cohort has exactly three patients who are all evaluable. 
For each scenario, the probability of overdose for the current dose, as well as the next 
potential dose and related probabilities of under-dosing, target dose, and over-dosing are 
shown.
For example, scenario 1 represents the case that no DLT is observed in the first three patients 
at the starting dose combination of 200 / 240. In this case, the next optimal dose combination 
is 400 / 240. 
Scenario 2 shows the case that one patient out of the 3 treated patients at 200 / 240 
experiences a DLT, then the model would still recommend to treat the next patient with the 
same dose combination of 200 / 240. 
Scenario 3 shows the case that 2 DLTs are observed in the first three patients at the starting 
dose combination of 200 / 240. The model then allows the next dose combination to be 
de-escalated to 100 / 240.
Finally, scenario 4, 5 and 9 illustrate a case where escalation has proceeded up to the highest 
dose combination of 400 / 240, where the MTD could be declared at that dose combination.


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Table 10.4.2: 1 Hypothetical data scenarios
Scenario
Dose 
combination 
(mg)
# 
Patients
# 
DLT
Current 
Dose: 
P (OD)
Next 
recommended 
dose
combination
Next dose:
P 
(UD)
P (TD)
P (OD)
1
200 / 240
3
0
0.024
400 / 240
0.572
0.251
0.178
2
200 / 240
3
1
0.110
200 / 240
0.501
0.389
0.110
3
200 / 240
3
2
0.350
100 / 240
0.485
0.369
0.147
4
200 / 240
400 / 240
3
6
0
0
0.015
400 / 240
0.857
0.128
0.015
5
200 / 240
400 / 240
3
6
0
1
0.085
400 / 240
0.567
0.348
0.085
6
200 / 240
400 / 240
3
6
0
2
0.282
200 / 240
0.632
0.350
0.018
7
200 / 240
400 / 240
3
6
0
3
0.567
200 / 240
0.420
0.523
0.057
8
200 / 240
400 / 240
3
6
0
4
0.813
200 / 240
0.268
0.594
0.138
9
200 / 240
400 / 240
3
6
1
1
0.173
400 / 240
0.392
0.436
0.173
10
200 / 240
400 / 240
3
6
1
2
0.422
200 / 240
0.406
0.526
0.068
Operating characteristics:
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose with true DLT rate in the target 
interval can be approximated via simulation. Table 10.4.2: 2 describes 6 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. 
These scenarios reflect a wide range of possible cases as follows:
∀
Scenario 1: aligned with prior means
∀
Scenario 2: high-toxicity scenario
∀
Scenario 3: low-toxicity scenario
∀
Scenario 4: non-logistic dose-toxicity scenario
∀
Scenario 5: low-toxicity followed by high-toxicity
∀
Scenario 6: super high-toxicity scenario


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Table 10.4.2: 2 
Assumed true dose-toxicity scenarios
Scenario
Dose combination (mg)
25 / 240
50 / 240
100 / 240
200 / 240
400 / 240
1: Prior
P(DLT)
0.081
0.093
0.114
0.159
0.257
2: High Tox
0.161
0.194     
0.253    0.398     0.607
3: Low Tox
0.068
0.095
0.101
0.124
0.251
4: Non-Logistic
0.023
0.032
0.150
0.168
0.467
5: Low-High
0.011
0.028
0.072
0.170
0.535
6: Super High 
Tox
0.260
0.450
0.578
0.660
0.737
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rules:
∀
Escalate to the dose combination which maximises the probability of the targeted 
toxicity region and satisfies the overdose criterion if it is ≤ 100% increase from the 
current dose.
∀
If the recommended dose combination satisfying the overdose criterion is > 100% 
increase in dose, then escalate to the highest dose level which is ≤ 100% increase 
from the current dose.
The MTD was considered reached if at least 6 patients have been evaluated at a dose level
which is the model’s recommendation for the next dose cohort and for which the posterior
probability of targeted toxicity was at least 50%.
It was then assessed how often a dose combination was declared as MTD with true DLT rate 
in the under-, targeted or over-dose range.
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.4.2: 3.


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Table 10.4.2: 3 
Simulated operating characteristics
% of trials declaring a MTD with true DLT rate in
# Patients
# DLTs
underdose
target dose
overdose
Stopped
Mean 
(Min-Max)
Mean
(Min-Max)
1
55.1
43.6
0.0
1.3
11.5 (3-42)
2.2 (0-7)
2
0.0
29.8
48.5
21.7
10.3 (3-30)
3.9 (1-11)
3
47.7
51.5
0.0
0.8
11.8 (3-42)
2.1 (0-6)
4
3.9
79.6
14.7
1.8
11.1 (3-30)
2.9 (1-8)
5
2.7
88.6
7.7
1
11.1 (3-24)
3.0 (1-7)
6
0
7.8
27.6
64.6
11.0 (3-30)
5.2 (2-13)
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means,
43.6% of the simulated trials declared the dose combination 400 / 240 as MTD with true DLT 
rate under the targeted dose range.
Scenario 2 (high-toxicity scenario) shows, that when the true DLT rate is high, i.e. the
majority dose levels with true DLT rate above the target interval, only 29.8% of the simulated
trials declared a dose combination as MTD with true DLT rate in the targeted dose range, and 
48.5% in the overdose interval. 21.7% of the trials were stopped without declaring a MTD 
since all dose levels were too toxic. This is an expected situation for a high-toxicity scenario. 
Scenario 3 shows that when the true DLT rate is low, 51.5% of the simulated trials declared 
the dose combination 400 / 240 mg as MTD with true DLT rate under the targeted dose 
range, and 47.7% of the simulated trials declared a MTD in the underdose interval. 
Scenario 4 represents a case where the assumed true dose-toxicity curve does not follow a 
logistic shape. In this scenario, 79.6% of trials declared MTDs with true DLT rate in the 
target interval, and only a few trials declared MTDs with true DLT rate in the underdose 
interval. This illustrates that the model is not sensitive to model misspecification.
Scenario 5 shows that when the true DLT rate is low-high, 88.6% of the simulated trials 
declared a dose as MTD with true DLT rate in the targeted dose range.
Scenario 6 shows that when the true DLT rate is super high, 64.6% of simulated trials 
stopped, since none of the doses is considered tolerable anymore. This is an expected 
situation for a super high-toxicity scenario.
The mean patient numbers range from 10.3 patients (Scenario 2) to 11.8 patients (Scenario 3) 
and the maximum number of patients was 42. Therefore, the patient numbers are as expected 
and increase when moving away from the high-toxicity scenario.
In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.


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On-study recommendations based on the model 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 3.5.1 and JAGS was used for data scenarios and simulations.


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10.5
IRECIST RESPONSE ASSESSMENT
Immunotherapeutics may result in infiltration of immune cells leading to transient increase in 
the size in malignant lesions, or undetectable lesions becoming detectable. Therefore, overall 
response in this study will also be assessed using iRECIST (R17-0923) in addition to 
RECIST 1.1. The criteria of iRECIST are identical to those of RECIST 1.1 in many respects,
but have been adapted to account for instances where an increase in tumour burden, or the 
appearance of new lesions, does not reflect true tumour progression.
Key differences are described in this section. All responses defined using iRECIST criteria 
are designated with a prefix.
10.5.1
Confirming progression
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD.
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is 
seen as evidenced by one or more of the following:
∀
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions
1.
Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum
2.
Continued unequivocal progression in non-target disease with an increase in 
tumour burden
3.
Increase in size of previously identified new lesion(s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions.
∀
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) 
where progression was not previously identified, including the appearance of 
additional new lesions.
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). As can be seen in Table 10.5.2: 1 and Table 10.5.2: 2,
respectively, the prior documentation of iUPD does not preclude assigning iCR, iPR, or iSD 
in subsequent time-point assessments or as best overall response (BOR) providing that iCPD 
is not documented at the next assessment after iUPD.
10.5.2
New lesions
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in 
short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New 


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Lesion-Non-Target (NLNT) to allow clear differentiation from baseline target and non-target 
lesions.
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of new target lesions should NOT be included in the sum of 
measures of original target lesions identified at baseline. Rather, these measurements will be 
collected on a separate table in the case report form.
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at 
least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression from 
iUPD with either an increase of at least 5 mm in the absolute value of the sum of NLT OR an 
increase (but not necessarily unequivocal increase) in the size of NLNT lesions OR the 
appearance of additional new lesions.


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Table 10.5.2: 1 
Time point iResponse
Target
Lesions*
Non-Targe
t Lesions*
New
Lesions*
Time Point iResponse
No prior
iUPD**
Prior iUPD**; ***
iCR
iCR
No
iCR
iCR
iCR
Non-iCR/Non-
iUPD
No
iPR
iPR
iPR
Non-iCR/Non-
iUPD
No
iPR
iPR
iSD
Non-iCR/Non-
iUPD
No
iSD
iSD
iUPD with no
change OR
decrease from 
last TP
iUPD with no
change
OR
decrease from last
TP
Yes
NA
NLs confirms iCPD if NLs were previously
identified and increase in size (≥5 mm in
SOM for NLT or any increase for NLNT) or
number. If no change in NLs (size or number)
from last TP, remains iUPD
iSD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based
in further increase in size of NT disease (need
not meet RECIST 1.1 criteria for unequivocal
PD)
iUPD
Non-iCR/Non-
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based
on:
ofurther increase in SOM of at least 5 mm,
otherwise remains iUPD
iUPD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based
on further increase in:
∀
previously identified T lesion iUPD
SOM ≥5 mm and / or
∀
NT lesion iUPD (prior assessment -
need not be unequivocal PD)
iUPD
iUPD
Yes
iUPD
Remains iUPD unless iCPD confirmed based
on further increase in:
∀
previously identified T lesion iUPD ≥5
mm and / or
∀
previously identified NT lesion iUPD 
(need not be unequivocal) and/or
∀
size or number of new lesions
previously identified
Non-
iUPD/PD
Non-iUPD/PD
Yes
iUPD
Remains iUPD unless iCPD confirmed based on
∀
increase in size or number of new lesions
previously identified
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD would be
the same. ** in any lesion category. *** previously identified in assessment immediately prior to this TP.
iCPD = confirmed immune progression; iCR = immune complete response; iPR = immune partial response;
iSD = immune stable disease; iUPD = unconfirmed immune progression; NL = new lesion; NLT = new lesion - target; 
NLNT = new lesion - non-target; PD = progressive disease; SOM = sum of measures; TP = time-point


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Table 10.5.2: 2
iRECIST Best Overall Response
TPR1
TPR2
TPR3
TPR4
TPR5
iBOR
iCR
iCR,
iPR,
iUPD, NE
iCR, iPR, iUPD, NE
iUPD
iCPD
iCR
iUPD
iPR, iSD, NE
iCR
iCR, iPR, iSD, iUPD,
NE
iCR, iPR, iSD,
iUPD, iCPD, NE
iCR
iUPD
iPR
iPR, iSD, iUPD, NE
iPR, iSD, iUPD, NE,
iCPD
iPR, iSD, iUPD, NE,
iCPD
iPR
iUPD
iSD, NE
PR
iPR, iSD, iUPD, NE
iPR, iSD, iUPD,
iCPD, NE
iPR
iUPD
iSD
iSD, iUPD, NE
iSD, iUPD, iCPD, NE iSD, iUPD, iCPD,
NE
iSD
iUPD
iCPD
Anything
Anything
Anything
iCPD
iUPD
iUPD
iCPD
Anything
Anything
iCPD
iUPD
NE
NE
NE
NE
iUPD
∀
Table assumes a randomised study where confirmation of CR or PR is not required.
∀
NE = not evaluable that cycle.
∀
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation.
∀
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each
TPR but is not shown in the table for ease of presentation
TPR: Time point response
iBOR: iRECIST best overall response


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
28 Aug 2019
EudraCT number
EU number
Not applicable
BI Trial number
1379-0006
BI Investigational Medicinal 
Product(s)
BI 891065
BI 754091
Title of protocol
An open label, Phase I study of BI 891065 
monotherapy and combination therapy of BI 
891065 and BI 754091 in Asian patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Flow Chart
Description of change
f
Pregnancy tests are mandatory for women with 
child-bearing potential. A serum (or plasma) beta human 
chorionic gonadotropin (β-HCG) pregnancy test must be done 
at screening. Thereafter, either a serum (or plasma) or urine 
pregnancy test will be done on Day 1 of each cycle, at the 
EOT visit, and at the 30-day safety FU visit.
Rationale for change
Clarification
Section to be changed
Flow Chart
3.3.3
Exclusion criteria
5.2.3.6
Virology
Description of change
The following flow chart footnote was modified:
g
HBV, HCV, and HIV testing should be performed 
at screening unless (see section 5.2.3.6 for HBV and HBV 
test requirements). In Part A, these tests are exempted if
test results obtained in routine clinical practice within 6 
months before the informed consent date are available. In 
part B, HBV and HCV tests are mandatory but HIV 
testing is not mandatory if test results obtained in routine 
clinical practice within 6 months before the informed 
consent date are available.
Section 3.3.3 criteria 13 was modified:
Any of the following laboratory evidence of hepatitis virus 
infection. 

Positive results of hepatitis B surface (HBs) 
antigen

Presence of hepatitis B core (HBc) antibody
together with hepatitis virus B (HBV) 
Deoxyribonucleic acid (DNA)

Presence of hepatitis virus C (HCV) antibody 
together with HCV Ribonucleic acid (RNA)
In Part A, tTest results obtained in routine clinical 


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practice are acceptable if done within 6 months before 
the informed consent date.
Section 5.2.3.6 was modified:
HBV, HCV, and HIV testing should be performed at 
screening unless. In Part A these tests are exempted if test 
results obtained in routine clinical practice within 6 months 
before the informed consent date are available. In part B, 
HBV and HCV tests are mandatory but HIV testing is not 
mandatory if test results obtained in routine clinical 
practice within 6 months before the informed consent date 
are available.
The required test items are as follows:
For HBV: HBs antigen and HBc antibody tests are 
performed. HBV-DNA test is required only for patients with 
HBc antibody positive results. 
Similarly For HCV: HCV antibody test is performed.
HCV-RNA test is required only for patients with HCV 
antibody positive results.
Rationale for change
As there is a theoretical possibility of hepatitis virus 
reactivation with anti-PD-1 treatments, the HBV and HCV 
tests in screening are mandated even if test results obtained 
routine clinical practice within 6 months are available. Test 
items required for hepatitis virus tests are clarified.
Section to be changed
Flow Chart
1.4.2
Risks
5.2.6.1.4 Adverse events of special interest (AESIs)
Description of change
A footnote was added in Flow Chart:
r
Patients will remain hospitalised for at least 
three days after the first administration of BI 891065. On 
day four or later, the investigator will then evaluate 
whether it is appropriate to discharge the patient based 
on the patient's condition. For this evaluation, the 
investigator will perform the assessment of adverse events 
and if necessary haematology and clinical chemistry 
examination.
The mitigation strategy for Cytokine release syndrome in 
Table 1.4.2: 1 was modified:
To keep patients under close surveillance at study sites for 10 
hours hospitalised for 3 days after the first administration of 
BI 891065. Provide recommendation for the management of 
CRS in the clinical trial protocol.
Cytokine levels are measured.
A part of the description of Cytokine release syndrome in 
section 5.2.6.1.4 was modified:
Patients will remain under surveillance for 10 hours after the 
first administration of BI 891065 (i.e., until the blood 
sampling for PK on day 1 is completed). Although patients 
will not be required to stay overnight on the first day of 
monotherapy or combination therapy treatments, they should 
be advised to remain close to the study site where medical 
coverage will be ready to support them, if required


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hospitalised for at least three days after the first 
administration of BI 891065. On day four or later, the 
investigator will then evaluate whether it is appropriate to 
discharge the patient based on the patient's condition.
Thereafter, patients will be monitored with regular safety 
visits.
Rationale for change
Based on a feedback from a regulatory authority, a 
requirement of hospitalisation following the first 
administration was added, together with the 
assessment/examination to be performed before discharging 
patients.
Section to be changed
Description of change
Rationale for change
Section to be changed
3.3
Selection of trial population
Description of change
Approximately 21 patients (12 in Part A, 9 in Part B) are 
planned to be included. This trial will be conducted in Japan 
and Taiwan. Japanese patients will be recruited in all 
treatment cohorts, and Taiwanese patients will be recruited in 
the highest planned dose of each part in Part A and all 
cohorts in Part B (for details, please refer to section 4.1.3).
Rationale for change
Clarification
Section to be changed
4.1.7
Dose limiting toxicities
Description of change
∀
Neutropenia ≥Grade 3 with documented infection
(inequality symbol "≥" was added)
Rationale for change
Clarification based on a feedback from a regulatory authority
Section to be changed
4.1.7
Dose limiting toxicities
Description of change
∀
Grade 4 thrombocytopenia, or Grade 3 
thrombocytopenia with bleeding or a requirement for 
platelet transfusions
Rationale for change
The condition of platelet transfusion is already covered in 
another bullet point "Thrombocytopenia of any Grade which 
requires platelet transfusions ".
Section to be changed
4.1.7
Dose limiting toxicities
Description of change
∀
AST or ALT >3 times ULN and concurrent total 
bilirubin >2 times ULN without initial findings of 


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cholestasis (e.g., findings consistent with Hy's law or 
the FDA definition of potential DILI, see section 
5.2.6.1.4)
Rationale for change
Clarification
Section to be changed
4.2.1.2
Caution for concomitant medication and/or food
Description of change
The section was added with following information:
BI 891065 is a substrate of CYP3A4. In ongoing overseas 
trial of 1379-0001, the exposure (Cmax, AUC) tended to 
increase in two patients who took moderate CYP3A4 
inhibitor from 25 patients at 5 to 400 mg dose cohort. 
Caution is necessary for the intake of CYP3A4 inhibitor 
(ex. clarithromycin, erythromycin, fluconazole, 
itraconazole, verapamil, ketoconazole, and diltiazem) or 
grapefruits and their juices, because the possibility cannot 
be excluded for the increase of plasma concentration.
Rationale for change
Caution for the concomitant use of CYP3A4 inhibitors was 
added as the possibility of increases in the blood 
concentration of BI 891065 when CYP3A4 inhibitors are 
concomitantly used cannot be excluded.
Section to be changed
5.2.6.1.4 Adverse events of special interest (AESIs)
Description of change
Immune-related adverse event (irAE) (Part B only)
Immune-related AEs are AEs associated with immunotherapy 
treatments that appear to be associated with the immune 
therapy’s mechanism of action. These adverse reactions, 
which can be severe, may involve the gastrointestinal, skin, 
liver, endocrine, respiratory, renal, or other organ systems. 
The Sponsor has defined a list of potential irAEs which need 
to be reported as irAEs AESI in section 10.1.
Rationale for change
Correction of an error
Section to be changed
5.2.6.1.4 Adverse events of special interest (AESIs)
Description of change
Added:
The observation of the critical importance of altered liver 
function has been referred to informally as Hy’s Law, and 
is described in the FDA's guidance on drug induced liver 
injury. 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.
Rationale for change
Clarification


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Section to be changed
5.6.1
Immunogenicity testing
Description of change
After completion of the trial, pPlasma samples may be used 
for further methodological investigations, (e.g., stability 
testing.), Hhowever, only data related to the ADAs will be
generated by these additional investigations.
Rationale for change
The description was updated as methodological investigations 
using plasma samples may be performed before the 
completion of the trial.
Section to be changed
10.1
Immune-related adverse event of special interest
Description of change
Renal (report as AESI if an irAE is ≥ Grade 2)
∀
Nephritis
∀
Nephritis autoimmune
∀
Renal failure
∀
Renal failure acute
∀
Creatinine elevations (report as an irAEs AESI if ≥ 
Grade 3 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE)
Rationale for change
Correction of an error


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11.2
GLOBAL AMENDMENT 2
Date of amendment
09 Oct 2019
EudraCT number
EU number
Not applicable
BI Trial number
1379-0006
BI Investigational Medicinal 
Product(s)
BI 891065
BI 754091
Title of protocol
An open label, Phase I study of BI 891065 
monotherapy and combination therapy of BI 
891065 and BI 754091 in Asian patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
4.1.1
Identity of the Investigational Medicinal Products
Description of change
Table 4.1.1: 1 BI 891065
Unit strength: 5 mg, 20 mg, 50 mg, 100 mg tablets
Rationale for change
A new formulation, 100 mg tablets, became available.
Section to be changed
3.1
Overall trial design and plan
Description of change
*snip*
At any time in the trial, it will not be permitted to escalate to a 
dose which does not fulfil the EWOC principle (refer to 
section 5 7).
Rationale for change
Correction of error


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11.3
GLOBAL AMENDMENT 3
Date of amendment
23 Mar 2020
EudraCT number
EU number
Not applicable
BI Trial number
1379-0006
BI Investigational 
Medicinal Product(s)
BI 891065
BI 754091
Title of protocol
An open label, Phase I study of BI 891065 monotherapy and 
combination therapy of BI 891065 and BI 754091 in Asian 
patients with advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
General
Description of change
The originally planned dosing schedule of "once daily" was removed, and 
replaced with appropriate word depending on the context e.g., 400 mg per 
day once daily.
Rationale for change
BI decided to investigate b.i.d. dosing schedules that may potentially 
associated with better tolerability.
Section to be changed
Flow Chart
Description of change
Tumour biopsy was added in the flow chart table.
Following footnote was added:
n
The following tumour biopsies will be mandatory for all 
patients in Part B of the trial:
-
One fine needle biopsy must be freshly taken between 
screening and first trial drug treatment.
-
One fine needle biopsy from the same lesion on treatment as 
soon as possible after the 21-day observation period is 
completed and the patient has been on the uninterrupted and 
unchanged dose of BI 891065 for at least two continuous 
weeks. Biopsy collection should be delayed until these 
conditions are met. If it is absolutely impossible to obtain a 
biopsy from the same lesion, another lesion may be chosen.
Rationale for change
BI decided to test the cIAP1 degradation in tumour tissue in this trial, to 
reinforce the data obtained in preceding trial 1379-0001.
Section to be changed
Flow Chart
Description of change
The text in the flow chart table at "BI 891065 intake" was updated as 
follows:
Continuous daily dosing except for C1D2 in Part A
Continuous dosing of once or twice daily, with exceptions for PK 
assessment
Following footnote was added:
BI 891065 is taken either once daily (q.d.) or twice daily (b.i.d.), 
depending on the assigned treatment regimen. BI 891065 doses should 
be taken orally at approximately the same time each morning (and 
evening for patients with b.i.d. dosing). There are exceptions depending 
on the part (Part A or Part B) and dosing regimen (q.d. or b.i.d.):


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-
Part A q.d. dosing: a dose will be skipped on cycle 1 day 2
-
Part A b.i.d. dosing: following doses will be skipped in cycle 1 
– day 1 evening, day 2 morning and evening, and day 15 
evening
-
Part B q.d. dosing: no exceptions
-
Part B b.i.d. dosing: following doses will be skipped in cycle 1 
– day 1 evening and day 15 evening
Rationale for change
Q.d. and b.i.d. dosing schedules may be investigated. Exceptions of dosing 
schedule for PK are clarified per part per dosing schedule.
Section to be changed
Flow Chart
Description of change
Foot note h was updated:
[…] Urine samples are taken in Part A in once daily (q.d.) dosing 
schedule cohorts only.
Rationale for change
It is clarified that the urine PK is not required in b.i.d. dosing schedule 
cohorts.
Section to be changed
1.4.2
Risks
Description of change
Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy
Potential risks of 
clinical relevance for 
this trial
Summary of data, 
rationale for the risk
Mitigation strategy
[…]
Investigational Medicinal Product BI 754091
[…]
Infusion related 
reactions
As with any mAb, 
hypersensitivity 
reactions to study 
medication 
administration are 
possible and they are 
potentially severe.
Patients with history 
of severe 
hypersensitivity 
reactions to other 
mAbs are excluded. 
Recommendations 
for the management 
of infusion related 
reactions are given in 
this section 5.2.6.1.4.
[…]
Trial procedures
No trial specific risks are expected in relation to the trial procedures, as 
blood samplings and imaging examinations are routinely performed in 
this patient population. Frequency of blood sampling or radiation 
exposure from tumour imaging are considered to be slightly higher than 
that of routine clinical practice, but are kept as necessary minimum to 
ensure patients' safety and appropriate assessment of efficacy.
Tumour biopsy 
related AEs (Part B 
only)
Tumour biopsies are 
mandatory in Part 
B. There are known 
risks associated with 
biopsies such as pain 
or bleeding.
The risks are clearly 
explained in the 
informed consent 
document.


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[…]
Rationale for change
An error in the cross-reference in the mitigation strategy for infusion 
related reaction was corrected. Risks associated with biopsy were added 
with the mitigation strategy.
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
3.1
Overall trial design and plan
Description of change
After the completion of dose escalation in Part A (i.e., the MTD is reached 
or the safety in the highest dose is confirmed), Part B will commence and 
In Part B, successive cohorts of patients will receive escalating daily dose 
of BI 891065 in combination with a fixed dose of BI 754091 at 240 mg 
once every 3 weeks. The planned starting dose of BI 891065 in Part B is 
200 mg, and this cohort will commence after the safety of the same dose 
level in Part A is confirmed. but oOther doses may be investigated 
depending on the safety data obtained from Part A and from the preceding 
first-in-human trial (1379-0001).
Rationale for change
The completion of Part A is no longer a prerequisite to commence Part B.
Section to be changed
3.3.2
Inclusion criteria
Description of change
Added:
8.
For Part B: Patients must have at least 1 tumour lesion amenable 
to biopsy, and must be willing to undergo a biopsy prior to first 
treatment and after 3 weeks while on therapy.
9.
For Part B: Patients with following cancer types: bladder, colon, 
breast, NSCLC, ovarian, pancreatic, renal, esophagogastric, 
sarcoma, prostate, and melanoma.
Rationale for change
BI decided to test the cIAP1 degradation in tumour tissue in this trial, to 
reinforce the data obtained in preceding trial 1379-0001. The inclusion had 
to be limited to the cancer types specified in here, as the 
immunohistochemistry test for cIAP1 degradation is only validated in these 
cancer types.
Section to be changed
3.3.3
Exclusion criteria
Description of change
10.
Any of the following cardiac criteria
[…]


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
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 
with known or possible risk of to prolong the QT interval 
prolongation
Rationale for change
The cardiac risk exclusion criteria has been clarified.
Section to be changed
3.3.4.1
Discontinuation of trial treatment
Description of change
Following criteria for patient replacement was added:
•
Patients who have reduced BI 891065 dose level during the first 
treatment cycle, unless they develop a DLT
•
(Part B only) Patients who have received less than 50% of the BI 
754091 initial dose, unless they develop a DLT
Following criterion for patient replacement was modified:
•
Patient who misses ≥7 >5 doses of BI 891065 during the first 
treatment cycle for reasons other than treatment-related AEs and who 
does not experience DLTs
Rationale for change
To align the condition with the preceding trial 1379-0001.
Section to be changed
4.1.2.1
Starting dose of BI 891065
Description of change
It was clarified that twice daily dosing will be investigated in Part A and 
Part B.
The following sentence was added:
Twice daily dosing will be explored, aiming to reduce peak plasma 
concentrations compared to single dosing of the same daily dose, which 
may reduce occurrences of bilirubin increase, and may allow for better 
tolerability of similar total daily doses compared to once daily dosing, 
and potentially higher daily doses.
Rationale for change
The reason for investigating the twice daily dosing was provided.
Section to be changed
4.1.3
Dose-finding scheme
Description of change
Table 4.1.3: 1 Example of dose escalation in Part A
Dose level
Proposed daily dose
of BI 891065*
Participating 
countries
1
100 mg
Japan
2
200 mg**
Japan
3
400 mg**
Japan and Taiwan
*The total daily dose will be given in q.d. or b.i.d. dosing schedule.
**Actual dose level and dosing schedule assignment for a cohort will be 
communicated separately as determined by the SMC. Intermediate or lower 
dose level(s) may be investigated depending on the latest DLT rate 
estimate.
Table 4.1.3: 2 Example of dose escalation in Part B
Dose 
level
Proposed daily 
dose of 
BI 891065*
Proposed dose of 
BI 754091 (every 
three weeks)
Participating 
countries


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1
200 mg**
240 mg
Japan and Taiwan
2
400 mg**
240 mg
Japan and Taiwan
*The total daily dose will be given in q.d. or b.i.d. dosing schedule.
**Actual dose level and dosing schedule assignment for a cohort will be 
communicated separately as determined by the SMC. Intermediate or lower 
dose level(s) may be investigated depending on the latest DLT rate 
estimate.
Rationale for change
q.d. and b.i.d. dosing schedules may be investigated. The dosing schedule 
will be determined by SMC and be communicated to the investigators.
Section to be changed
4.1.5.1
Administration of BI 891065
Description of change
[…]
BI 891065 doses should be taken orally at approximately the same time 
each morning. The exception to this is Part A Cycle 1 Day 2 where study 
drug is not taken. BI 891065 is taken either q.d. or b.i.d., depending on 
the assigned treatment regimen. Refer to Flow Chart for exceptions of 
dosing schedule where study drug is skipped.
Patients will be asked to fast overnight (minimum of 10 hours) prior to the 
morning dose on the following intensive PK days:
Rationale for change
q.d. and b.i.d. dosing schedules may be investigated. Exceptions of dosing 
schedule for PK are clarified per part per dosing schedule in the Flow 
Chart.
Section to be changed
4.1.6
Dose modifications (pause, delay, dose reduction, and 
discontinuation)
Description of change
The description was updated as follows:
As a general rule, related AEs of ≥ Grade 2 deemed intolerable by the 
patient or the treating physician and not responding to appropriate medical 
management and any AEs of ≥ Grade 3 will result in a pause of treatment 
with BI 891065 (in Part A) and with BI 891065 and BI 754091 (Part B) 
until resolution to baseline or Grade 1. When the administration of BI
754091 is delayed in Part B, the start of the cycle is also delayed and the 
date of BI 754091 administration is always considered Day 1/Visit 1 of the 
cycle.
If the treatment pause is ≤12 weeks, the patient can be re exposed to BI 
891065 at one dose level lower than the dose administered before the pause 
(except for patients who are receiving the lowest dose allowed) according 
to Table 4.1.6: 1 and Table 4.1.6: 2, and the same fixed dose of BI 754091 
as long as the re exposure is considered clinically indicated by the 
Investigator.
In case the treatment has been paused for reasons other than related AEs, 
the dose of BI 891065 at the re exposure should be the same as before.
AEs that are immune related should be managed according to the 
Guidelines for irAE management (as outlined in Appendix 10.2). 
For Grade 4 AE/SAEs that are not immune related, study drug should 
be withdrawn. However, if it can be excluded with high certainty that 
the event was related to study medication, study drug should be 
paused, and resumption of study drug may be allowed after discussion 
with the Sponsor.


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For Grade 3 AE/SAEs that are not immune related, study drug should 
be paused. 
For Grade 2 AEs/SAEs that are not immune related but are deemed 
intolerable by the patient or the treating physician and not responding 
to appropriate medical management, the physician should decide if a 
pause of treatment is warranted considering relevant variables such as 
perceived relatedness to study drug.  
If, after a treatment pause of ≤12 weeks, the non-immune related 
SAE/AE resolves to baseline or Grade 1 and the physician thinks it is 
clinically appropriate to restart study drug, then the physician may 
choose to restart BI 891065 at one dose lower than the dose 
administered before the pause (except for patients who are receiving 
the lowest dose allowed) according to Table 4.1.6: 1 and Table 4.1.6: 2, 
and BI 754091 at the same fixed dose of BI 754091. Up to two dose 
reductions of BI 891065 are allowed per patient. If the AE/SAE 
prompting interruption has unequivocally been excluded to be drug 
related, reintroduction of BI 891065 at the same dose as prior to the 
pause may be considered.
There will be no dose reductions or escalations of BI 754091 in any one 
patient.  However, in the event of an infusion-related reaction ≤ 
Grade 2, the infusion rate of BI 754091 may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing 
infusion-related reactions ≤ Grade 2, subsequent infusions may be 
administered at 50% of the initial rate. If an infusion-related reaction 
is Grade 3 or higher in severity at any point during the study, 
treatment with BI 891065 and BI 754091 will be permanently 
discontinued.
As a general rule for Part B, both drugs (BI 891065 and BI 754091) will 
be stopped, paused, or re-exposed together. Exemptions have to be 
justified and aligned with the Sponsor in writing.
Table 4.1.6: 1
Dose reduction recommendations for BI 891065 in 
Part A q.d. dosing (up to two dose reductions are allowed per patient)
BI 891065 dose before the 
pause
BI 891065 dose at restart
400 mg
200 mg
200 mg
100 mg
100 mg
50 mg (lowest dose allowed)
Table 4.1.6: 2
Dose reduction recommendations for BI 891065 in 
Part B b.i.d. dosing
BI 891065 dose before the 
pause
BI 891065 dose at restart
400 mg
200 mg
200 mg x 2
100 mg x 2
100 mg x 2
50 mg x 2 (lowest dose allowed)


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50 mg
25 mg (lowest dose allowed)
Grade ≥3 infusion related reactions was added in the list of AEs that 
need permanent discontinuation of the study treatment.
Rationale for change
Dose reductions and dose delay text was clarified and aligned with the 
other edits made to the trial protocol.
Section to be changed
4.1.7
Dose limiting toxicities
Description of change
A criterion of non-haematological toxicities was updated
∀
Any AEs that require dose reduction or treatment discontinuation 
according to section 4.1.6 will be assessed by SMC and may be 
considered as DLTs unless the SMC considers the dose reduction 
as not strictly medically warranted
∀
Permanent treatment discontinuation according to section 4.1.6
Rationale for change
To align the condition with the preceding trial 1379-0001.
Section to be changed
5.2.2
Vital signs
Description of change
Vital signs will be evaluated at the time points specified in the flowchart, 
prior to blood sampling, or after a sufficient period of rest (usually 5 
minutes is sufficient, but a longer rest may be required if there are any 
problems at the blood sampling).
Rationale for change
Conditions to assess vital signs were clarified.
Section to be changed
5.2.3.2
Biochemistry
Description of change
The standard biochemistry panel will consist of glucose (serum or plasma), 
sodium, potassium, chloride, calcium, phosphate, urea, serum creatinine 
(measured by enzymatic assay, Isotope dilution mass spectroscopy [IDMS] 
standardised Jaffe assay, or non-IDMS Jaffe assay), AST, ALT, alkaline 
phosphatase, lactate dehydrogenase, gamma glutamyl transferase,
bilirubin (total, direct, and indirect bilirubin), haptoglobin, total protein, 
albumin, urea or urea nitrogen, uric acid and creatine kinase (CK). If CK is 
elevated, then CK-MB [cardiac], Troponin (either I or T), and myoglobin 
should be reactively tested.
Rationale for change
Gamma glutamyl transferase was added to investigate the mechanism of 
bilirubin elevation. It is clarified that urea and urea nitrogen are 
interchangeable and testing either one of them based on the availability at 
the local lab is sufficient.
Section to be changed
5.2.6.2.3 Pregnancy
Description of change
The following paragraph was added:
Similarly, potential drug exposure during pregnancy must be reported 
if a partner of a male trial participant becomes pregnant. This requires 
a written consent of the pregnant partner. Reporting and consenting 
must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
Rationale for change
To update information on pregnant partner with current template.
Section to be changed
5.3.1
Assessment of pharmacokinetics
Description of change
Date and clock times of PK sampling will be recorded in the CRFs, and the 
following information should be collected in the eCRF for the last 4 days
administrations prior to PK sampling and on the day of PK sampling for 
BI 891065:


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1.
Date and clock times of drug administration
2.
Information with respect to food intake (date and time) in case the 
patient takes the drug after breakfast meals
3.
If vomiting or diarrhoea occurs within 3 hours after drug 
administration, the time of the onset of the episode(s)
Rationale for change
Requirements were adjusted to allow the PK assessment in both q.d. and 
b.i.d. dosing schedule.
Section to be changed
Description of change
Rationale for change
Section to be changed
7.1
STATISTICAL DESIGN – MODEL
Description of change
Descriptions of BI 891065 doses in section 7.1 tables were updated to 
clarify whether they are q.d. or b.i.d.
Rationale for change
Clarification
Section to be changed
7.1.1
Part A
Description of change
Added:
The BLRM is set up for a fixed dosing schedule of once daily (q.d.) 
across dose levels of BI 891065. For the purpose of dose-toxicity 
modelling, a b.i.d. regimen will be converted in the BLRM to an 
equivalent q.d. regimen that has a similar Cmax at steady state, based 
on the assumption that safety events are triggered by Cmax at steady 
state. For example, the 200 mg b.i.d. regimen will be modelled as 
equivalent to a 300 mg q.d regimen in reference to the simulation 
results from trial 1379-0001. For any other b.i.d. doses considered, 
their conversions will be specified in the TSAP. If multiple b.i.d. doses 
are tested, appropriate modifications to the BLRM to account for the 
heterogeneity of different dosing schedules might be considered. 
Details will be specified in the TSAP if needed.
Rationale for change
Methods of using BLRM in b.i.d. dosing were clarified.
Section to be changed
7.1.2
Part B
Description of change
The BLRM is set up for a fixed dosing schedule of once daily (q.d.) 
across dose levels of BI 891065. For the purpose of dose-toxicity 
modelling, a b.i.d. regimen will be converted in the BLRM to an 
equivalent q.d. regimen that has a similar Cmax at steady state, based 
on the assumption that safety events are triggered by Cmax at steady 
state. For example, the 200 mg b.i.d. regimen will be modelled as 
equivalent to a 300 mg q.d regimen in reference to the simulation 
results from trial 1379-0001. For any other b.i.d. doses considered, 
their conversions will be specified in the TSAP. If multiple b.i.d. doses 
are tested, appropriate modifications to the BLRM to account for the 
heterogeneity of different dosing schedules might be considered. 
Details will be specified in the TSAP if needed.


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Rationale for change
Methods of using BLRM in b.i.d. dosing were clarified.


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11.4
GLOBAL AMENDMENT 4
Date of amendment
30 Apr 2021
EudraCT number
EU number
Not applicable
BI Trial number
1379-0006
BI Investigational 
Medicinal Product(s)
BI 891065
BI 754091
Title of protocol
An open label, Phase I study of BI 891065 monotherapy and 
combination therapy of BI 891065 and BI 754091 in Asian 
patients with advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Flowchart footnote and sections 6.2.3.5 and 10.3.
Description of change
Descriptions to reduce the required study procedures and data collections 
were added.
Rationale for change
The assessments of primary and secondary endpoints have been completed, 
and sufficient data have been collected for further endpoint by an interim 
DBL on 29 Mar 2021. The CTR will be prepared based on the data locked 
at this interim DBL. As of April 2021, one patient is still receiving the 
study treatment as per the protocol, but further data collection is no longer 
needed for the analysis. Therefore, the data to be collected will be reduced 
to a necessary minimum. The assessments will be performed as medically 
indicated to monitor the safety at the discretion of the investigator, and the 
results will be documented in the source data but will not be collected in 
the eCRF except for AE/SAE and the information about the treatment 
continuation and study termination.
Section to be changed
Section 5.4.4
Description of change
A statement was added that the genotyping analysis was cancelled.
Rationale for change
Based on the clinical outcome, the sponsor concluded that the genotyping 
analysis would not result in gaining additional supportive information.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
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SAP_001.pdf: 
 
TRIAL STATISTICAL ANALYSIS PLAN
c33486288-01
BI Trial No.:
1379.6
Title:
An open label, Phase I study of BI 891065 monotherapy and 
combination therapy of BI 891065 and BI 754091 in Asian 
patients with advanced solid tumours 
Including Protocol Amendments 1, 2 and 3 (c27190653-04)
Investigational
Product(s):
BI 891065 + BI 754091
Responsible trial 
statistician(s):
Phone: +
Date of statistical 
analysis plan:
18 MAR 2021 SIGNED
Version:
Final
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! 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
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 ..........................................................14
6.1
TREATMENT(S)................................................................................................14
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY ENDPOINT(S) ................................................................................21
7.4.1
Primary analysis of the primary endpoint(s) ...................................................21
7.5
SECONDARY ENDPOINT(S) ..........................................................................22
7.5.1
Key secondary endpoint(s).................................................................................22
7.5.1.1
Primary analysis of the key secondary endpoint(s) ..............................................22
7.5.2
(Other) Secondary endpoint(s) ..........................................................................22
7.7
EXTENT OF EXPOSURE.................................................................................23
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data ..................................................................................................24


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7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................30
8.
REFERENCES....................................................................................................31
10.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.2: 1
Handling of iPDs..............................................................................................15
Table 6.6: 1    Interpretation of qualitative ECG findings .......................................................18
Table 6.7: 1 
Nominal time points and windows for imaging...............................................19
Table 7.8.2: 1 Primary laboratory tests....................................................................................25
Table 7.8.2: 2 Secondary laboratory tests................................................................................25
Table 7.8.2: 3 Conversion of urine measurements based on dipsticks....................................26
Table 7.8.4: 1 Maximum acceptable time deviations between PK sample and ECG 
recording...........................................................................................................29
Table 10: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug Antibody
AE
Adverse Event
AESI
AGP
ALT
ANC
aPTT
Adverse Event of Special Interest
Alpha-1 Acid Glycoprotein
Alanine Aminotransferase
Absolute Neutrophil Count
Activated Partial Thromboplastin Time
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
cIAP
Cellular Inhibitor of Apoptosis
CR
Complete Response
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug-induced Liver Injury
DLT
Dose-limiting Toxicity
ECG
Electrocardiogram
ECGPCS
Electrocardiogram Pharmacokinetic Concentration Set
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ES
Enrolled Set
HR
Heart Rate
ICH
International Conference on Harmonization
iCPD
Immune Confirmed Progressive Disease
iCR
Immune Complete Response
iPR
Immune Partial Response
iPD
Important Protocol Deviations
iRECIST
modified RECIST 1.1 for immune-based therapeutics


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iSD
Immune Stable Disease
iUPD
Immune Unconfirmed Progressive Disease
MedDRA
Medical Dictionary for Regulatory Activities
msec
milliseconds
MTD
Maximum Tolerated Dose
NSCLC
Non-small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
PBMCs
Peripheral Blood Mononuclear cells
PD
Progressive Disease
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
PR
Partial Response
PR interval
ECG interval from the onset of the P wave to the beginning of the QRS 
complex
PT
Preferred Term
QRS
Combination of the Q, R and S waves
QT
ECG interval from the beginning of the QRS complex to the end of the T 
wave
QTc
Generic term for QTcF and QTcB intervals
QTcB
QT interval, corrected by Bazett’s formula
QTcF
QT interval, corrected by Fridericia’s formula
RECIST
Response Evaluation Criteria In Solid Tumours
REP
Residual Effect Period
SCR
Screened Set
SD
SMAC
SMC
Stable Disease
Second Mitochondrial Activator of Caspases
Safety Monitoring Committee
SOC
System Organ Class
StD
Standard Deviation
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO DD
World Health Organisation Drug Dictionary 


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3.
INTRODUCTION
As per International Conference on Harmonisation E9 (ICH E9) (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 Trial Statistical Analysis Plan (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, and definition of measurements and variables.
The study was planned as a multicentre study consisting of two study parts. Part A is an 
open-label, BI 891065 monotherapy dose-escalation. Part B was planned to be an open-label 
dose-escalation of BI 891065 in combination with a fixed dose of BI 754091. In June 2020, 
BI decided to cancel Part B. Consequently, this TSAP will describe the analysis of Part A 
only.
For the primary objective of Part A of the trial, refer to Section 2 of the CTP. 
This TSAP describes the analysis of all aspects of the trial. Analyses with regards to these 
will be described in a separate analysis plan and results will be reported in a separate report 
outside of the CTR. The measurements of the cytokine analyses will be included in the CTR 
and described in this TSAP.
In the following, study medication always refers to BI 891065 monotherapy.
SAS® Version 9.4 or higher will be used for all analyses besides pharmacokinetic (PK) 
analyses if not specified otherwise. Phoenix® WinNonlin® 8.1 will be used for PK analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in the CTP will be carried out. 


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Part A:
The primary endpoints for Part A of the trial are:
∀
Maximum tolerated dose (MTD)
∀
the number of patients with dose-limiting toxicities (DLTs) during the MTD 
evaluation period (first treatment cycle).
For definition of the MTD, refer to Section 2.1.1 of the CTP.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Part A:
∀
The pharmacokinetics (PK) parameters of BI 891065 will be calculated in cycle 1:
Cmax(ss), AUC0-24 and AUCτ,ss of BI 891065 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
In Part A of this Phase I trial, treatments are not randomized. Different dose levels and dose 
schedule of BI 891065 monotherapy are being administered.
The data will be presented only for Part A, because Part B was cancelled, as mentioned 
earlier. 
For safety summaries events that start from the first administration of any trial medication 
until 30 days (REP) after the last administration of any trial medication will be considered as 
having occurred “on-treatment”. If not specified otherwise, all safety tables will be based on 
the on-treatment period. Adverse events that have 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 defined as the period from 1st treatment 
administration (day 1) till day 21 inclusively. 
Labels of each treatment period, the labels used for displays in the tables and listings in the 
CTR, as well codes, decodes, sort order and labels for each trial medication are provided in 
the TSAP technical documents.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Important protocol deviations will be summarised. The IQRMP specifies the important 
protocol deviations in detail. The following table specifies the different categories of IPDs. 


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Table 6.2: 1
Handling of iPDs 
iPD code
iPD Category & Brief Description
Excluded from analysis set
A
In/Exclusion criteria not met
None
A1
Inclusion criteria not met
None
A2
Exclusion criteria not met
None
B
Informed consent not available/not 
done
B1
Informed consent not available/not 
done
All
B2
Informed consent too late
None
C
Trial medication and randomization 
violations
C1
Incorrect trial medication taken
None
C2
Administration not according to protocol
None
C3
Administration of study medication which 
exceeded the limit of in-use stability
None
D
Prohibited medication use
D1
Concomitant medication
None
E
Missing critical data
E1
Missing of Vital signs (BP, PR, BT and 
SpO2)
None
E2
Missing of 12-Lead ECG
None
E3
Missing of Safety laboratory parameters
None
E4
Important AE related data missing
None
6.3
SUBJECT SETS ANALYSED
The Screened Set (SCR) includes all patients who signed the informed consent form and will 
be used to summarise patient disposition.
The Enrolled Set (ES) includes all patients who have been enrolled into the study.
The Treated Set (TS) consists of all patients who have received at least one administration of 
trial medication and will be used for all planned safety, efficacy and biomarker analyses in 
the CTR besides the MTD determination.


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The MTD Evaluation Set includes all patients who were documented to have received at least 
one dose of trial medication and were considered evaluable for MTD evaluation. This set will 
be used for the primary analyses of DLTs and MTD determination.
Rules for replacement of patients are defined in CTP Section 3.3.4.1. The list of replaced 
patients will be stored in the trial master file. 
The Pharmacokinetic Parameter Set (PKS) consists of all patients in the TS who have at least 
one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability.
The ECG Set includes all patients in the treated set who do not have an artificial pacemaker 
and have at least one on-treatment value for at least one ECG variable.
6.5
POOLING OF CENTRES
This section is not applicable since there will be no inferential analyses. Thus, no statistical 
model in which centre or country is included as factor will be applied.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (4). Missing data and 
outliers of PK data are also handled according to BI standards (5). PK parameters that cannot 
be reasonably calculated based on the available drug concentration-time data will not be 
imputed. Potential outliers will be reported and analysed as observed. In general, missing data 
not discussed in (4) and (5) will not be imputed unless required for the following analyses 
and definitions. Then the rules as described below apply.
1) 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. 
2) 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


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∀
If only the year is given, the 31st of December of the given 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.
3) ECG analysis
Quantitative and derived categorical ECG endpoints
∀
If single cardiac cycles are missing, the arithmetic means per single ECG will 
be computed with the reduced (1, 2 or 3) number of cardiac cycles.
∀
If replicate ECG recordings are missing, the arithmetic means per time point 
will be computed with the reduced (1 or 2) number of recordings.
∀
If the actual times of all triplicate pre-dose ECG recordings on Day 1 or the 
time of the first drug administration are missing, or the planned pre-dose 
ECGs are recorded after the first drug administration, they will not be used as 
baseline values and will be excluded from the analyses.
∀
If baseline is missing, a QTcF/QT interval > 500 msec at any time on 
treatment will be a notable finding. 
Qualitative ECG findings
∀
In case a certain qualitative ECG finding is not reported at baseline but 
occurring on-treatment, this will be categorized as a ’new onset’ of this 
finding.
∀
For the analysis of overall ECG interpretation values (comparison of on-
treatment with baseline results), missing values will be handled as indicated in 
the following table.


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Table 6.6: 1 Interpretation of qualitative ECG findings
Condition: Overall ECG interpretation
Aggregated 
result presented 
in Table
At baseline
On treatment
(specific time interval under consideration)
Overall ECG 
interpretation
Normal, 
abnormal or 
missing/not 
evaluable
Normal (all time points)
Normal
Abnormal
Abnormal (at least one time point)
Abnormal, and 
abnormal at 
baseline
Normal or 
missing/not 
evaluable
Abnormal (at least one time point)
Abnormal 
(new onset) 
Normal, 
abnormal or 
missing/ not 
evaluable
Missing/not evaluable (at least one time point), normal 
or missing/not evaluable at the other time points
Missing/not 
evaluable
Exposure-response analysis
∀
Missing BI 891065 plasma concentration data which are identified by “BLQ” 
in the comment field (below lower limit of quantification) will be replaced by 
½ LLOQ (lower limit of quantification) if measured on-treatment.
4) Biomarker and pharmacodynamic analysis
Cytokines: For cytokines, we impute BLQ values with ½ LLOQ . 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flowchart in the CTP. 
Unless otherwise specified baseline is defined as the time point closest to but prior to the first 
administration of 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 


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is no measurement earlier than the first administration of study medication, then no baseline 
will be derived.
Laboratory values: 
Baseline is defined as the latest time point before the very first administration of study 
medication. For laboratories where not only the examination date but also time are recorded, 
examination time has to be taken into account when defining baseline. That is, a laboratory 
value on the same date as the first administration of study medication is considered as 
baseline value only if the time of laboratory assessment is before or the same as the time of 
first study drug administration.
If any of these times is missing and the date of laboratory assessment is equal to the date of 
first administration of study medication, then the laboratory assessment will be considered as 
according to protocol, i.e. as prior to first study medication.
Imaging time windows:
In order to identify whether consecutive imaging time points are missing for a given patient, a 
nominal time point (6, 12, … weeks etc.) will be assigned to each and every image. This is 
achieved by creating windows for every radiological response assessment. These windows 
are defined in Table 6.7: 1.
Table 6.7: 1
Nominal time points and windows for imaging
Nominal time point 
(weeks from start of 
study medication)
Planned date of scans 
(relative day*)
Window (days)
6
43
1 to ≤64
12
85
65 to ≤106
18
127
107 to ≤148
24
169
149 to ≤200
33
232
201 to ≤263 
42
295
264 to ≤326
51
358
327 to ≤389
Etc., 9 week interval
Etc.
Etc.
* the date of the first dose of study medication is Day 1
If a patient does not have an image in one of the windows described above, he/she will be 
said to have missed an assessment for that time point.
ECG analysis: 
Baseline values will be derived from the 1-3 triplicate ECG recordings prior to the first drug 
administration on Day 1 (refer to Section 7.8.4).


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7.
PLANNED ANALYSIS
The labelling and display format of statistical parameters will follow the BI guideline (8).
All analyses are presented only for Part A, as Part B was cancelled.
For End-of-Text 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, StD, Min and Max.
For time-to-event analysis tables the set of statistics is: number of patients [N(%)], number of 
patients with event [N(%)], <time to event> [months] followed by P25 (25th percentile), 
median, P75 (75th percentile) and number of patients censored [N(%)]. If not specified 
otherwise the duration as well as the time to event will be displayed in months.
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 treatment group (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. The 
denominator of the main categories is defined by the number of patients in the used patient 
set. The main categories define the denominators of the subcategories. Subcategories should 
be intended and “[N(%)]” will be displayed only for the main category. If a table includes 
only categorical data, “[N(%)]” is to be displayed in the column header.
Sort order for general categorical variables: If categories correspond to the collected 
categories on 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. 
categorised 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
Descriptive statistics are planned for demographic characteristics, disease history, prior 
therapies, medical history, alcohol and tobacco use, baseline eastern cooperative oncology 
group (ECOG) performance status, and baseline disease assessment.


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7.2
CONCOMITANT DISEASES AND MEDICATION
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 categorise CTs by therapy type. In situations where a medical 
product may be used for more than one equally important indications, there are often several 
classification alternatives. As appropriate, patients receiving CTs with more than one possible 
ATC level 3 categories will be counted more than once. Footnotes will clarify this possible 
double counting in tables.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be listed in the appendix of the CTR. In general, the amount of 
and time for which BI 891065 is taken will be interpreted in light of treatment exposure, 
efficacy, and safety. Refer to Section 5.4.2 and Section 7.7 for further details on exposure 
analysis.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary endpoints of Part A are the MTD of BI 891065 and the number of patients with 
DLTs in the first treatment cycle. The number of patients with DLTs at each dose level will 
be presented for the first cycle for the MTD evaluation set and for the whole on-treatment 
period for the treated set separately.
The MTD will be determined by the SMC using recommendations from a Bayesian logistic 
regression model (BLRM, see CTP Section 7 for details on the model and on the prior). 
BLRM evaluations for the CTR will be performed once using the number of patients with 
DLTs during the first cycle from the MTD evaluation set and once using the number of 
patients with DLTs during the whole on-treatment period from the treated set.
Tables and bar charts displaying the posterior probabilities of the true DLT rates being in 
either the underdosing interval, the targeted toxicity interval or the over toxicity interval will 
be produced.   


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Not applicable as no key secondary endpoints have been defined in the CTP.
7.5.1.1
Primary analysis of the key secondary endpoint(s)
NA
7.5.2
(Other) Secondary endpoint(s)
Part A: 
PK endpoints will be analysed descriptively as well. Plasma (and urine) concentrations of BI 
891065 will be plotted against time. The calculation of the PK parameters, as well as the 
descriptive and comparative analysis of the PK parameters, will be based on the methods 
outlined in Section 7.3.1.2 of the CTP, as well as in (9). 


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7.7
EXTENT OF EXPOSURE
For Part A, duration of BI 891065 intake will be summarised descriptively. The number of 
patients with at least one dose reduction of BI 891065 will be displayed descriptively, and 
the time to first dose reduction of BI 891065 will be analysed descriptively as well using 
Kaplan-Meier methods based on the treated set. Patients who discontinue BI 891065 without 
a dose reduction will be censored at the date of the last BI 891065 intake for this analysis. 
Furthermore, dose intensity of BI 891065 will be calculated.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS, besides the analyses of MTD determination. 
These will be performed on the MTD evaluation set. 
7.8.1
Adverse Events
The analyses of AEs will be descriptive in nature. All analyses will be based on the number 
of patients with AEs (not on the number of AEs). The analysis will be based on BI standards 
(6). AEs will be coded using the most recent version of MedDRA. According to the BI 
standards multiple overlapping or adjacent recordings (AE occurrences) of the same AE are 
collapsed into one AE event if all AE attributes are identical (lower level term, severity, 
action taken, therapy required, seriousness, reason for seriousness, relationship, outcome, AE 
of special interest (AESI) flag).
The analyses of AEs will be based on the concept of treatment-emergent AEs, where a 
treatment-emergent AE has an onset in the analysing treatment period. The AE analysis will 
be based on the on-treatment period which starts with the date of the first administration of 
study medication and ends 30 days after the last administration of study medication. AEs 
with an onset date in the screening period (time between informed consent date and date of 
the first administration of study medication) or follow-up period (time after the on-treatment 
period) will be tabulated and listed separately.
Sorting order: In AE tables, system organ classes (SOCs) will be sorted alphabetically and 
preferred terms (PTs, within SOCs) will be sorted by descending frequency.
Listings of AEs will be displayed by patient. The actual planned dose of BI 891065 will be 
derived and included in the listings. AEs will be reported with start day and end day as 
calculated from the first day of treatment with study 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. 
The incidence of AEs overall, related AEs and serious AEs (SAEs) will be reported by 
severity according to common terminology criteria for adverse events (CTCAE) grades.
Drug-related serious AEs will also be tabulated. Protocol-specified AESI will be analysed 
based on data reported in the eCRF.


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AEs leading to death during the on-treatment period will be tabulated by SOC and PT. 
Reported fatal AEs during the follow-up period will be listed. 
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
of BI 891065 or permanent discontinuation of study medication. Their incidence will be 
reported by severity according to CTCAE grades. A listing of patients who developed other 
significant AEs will be provided and a flag for serious and non-serious will be included. In 
addition, AEs leading to treatment interruption will be reported by severity according to 
CTCAE grades. 
7.8.2
Laboratory data
The analysis of laboratory data will be descriptive in nature and will be based on BI standards 
(7). The same on-treatment period as considered for the analysis of adverse events will be 
applied for laboratory values. Patients having at least one post-baseline laboratory value will 
be displayed in the descriptive analyses. Patients with missing CTCAE grade at baseline or 
no baseline value but with post-baseline values will be displayed in a new category “missing 
CTCAE grade at baseline” for those laboratory parameters where CTCAE grading is 
applicable. Descriptive statistics, including change from baseline and frequency of patients 
with transitions relative to the reference range, will be provided. CTCAE grades for 
applicable laboratory parameters will be calculated according to CTCAE v5.0.
For Primary laboratory tests listed in Table 7.8.2: 1, the following outputs will be presented:
∀
Descriptive statistics, including changes from baseline
∀
Shift tables in terms of:
o
CTCAE grade, for laboratory tests with CTCAE grade defined;
o
Upper and lower reference limits, for laboratory tests without CTCAE grades;
o
Multiples of upper reference limit for customized shift tables of ALP, ALT, 
AST, total bilirubin and creatinine.
∀
Frequency of patients with potential clinically significant abnormalities. 
For secondary laboratory tests listed in Table 7.8.2: 2, analyses will be limited to frequency 
of patients with potential clinically significant abnormalities.
For other laboratory tests, only listing of observed values will be presented.
Analyse of descriptive statistics should use normalized lab values. Analyses of frequencies of 
patients with potential clinical significance, analyses of shift, and liver function categories 
tables should use converted values.


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Table 7.8.2: 1 Primary laboratory tests
Table 7.8.2: 2 Secondary laboratory tests
Label
Lab test name
Direction 
of interest
Potential Clinical significance 
rule
ALB
Albumin
Low
A1
APTT
Activated Prothrombin Time
High
A1,2
CA
Calcium
Low, High
A1
CL
Chloride
Low, High
Low: <80 mmol/L and <baseline 
High: >120 mmol/L and 
>baseline 
No CTCAE defined
EOS
Eosinophils
High
>1.0*10^9/L and > baseline
No CTCAE defined
GGT
Gamma Glutamyl 
transferase
High
CTCAE Grade 2 or higher
PHOS
Phosphate
Low, High
High: >1.7 mmol/L and 
>baseline
Low: <0.7 mmol/L and 
<baseline
No CTCAE defined
PROT
Serum Protein
High
>ULN and >baseline 
No CTCAE defined
PT
Prothrombin Time
High
>ULN and > baseline
No CTCAE defined
URIC
Uric Acid
High
Females: >600 umol/L and 
>baseline
Males: >650 umol/L and 
>baseline
CTCAE based upon AE
1A= CTCAE grade 2 or greater with an increase of at least one CTCAE grade from baseline
2CTCAE grading will not consider symptoms presence of bleeding or use of anticoagulation. 
Worst laboratory value and its CTCAE grade (highest CTCAE grade) over all courses will be 
calculated for each laboratory parameter. 
The last laboratory value on treatment is the laboratory value of the last visit during the on-
treatment period of each patient. 
Laboratory values without CTCAE grading will be compared to their reference ranges and 
frequency tables will be provided for the number of patients within and outside the reference 
range at baseline, for the maximum value on treatment and for the last measurement on 
treatment.
Differential blood count:


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Differential blood counts were to be measured in absolute values according to the CTP. In 
case a subject’s differential blood count is reported in percentage, the following conversion 
will be applied:
Differential [10^9/L] = Differential [%] * (White blood cell count value / 100) 
The corresponding reference ranges of the converted differential blood values are not allowed 
to be converted like the individual laboratory measurements. The reference range is taken 
from the BI standard reference range definition.
Urine analysis based on dipstick: 
To ensure medically rational and consistent BI internal handling of urine laboratory values 
assessed by dipstick only, no analyses based on CTCAE grades will be done for urine. For 
urine measurement based on dipsticks the indicated results will be converted as described in 
Table 7.8.2: 3 for the analysis and displayed in the urine analysis tables.
Table 7.8.2: 3 Conversion of urine measurements based on dipsticks
Original dipstick measurement
Converted dipstick measurement
“-” ; “NEG” ; “NEGATIVE” ; “NORMAL”
0.0
“0.5” ; “TRACES” ; “TRACE” ; “+/-” ; “+-” ; “-/+”
0.5
“+” ; “1+”; “SMALL”      
1.0
“++” ; “2+”; “MODERATE”   
2.0
“+++” ; “3+”; “LARGE”     
3.0
“++++” ; “4+”    
4.0
Handling of CTCAE grade -1 and -9 laboratory parameters:
Generally, in case only one direction of worsening (high or low laboratory value) is specified 
in the CTCAE document, there is no need to examine the other direction. Therefore, for 
calculating the change in CTCAE grade, patients with a CTCAE grade of -9 (no CTCAE 
grade defined) will be automatically treated as CTCAE grade 0 for all analyses. In laboratory 
listings, the CTCAE grade will be displayed as -9.
There are certain parameters for which CTCAE grades can only be attributed by taking 
physiological consequences into account. These laboratory values will be coded as -1. As 
these definitions aggregate laboratory data and adverse events or concomitant therapies no 
analyses based on CTCAE grades will be done. Instead standard laboratory analyses as for 
laboratory parameters without CTCAE grade definitions will be done. Nevertheless, a 
laboratory listing including -1 values will be added to the CTR.
Corrected calcium:
The grading of hypocalcemia 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.


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Corrected calcium can be only derived at a certain time points 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. The events can occur in any order, but must occur within 14 days of the 
previous event, i.e. the second event must occur within 14 days of the first event, and the 
third event must occur within 14 days of the second event, etc. Patients with missing 
laboratory values for liver enzymes will be excluded from these analyses, but presented 
separately.
Tabulations of hepatic enzyme elevations and liver laboratory values will be done according 
to the FDA Drug Induced Liver Injury (DILI) guidance (10).
Hepatic enzyme elevations will be displayed for the treated set for the whole on-treatment 
period. 
7.8.3
Vital signs
Descriptive statistics are planned for the analysis of vital signs.
7.8.4
ECG
For Part A, analyses of ECG will be descriptive in nature. Newly emergent abnormalities will 
be recorded and analysed as adverse events. CTCAE Version 5.0 will be used for those ECG 
variables.
In addition, statistical ECG analyses will be performed for the centrally evaluated digital 
ECG recordings as follows.
Derivation of ECG variables
Three replicate digital ECG recordings will be collected as specified in the flowchart of the 
CTP. Each of the three recorded single ECGs will then be evaluated semi-automatically for 
cardiac intervals, which comprise the RR, PR and QT interval and the QRS complex.
Measurements of these intervals will be made on four (possibly consecutive) cardiac cycles 
from the lead chosen (usually lead II). The measurements of the cardiac cycles will be stored 
in the database, i.e. usually 12 values per time point. The four cardiac cycles will be averaged 
prior to the calculation of the heart rate and heart rate corrected QT intervals (QTc).
The heart rate will be derived from the RR interval as 
HR [beats/min] = 60000/RR [msec]


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Heart rate corrected QT intervals (generally denoted by QTc) will be calculated using 
Fridericia’s (QTcF) formula and Bazett’s formula (QTcB):
∀
QTcF [msec] = (1000/RR)^(1/3) * QT [msec]
∀
QTcB [msec] = (1000/RR)^(1/2) * QT [msec]
Further aggregation of the three replicate ECG intervals and HR at each scheduled time point 
will then be performed using arithmetic means. Additional averaging over 3 time points will 
be performed to derive the baseline values: they will be calculated as the mean values of the 3 
triplicate ECG recordings collected pre-dose on Day 1.These mean values will be used for the 
derivation of the ECG variables as they are specified in Section 5.4.3.
ECG analyses
For all ECG variables, listings of individual data will be shown in the appendix of the CTR. 
Absolute values and changes from baseline in QTcB interval as well as the percentage 
changes for PR interval and QRS complex will only be displayed in listings. 
Absolute values and changes from baseline in QTcF interval, QT interval, HR, PR interval, 
and QRS complex will be summarised descriptively by treatment, cycle, day, and time point 
using the ECG set. The time profiles of mean and standard deviation for the absolute values 
and changes from baseline on treatment will be displayed graphically by treatment.
Frequency tables will be provided for all categorical variables including notable findings and 
qualitative ECG findings. The tables will be presented separately for the visit days where an 
ECG profile has been taken as well as for the overall on-treatment period using the maximum 
value per patient. Frequencies of the increases in QTcF and QT intervals above thresholds as 
defined in Section 5.4.3 between baseline and on-treatment will be displayed in two-way shift 
tables by treatment. Frequency tables with regard to the new onset of qualitative 
(morphological) ECG findings will display categories of grouped findings based on the 
CDISC (EGTEST) terminology as well as the frequencies per each observed type of finding. 
These descriptive analyses will be performed for patients in the ECG Set for Part A.
For all patients with any notable finding (see Section 5.4.3), a separate listing in Section 15 of 
the CTR will be created and the corresponding time profiles will be shown. Notable findings 
of patients in the TS who are excluded from the ECG Set will be listed in separate listings.
Exposure-response analysis
All exposure-response analyses will be based on the ECGPCS. The decision whether plasma 
concentration values, which are excluded from the descriptive PK analyses, are to be 
excluded from the exposure-response analysis as well, is to be made no later than at the RPM 
before data base lock. Pairs of BI 891065 plasma concentrations and QTcF changes from 
baseline that are not time-matched (i.e. an unacceptable time deviation between PK blood 
sampling and ECG recording) will be excluded from the analysis. The maximum time 
deviation between PK blood sampling and ECG recording at different time points during the 
trial that will be accepted for the analysis are listed in Table 7.8.4: 1. For pre-dose pairs, both 
measurements had to be collected before the corresponding drug administration; for post-


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dose pairs, both measurements had to be collected after the corresponding drug 
administration. In case the collecting time of the PK blood sample and/or the ECG recording 
is not available, the pair will also be excluded from the analysis.
Table 7.8.4: 1 Maximum acceptable time deviations between PK sample and ECG recording
Timepoint of ECG recording*
Acceptable 
deviation
Timepoint of 
ECG recording*
Acceptable 
deviation
C1D1, -1:00, -0:30, -0 :15
NA
C1D15 predose
NA**
C1D1 1:00
+ 8 minutes
C1D15 1:00
+ 8 minutes
C1D1 2:00
+ 8 minutes
C1D15 2:00
+ 8 minutes
C1D1 3:00 
+ 8 minutes
C1D15 3:00 
+ 8 minutes
C1D1 24:00 (Part A) 
NA**
C1D16 predose
NA**
*Time relative to BI 891065 administration
** No restrictions on the acceptable deviation are imposed in both directions. However, if the PK sample 
was taken before the ECG recording but the resting time in between was shorter than 10 minutes, the pair of
measurements will be excluded.
Graphical representations:
The relationship between BI 891065 plasma concentrations and QTcF, HR and QT changes
from baseline will be investigated graphically. To inspect whether the peaks of the time-
profiles for BI 891065 plasma concentrations and QTcF interval changes from baseline (or 
HR/QT changes from baseline respectively) coincide, figures of the individual time profiles 
of BI 891065 plasma concentrations and QTcF will be generated for each patient.
For further visualization of the relationship, plasma concentration against QTcF changes from 
baseline (or HR/QT changes from baseline, respectively) will be plotted. 
If deemed necessary, these analyses might also be performed in addition using the 
corresponding variables based on the PR interval and the QRS complex.
Appropriateness of QT interval correction methods
To evaluate the appropriateness of the methods, slopes of the relationship of QT, QTcF, and 
QTcB interval versus RR interval (log-transformed values) will be estimated by applying a 
random coefficient model. This analysis will be based on the three single on-treatment ECG 
recordings per time point. A table of the resulting (fixed effects) slopes will be displayed 
together with two-sided 95% confidence intervals in the appendix of the CTR. The model is 
defined as follows (11): 
 =  +  + ( + )  + ! ,


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(#, ) ~ % (&, '), !~ (() %(0, +),
where i=1,...,I indicates the patient and k=1,…,K the number of the measurement,
,
is the log-transformed QT interval of measurement k in patient i,

is the overall intercept,

is the random effect on intercept associated with patient i,

is the common slope associated with the relationship between the log-transformed 
QT and RR intervals,

is the random effect on slope associated with patient i,
 
is the log-transformed RR interval of measurement k in patient i,
!
is the random error associated with the measurement k in patient i, and
'
is a 2-by-2 unstructured covariance matrix.
The random effects  and  are assumed to be independent of the random errors !.The 
analysis will be based on single ECG recordings that will be log-transformed using the 
natural logarithm.
7.8.5
Others
Pregnancy tests: 
A listing showing the results of pregnancy tests will be provided. 
Cytokine data:
Descriptive statistics for absolute values, absolute change from baseline and mean change
from baseline by treatment will be provided. 


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8.
REFERENCES
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.
2.
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 Jan; 45(2): 228-47 [R09-0262]
3.
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): e148-e152 [R17-0923]
4.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
5.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
6.
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
7.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
8.
001-MCP-090: "BI Style Guide", current version; IDEA for CON.
9.
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON.
10. Guidance for industry: drug-induces liver injury: premarketing clinical evaluation 
(July 2009).
Silver Spring: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER) (2009) [P09-12413]
11. Ring A. Statistical models for heart rate correction of the QT interval.
Stat Med 29, 786 - 796 (2010) [R10-2920]
12. Hoffman D, Kringle R, Lockwood G, Turpault S, Yow E, Mathieu G. Nonlinear 
mixed effects modelling for estimation of steady state attainment. Pharm Stat. 2005. 
[R05-0788]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Initial
31-Jul-2020
None
This is the initial TSAP with 
necessary information for trial 
conduct
Final
18-Mar-2021
All
This is the final TSAP
Revised


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