Clinical trial NCT03604445
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2018-08-08; Completion date: 2022-07-27
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is open to adults with different types of advanced cancer (solid tumours). This study is open to people in whom previous treatments were not successful. The purpose of this study is to find out the highest dose of BI 905677 the participants can tolerate. BI 905677 is a type of an antibody that is being developed to treat cancer.

One dose of BI 905677 is given to the participants every 2 or 3 weeks as infusion into a vein. In this study, BI 905677 is given to humans for the first time. The participants visit the study site at least once a week so that the doctors can check their general health. The participants are in the study for as long as they benefit from and can tolerate treatment.

Detailed description:

Arms: arm 1: 0.05 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 2: 0.1 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 3: 0.2 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 4: 0.4 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 5: 0.8 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 6: 1.6 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 7: 2.4 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 8: 2.8 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met. arm 9: 3.6 milligrams (mg) per kilogram (kg) solution for infusion BI 905677 were administered intravenously on Day 1 of each 3-week treatment cycle. Patients may continue on treatment for unlimited cycles, until disease progression or other criteria for stopping treatment are met.
Interventions: intervention 1: BI 905677
Intervention descriptions: intervention 1: Solution for infusion

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c18134159-05
EudraCT No.:
2017-002945-31
BI Trial No.:
1401-0001
BI Investigational 
Product(s):
BI 905677
Title:
An open-label, Phase I trial to determine the maximum-tolerated 
dose and investigate safety, pharmacokinetics and efficacy of 
BI 905677 administered intravenously in patients with advanced 
solid tumours
Lay Title:
This study aims to find and test a safe dose of BI 905677 in 
patients with different types of cancer (solid tumours)
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Tel: +
Coordinating 
Investigator:
Tel +
Fax +
Status:
Final Protocol (Revised Protocol (based on Global Amendment 
3))
Version and Date:
Version: 4.0
Date: 02 August 2018
Page 1 of 94
Proprietary confidential information.
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Finished product name
Not applicable
Active ingredient name:
BI 905677
Protocol date
31 January 2018
Revision date
02 August 2018 (Global Amendment 3)
Trial number
1401-0001
Title of trial:
An open-label, Phase I trial to determine the maximum-tolerated dose 
and investigate safety, pharmacokinetics and efficacy of BI 905677
administered intravenously in patients with advanced solid tumours
Coordinating 
Investigator:
Tel 
Fax
Trial site(s):
Multi-centre trial
Clinical phase:
I
Objective(s):
The primary objective of this trial is to determine the maximum 
tolerated dose (MTD) of BI 905677 given as an intravenous infusion 
and to determine the recommended dose and dosing schedule for 
further trials in the development of BI 905677. 
Methodology:
Open-label, single arm, dose escalation of BI 905677
Number of patients
entered: 
Up to 60
Number of patients on 
each treatment:
Two dose escalation schedules with approximately 30 patients on 
each schedule
Diagnosis :
Patients with histologically or cytologically confirmed advanced, 
unresectable and/or metastatic solid tumours who are either refractory 
after standard therapy for the disease or for whom standard therapy is 
not appropriate. Patients must also have exhausted treatment options 
known to prolong survival for their disease.
Main in- and exclusion 
criteria

Histologically or cytologically confirmed diagnosis of an 
advanced, unresectable and/or metastatic non-haematologic 
malignancy. Patient must have measurable or evaluable lesions 
(according to RECIST 1.1).

Patient who has failed conventional treatment or for whom no 
therapy of proven efficacy exists or who is not eligible for
established treatment options. Patient must have exhausted 


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treatment options known to prolong survival for their disease.

Patient willing to undergo mandatory skin biopsy at the 
timepoints specified in the protocol.

Eastern Cooperative Oncology Group score of 0 or 1.

Adequate hepatic, renal and bone marrow function 

Recovered from any previous therapy-related toxicity to ≤ 
CTCAE Grade 1 at start of treatment (except for alopecia and 
stable sensory neuropathy which must be ≤ CTCAE Grade 2).

At least 18 years of age at the time of consent or over the legal 
age of consent in countries where that is greater than 18 years.

Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.

Life expectancy ≥ 3 months at the start of treatment in the opinion 
of the investigator.
Test product(s):
BI 905677
dose:
The starting dose will be:
Schedule A – 0.05 mg/kg every 3 weeks
Schedule B – starting dose to be determined based on safety 
information and schedule A MTD. Drug administration every 2 
weeks (Day 1 and Day 15 of 4 week cycle)
mode of 
administration:
Intravenous infusion
Comparator products:
Not applicable
Duration of treatment:
Patients may continue on treatment for unlimited cycles, until disease 
progression or other criteria for stopping treatment are met
Endpoints
Primary endpoints;

The maximum tolerated dose (MTD) of BI 905677 which will 
be assessed based on the number of patients experiencing 
Dose Limiting Toxicities (DLTs), graded according to 
CTCAE Version 5.0, in the first cycle of treatment (3 weeks in 
Schedule A and 4 weeks in Schedule B). Separate MTDs will 
be determined for Schedule A and Schedule B.

Number of patients experiencing adverse events (AEs) during 
the entire treatment period
Secondary endpoints;

The following pharmacokinetic (PK) parameters of BI 905677  
will be evaluated after the first administration of BI 905677 (if 
feasible):


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o
Cmax: maximum measured concentration of BI 905677
in serum after first infusion
o
AUC0-tz: area under the serum concentration-time 
curve over the time interval from 0 to the last 
measured time point (tz)
Safety criteria:
Incidence and severity of adverse events graded according to the 
common terminology criteria for adverse events (CTCAE, version 
5.0), incidence of dose limiting toxicities, laboratory parameters,
physical examination, vital signs, ECOG performance status, ECG, 
ophthalmology, bone biomarkers and densitometry.
Statistical methods:
Dose escalation guided by a Bayesian Logistic Regression Model 
(BLRM) with overdose control that will be fitted to binary toxicity 
outcomes. The estimate of parameters will be updated as data are 
accumulated using the BLRM. At the end of the dose escalation, the 
toxicity probability at each dose level will be calculated to determine 
an estimate of the MTD. All endpoints will be analysed descriptively.


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FLOWCHART
SCHEDULE A; CYCLE DURATION = 3 WEEKS
Trial Period
Screening
Treatment Cycles*
(1 Cycle = 21 Days)
End of 
Treatment 
(EOT)
Follow-
up**
Timing
1-28 days
prior to 
first dose
Day 
1***
Day 
4****
±1 day
48-96
hours 
after 
dosing
Day 8
±1 day
Day 15
±2 days
Within 7 days 
of EOT 
decision*****
42-49 
days 
after last 
dose
Informed consent
X
Review of in-/exclusion 
criteria
X
Demographics and 
smoking/alcohol history
X
Medical History
X
Physical Examination
X
X
X
X
ECOG Performance 
Status
X
X
X
X
Vital Signs
X
Xa
X
X
X
X
12 lead-
electrocardiogram (ECG)
X
Xb
Xb
X
Safety laboratory blood 
tests and urinalysis
X
X
Xc
Xc
Xc
Xd
Vitamin D blood test
X
Xe
X
Pregnancy testf
X
X
X
Bone densitometry
X
Every 12 weeks (± 7 days) from start of 
treatment until EOT
Xg
Ophthalmologic 
assesment
X
Repeated if clinically indicated – see section 5.2.5.4
Height
X
Weight
X
X
X
Tumour Assessment
Xh
Every 6 weeks (± 7 days) from start of treatment until documented 
progressioni
Skin Biopsy
Xj
Xj
Xj
Blood sample for bone 
biomarkers
Xk
X
Blood samples for 
cytokine release testing
Xl
Blood samples for 
Pharmacokinetics
Xm
Xm
Xm
Xm
Xm
Xm
Blood sample for anti-
drug antibodies (ADAs)
X
X
X
Assess eligibility for 
further treatment
Xn
BI 905677 Infusiono
X
Adverse events
X
X
X
X
X
X
X
Concomitant Therapies
X
X
X
X
X
X
X
Completion of patient
participation
X


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* Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met (see 
Section 3.3.4)
** Wherever possible the follow-up visit must be performed in person, but if the investigator judges appropriate, 
follow-up information may be collected by telephone.
*** Cycle 1 Day 1 assessments (Physical examination, ECOG performance status, vital signs, ECG, safety 
laboratory blood tests, urinalysis, pregnancy test, weight) do not need to be performed if done within 2 calendar 
days (during the Screening visit) and in the opinion of the investigator a repeat is not required. In this case the 
latest value prior to start of treatment will be considered the baseline.
**** Cycle 1 and Cycle 2 only
***** If the decision to permanently discontinue trial treatment is taken during a scheduled visit, the EOT visit 
should be performed instead of the scheduled visit.
a
See section 5.2.2 for details of vital signs measurement on day of infusion
b
ECG required on Day 8 of Cycle 1 but not on Day 8 of Cycle 2 and subsequent cycles. For detailed 
schedule, refer to Appendix 10.2.
c
In case of haematological toxicity of Grade 4 a complete blood count has to be performed at least twice 
per week until improvement to a lower grade.
d
Safety laboratory tests and urinalysis at follow-up are optional and at the discretion of the investigator.
e
Vitamin D will be tested on Day 1 of every third cycle (i.e. Cycle 3 Day 1, Cycle 6 Day 1)
f
Pregnancy test is only required for women of childbearing potential. See Section 3.3.2 for further 
details.
g
Bone densitometry at the EOT visit is not required if bone densitometry has been performed within the 
previous 4 weeks.
h
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 the Screening visit 
window.
i
Tumour assessment should be performed every 6 weeks calculated from start of treatment until 
documented progression. In the event of early discontinuation or an interruption/delay to treatment, 
wherever possible the tumour assessment schedule should not be changed. See Section 5.1.1 for further 
details.
j
Skin biopsy is mandatory for all patients who start treatment after certain criteria are met – see Section 
5.4. A total of two skin biopsies are required. The first skin biopsy may be obtained any time prior to 
the first dose. A second skin biopsy sample will be obtained within 48-96 hours of receiving treatment 
in Cycle 2. See Section 5.4 for further details.
k
Bone biomarkers will be assessed on Cycle 1 Day 1, Cycle 2 Day 1 and then on Day 1 of every odd-
numbered cycle.
l
For detailed schedule, refer to Appendix 10.2
m
For detailed PK sampling schedule, refer to Appendix 10.2. PK sampling on Day 8 and Day 15 is only 
required in Cycles 1-4.
n
Assessment of eligibility for further treatment is required prior to dosing on Day 1 of each cycle from 
Cycle 2 onwards.
o
Patients will be monitored for cytokine release syndrome for 6 hours after the first three administrations
of BI 905677 and for 3 hours following subsequent administrations if the previous administrations were 
well-tolerated. See Section 5.2.5.3 for details.


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SCHEDULE B; CYCLE DURATION = 4 WEEKS
Trial Period
Screening
Treatment Cycles*(1 Cycle = 28 Days)
End of 
Treatment 
(EOT)
Follow-
up**
Timing
1-28 days
prior to 
first dose
Day 
1***
Day 
4****
±1 day
48-96
hours 
after 
dosing
Day 8
±1
days
Day 15
±1 day
Day 22
±1
days
Within 7
days of EOT 
decision 
*****
42-49 
days after 
last dose
Informed consent
X
Review of in-/exclusion 
criteria
X
Demographics and 
smoking/alcohol history
X
Medical History
X
Physical Examination
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
Vital Signs
X
Xa
X
Xa
X
X
X
12 lead-
electrocardiogram 
(ECG)
X
Xb
Xb
Xb
X
Safety laboratory blood 
tests and urinalysis
X
X
Xc
Xc
Xc
Xc
Xd
Vitamin D blood test
X
Xe
X
Pregnancy testf
X
X
X
Bone densitometry
X
Every 12 (± 7 days) weeks from start of 
treatment until EOT
Xg
Ophthalmologic 
assessment
X
Repeated if clinically indicated – see section 5.2.5.4
Height
X
Weight
X
X
X
X
Tumour Assessment
Xh
Every 8 weeks (± 7 days) from start of treatment until documented 
progressioni
Skin Biopsy
Xj
Xj
Xj
Blood sample for bone 
biomarkers
Xk
X
Blood samples for 
cytokine release testing
Xl
Xl
Blood samples for 
Pharmacokinetics
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Blood sample for anti-
drug antibodies (ADAs)
X
Xn
X
X
Assess eligibility for 
further treatment
Xo
Xo
BI 905677 Infusionp
X
X
Adverse events
X
X
X
X
X
X
X
X
Concomitant Therapies
X
X
X
X
X
X
X
X
Completion of patient
participation
X
* Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met (see 
Section 3.3.4)


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** Wherever possible the follow-up visit must be performed in person, but if the investigator judges appropriate, 
follow-up information may be collected by telephone.
*** Cycle 1 Day 1 assessments (Physical examination, ECOG performance status, vital signs, ECG, safety 
laboratory blood tests, urinalysis, pregnancy test, weight) do not need to be performed if done within 2 calendar 
days (during the Screening visit) and in the opinion of the investigator a repeat is not required. In this case the 
latest value prior to start of treatment will be considered the baseline.
**** Cycle 1 and Cycle 2 only
***** If the decision to permanently discontinue trial treatment is taken during a scheduled visit, the EOT visit 
should be performed instead of the scheduled visit.
a
See section 5.2.2 for details of vital signs measurement on day of infusion
b
ECG required on Day 8 and 15 of Cycle 1 but not on Day 8 and 15 of Cycle 2 and subsequent cycles.
For detailed schedule, refer to Appendix 10.3.
c
In case of haematological toxicity of Grade 4 a complete blood count has to be performed at least twice 
per week until improvement to a lower grade.
d
Safety laboratory tests and urinalysis at follow-up are optional and at the discretion of the investigator.
e
Vitamin D will be tested on Day 1 of every third cycle (i.e. Cycle 3 Day 1, Cycle 6 Day 1)
f
Pregnancy test is only required for women of childbearing potential. See Section 3.3.2 for further 
details.
g
Bone densitometry at the EOT visit is not required if bone densitometry has been performed within the 
previous 4 weeks.
h
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 the Screening visit 
window.
i
Tumour assessment should be performed every 8 weeks calculated from start of treatment until 
documented progression. In the event of early discontinuation or an interruption/delay to treatment, 
wherever possible the tumour assessment schedule should not be changed. See Section 5.1.1 for further 
details.
j
Skin biopsy is mandatory for all patients who start treatment after certain criteria are met – see Section 
5.4. A total of two skin biopsies are required. The first skin biopsy may be obtained any time prior to 
the first dose. A second skin biopsy sample will be obtained within 48-96 hours of receiving treatment 
in Cycle 2. See Section 5.4 for further details.
k
Bone biomarkers will be assessed on Cycle 1 Day 1, on Cycle 2 Day 1 and then on Day 1 of every odd-
numbered cycle.
l
For detailed schedule, refer to Appendix 10.3.
m
For detailed PK sampling schedule, refer to Appendix 10.3. PK sampling on Day 8 and Day 22 is only 
required in Cycles 1-4. PK sampling on Day 15 is only required in Cycles 1-6.
n
Blood sample for ADAs is only required on Day 15 of Cycle 1 and Cycle 2. For detailed schedule, refer 
to Appendix 10.3.
o
Assessment of eligibility for further treatment is required prior to dosing on Day 1 and Day 15 of each 
cycle from Cycle 1 Day 15 onwards.
p
Patients will be monitored for cytokine release syndrome for 6 hours after the first three administrations
of BI 905677 and for 3 hours following subsequent administrations if the previous administrations were 
well-tolerated. See Section 5.2.5.3 for details.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART.........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................16
1.2.1
Pharmacology......................................................................................................16
1.2.2
Pharmacokinetics................................................................................................17
1.2.3
Toxicology............................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........21
2.1.1
Main objectives....................................................................................................21
2.1.2
Primary endpoints...............................................................................................21
2.1.3
Secondary endpoints...........................................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.1.1
Trial Stopping Rules...........................................................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS.........................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from therapy or assessments .....................................28
3.3.4.1
Withdrawal from trial treatment ...........................................................................28
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the Investigational Medicinal Product ...........................................30
4.1.2
Selection of doses in the trial..............................................................................30
4.1.2.1
Starting Dose for Schedule A................................................................................30
4.1.2.2
Starting Dose for Schedule B................................................................................32
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................32
4.1.4.1
Re-treatment criteria .............................................................................................33
4.1.4.2
Management of infusion-related reactions............................................................33


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4.1.4.3
Management of Cytokine Release Syndrome (CRS)............................................34
4.1.4.4
Management of bone toxicity ...............................................................................35
4.1.4.5
Management of retinal toxicity.............................................................................35
4.1.4.6
General management of toxicities.........................................................................35
4.1.4.7
Dose Reduction.....................................................................................................37
4.1.5
Blinding and procedures for unblinding...........................................................37
4.1.6
Packaging, labelling, and re-supply...................................................................37
4.1.7
Storage conditions...............................................................................................37
4.1.8
Drug accountability.............................................................................................37
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................38
4.2.1
Other treatments and emergency procedures..................................................38
4.2.2
Restrictions ..........................................................................................................38
4.2.2.1
Restrictions regarding concomitant treatment ......................................................38
4.2.2.2
Restrictions on diet and life style..........................................................................39
4.2.2.3
Restrictions regarding women and men of childbearing potential .......................39
4.3
TREATMENT COMPLIANCE........................................................................39
5.
ASSESSMENTS..................................................................................................40
5.1
ASSESSMENT OF EFFICACY........................................................................40
5.1.1
Tumour assessment.............................................................................................40
5.2
ASSESSMENT OF SAFETY.............................................................................40
5.2.1
Physical examination ..........................................................................................40
5.2.2
Vital signs.............................................................................................................40
5.2.3
Safety laboratory parameters ............................................................................41
5.2.4
Electrocardiogram ..............................................................................................42
5.2.5
Other safety parameters.....................................................................................42
5.2.5.1
Safety biomarkers for bone resorption..................................................................42
5.2.5.2
Bone densitometry ................................................................................................43
5.2.5.3
Testing for Cytokine Release................................................................................43
5.2.5.4
Ophthalmologic Assessment.................................................................................43
5.2.6
Assessment of adverse events.............................................................................44
5.2.6.1
Definitions of AEs ................................................................................................44
5.2.6.2
Adverse event collection and reporting ................................................................47
5.2.7
Definition of Dose Limiting Toxicity (DLT) .....................................................49
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................50
5.3.1
Assessment of pharmacokinetics .......................................................................50
5.3.2
Methods of sample collection .............................................................................51
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................51
5.4
ASSESSMENT OF BIOMARKERS.................................................................51
5.4.1
Biomarker analysis .............................................................................................51
5.4.1.1
Methods of sample collection for skin biopsies....................................................52
5.4.2
Biobanking...........................................................................................................52
5.5
OTHER ASSESSMENTS...................................................................................52
5.5.1
Demographics and history..................................................................................52
5.5.2
Sampling for anti-drug antibodies (ADAs).......................................................53
5.5.2.1
Methods of ADA sample collection......................................................................53


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5.6
APPROPRIATENESS OF MEASUREMENTS..............................................53
6.
INVESTIGATIONAL PLAN.............................................................................54
6.1
VISIT SCHEDULE.............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................54
6.2.1
Screening period..................................................................................................54
6.2.2
Treatment period ................................................................................................55
6.2.3
Follow up period and trial completion..............................................................55
6.2.3.1
End of treatment visit............................................................................................55
6.2.3.2
Follow-up visit......................................................................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
7.1
STATISTICAL DESIGN – MODEL ................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.3
PLANNED ANALYSES.....................................................................................58
7.3.1
Primary endpoint analyses.................................................................................59
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................59
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................60
7.4
INTERIM ANALYSES ......................................................................................62
7.5
HANDLING OF MISSING DATA ...................................................................62
7.6
RANDOMISATION ...........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE .........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........63
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................63
8.2
DATA QUALITY ASSURANCE ......................................................................64
8.3
RECORDS...........................................................................................................64
8.3.1
Source documents ...............................................................................................64
8.3.2
Direct access to source data and documents.....................................................65
8.3.3
Storage period of records ...................................................................................65
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................66
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........66
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................66
8.6
TRIAL MILESTONES.......................................................................................66
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................67
9.
REFERENCES....................................................................................................69
9.1
PUBLISHED REFERENCES............................................................................69
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................73
10.1
PHARMACOKINETIC ANALYSES...............................................................73


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10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA AND 
CYTOKINE BLOOD SAMPLING AND ECG ASSESSMENT IN 
SCHEDULE A.....................................................................................................75
10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA AND 
CYTOKINE BLOOD SAMPLING AND ECG ASSESSMENT IN 
SCHEDULE B.....................................................................................................76
10.4
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS .................................................................................78
10.5
ECOG PERFORMANCE STATUS..................................................................84
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................85


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ABBREVIATIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
ANCOVA
Analysis of Covariance
APC
Adenomatous Polyposis Coli
AST
Aspartate amino transferase
AUC
Area under the Curve
BAP
Bone Alkaline Phosphatase
BI
Boehringer Ingelheim
BLQ
Below the limit of Quantification
BLRM
Bayesian Logistic Regression Model
BCVA
Best Corrected Visual Acuity
CA
Competent Authority
CL
Clearance
CML
Clinical Monitor Local
CR
Complete Response
CRA
Clinical Research Associate
CRC
Colorectal Cancer
CRF
Case Report Form
CRO
Contract Research Organisation
CRS
Cytokine Release Syndrome
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTX
Carboxy-terminal Telopeptide
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDTA
Ethylendiaminetetracetic Acid
EMA
European Medicines Agency
EOT
End of Treatment
ETDRS
Early Treatment Diabetic Retinopathy Score
EU
European Union
EudraCT
European Clinical Trials Database
EWOC
Escalation with Overdose Control
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GI
Gastrointestinal
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
GSK
Glycogen Synthase Kinase


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HED
Human Equivalent Dose
HIV
Human Immunodeficiency Virus
HNSTD
Highest non-severely-toxic dose
HSA
Human Serum Albumin
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin
INR
International Normalised Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
LDH
Lactate Dehydrogenase
LPDD
Last Patient Drug Discontinuation
LRP
Low-density lipoprotein receptor-related protein
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMTV
Mouse Mammary Tumour Virus
mRNA
Messenger Ribonucleic Acid
MRSD
Maximum Recommended Starting Dose
MRT
Mean Residence Time
MTD
Maximum Tolerated Dose
N/A
Not Applicable
NC
Not Calculated
NCA
Non Compartmental Analysis
NOA
Not Analysed
NOAEL
No Observed Adverse Effect Level
NOP
No Peak Detectable
NOR
No Valid Result
NOS
No Sample
OPU
Operative Unit
OR
Objective Response
PD
Progressive Disease
PFS
Progression Free Survival
PK
Pharmacokinetics
P1NP
Procollagen type I N Propeptide
PR
Partial Response
PTF
Peak-Trough Fluctuation
PTT
Partial Thromboplastin Time
RA
Accumulation Ratio
RBC
Red Blood Cells
RDE
Recommended Dose for Expansion
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RNF
Ring Finger Protein
SAE
Serious Adverse Event
SD
Stable Disease
SD-OCT
Spectral Domain Optical Coherence Tomography
SMC
Safety Monitoring Committee


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SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCF
T-Cell Factor
TDMAP
Trial Data Management and Analysis Plan
TK
Toxicokinetic
TNBC
Triple Negative Breast Cancer
TRACP
Tartrate-resistant Acid Phosphatase
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
Vss
Volume of Distribution at steady state
WBC
White Blood Cells
WHO
World Health Organisation
WNT
Wingless Type MMTV Integration Site
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 2012 there were approximately 14 million new cancer cases and 8.2 million 
cancer-related deaths worldwide (R15- 3504). In the majority of cases the disease is 
diagnosed in late, advanced stages and the vast majority of patients progress on available 
treatments and succumb to their disease. Therefore, there is a substantial need for novel 
therapeutic agents and treatment strategies to improve the treatment outcome for cancer 
patients. 
Ligand- dependent Wnt signaling, mediated by LRP5 and LRP6, is highly activated in a 
subset of solid tumours (e.g. colorectal cancer (CRC), triple negative breast cancer (TNBC) 
and non-small cell lung cancer (NSCLC)). Activation leads to accumulation of intracellular 
-catenin and expression of -catenin dependent genes that promotes cancer cell proliferation 
and resistance to chemotherapy/immunotherapy. An antagonistic bi-paratopic antibody that 
binds LRP5 and LRP6 and blocks binding of Wnt ligands will block proliferation of 
malignant cells with activated Wnt signaling and increase sensitivity to immunotherapy. 
Therefore, the development of a LRP5/6 antagonist may constitute a valid therapeutic option 
against cancer.
1.2
DRUG PROFILE
1.2.1
Pharmacology
The LRP5/LRP6 antagonist BI 905677 is a new biological entity (potentially first in class) 
consisting of a tri-modular antagonistic antibody comprising two modules binding to distinct 
domains of LRP5 and LRP6 receptors and one module binding to human serum albumin 
(HSA). Modules are derived from single variable domains of camelidae heavy-chain 
antibodies (called nanobodies). BI 905677 binds to LRP5 and LRP6 and blocks binding of 
Wnt ligands to LRP5 or LRP6 receptors, leading to inhibition of Wnt/-catenin signaling. 
BI 905677 has not been tested in humans.
The Wnt ligands, which bind to LRP5 and LRP6 and Frizzled receptor leading to activation 
of downstream signaling, can be divided into Wnt1 class and Wnt3a class, each requiring 
different domains of LRP5 and LRP6 for signaling [R17-1851]. In particular, BI 905677
binds to these different domains of LRP5 and LRP6 receptor (bi-paratopic binding), thereby 
blocking Wnt signaling mediated by both Wnt1 and Wnt3a class ligands, leading to: 
1) Inhibition of LRP5 or LRP6 phosphorylation;
2) Activation of β-catenin degradation complex formed by APC/Axin/GSK3; 
3) Blockade of β-catenin nuclear translocation and binding to the TCF transcription factors;
4) Inhibition of transcription of Wnt/-catenin target genes (e.g. Axin2 and Notum).


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Blockade of LRP5 and LRP6 phosphorylation and inhibition of transcription of Wnt/-
catenin target genes (including, but not limited to, Axin2 and Notum), can be monitored in 
vivo as direct and indirect biomarkers for selective pathway engagement, respectively, in a 
Wnt driven tumour xenograft tissue [n00256247]. Inhibition of Wnt target gene expression in 
tumour cells is necessary but not sufficient for antitumour efficacy (in vitro and in vivo), 
indicating that it represents a pharmacodynamic biomarker, but not a biomarker of response 
to treatment with BI 905677. In mice pharmacodynamic biomarker modulation can be 
monitored in vivo in skin as surrogate tissue via detection of Axin2 gene expression 
[n00256248].
In a subset of cancer patients, activation of ligand dependent Wnt signaling is mediated by, 
amongst others, RNF43 mutations or by R-spondin 3 fusion transcripts (R17-1850, R17-
1849); hence, patients with tumours harbouring a loss of function RNF43 mutation or R-
spondin fusion could benefit from Wnt pathway inhibition by blocking the Wnt receptors 
LRP5 and LRP6. Nonclinical pharmacology and biomarker data support a patient enrichment 
biomarker strategy. Nonclinical proof of concept (efficacy and inhibition of Wnt/ β-catenin 
signalling) was demonstrated with BI 905677 in disease relevant models harboring either 
RNF43 mutation or R-spondin fusion. In contrast, BI 905677 did not show blockade of Wnt 
signaling nor impact on cell viability in RNF43 wild type tumour models (n00256243, 
n00256244).
1.2.2
Pharmacokinetics
The pharmacokinetics (PK) for BI 905677 were investigated in the cynomolgus monkey in a 
single dose PK and repeated dose toxicokinetic (TK) studies. Human i.v. PK prediction for 
BI 905677 was performed using single species scaling from cynomolgus monkey to human 
using a Dedrick plot. The PK curves were fitted using a 2-compartment model. BI 905677
demonstrated dose-proportional increases in Cmax and Area under the Curve (AUC) with 
increasing dose levels in the PK and TK studies. A relatively high clearance (CL) and volume 
of distribution (Vss) was observed. BI 905677 is cross-reactive with mouse LRP5 and LRP6
and a biodistribution study performed in the mouse demonstrated a rapid clearance of 
BI 905677 in the blood and rapid distribution predominantly to the liver. 
Based on human PK parameter predictions and the minimal efficacious dose in the mouse 
MMTV-WNT1 breast cancer model, the predicted human therapeutic dose for BI 905677 is 
1.1 mg/kg i.v. q1w (or 77 mg/patient q1w for a fixed-dose regimen in patients with an 
average body weight of 70 kg). Alternatively, a less frequent dosing schedule can be chosen 
while keeping the AUC/week constant, e.g. 3.3 mg/kg i.v. q3w (or 231 mg/patient q3w for a 
fixed-dose regimen in patients with an average body weight of 70 kg).
1.2.3
Toxicology
The toxicity profile for BI 905677 has been assessed in the repeat dose toxicity studies in 
monkeys and mice, in an in vitro cytokine release assay, and in an in vitro hemocompatibility 
study. The 6-week GLP repeat dose study in monkeys included safety pharmacology 
(cardiovascular,respiratory and neurological function) and immunotoxicology endpoints. 
Consistent with the mechanism of action, BI 905677-related key target organ of toxicity was 
the gastrointestinal (GI) tract and the adverse effects on the gastrointestinal tract 
(lymphoplasmacytic inflammation with epithelial loss, and/or erosive lymphoplasmacytic 


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inflammation with epithelial loss) were dose limiting toxicities that resulted in early 
euthanasia of some animals.
The results from the 6-week GLP monkey study indicated that animals given high dose level 
with less frequent dosing schedule showed better tolerability, lesser magnitude of the 
gastrointestinal tract injury, and better reversibility as compared to the administration of low 
dose level more frequently while the pharmacodynamic effects were still maintained with less 
frequent dosing schedule.
As anticipated with the role of Wnt signaling in skeletal development and homeostasis, there 
was a trend of marginal to slight decreases in bone formation markers (BAP and P1NP) due 
to Wnt signaling inhibition by BI 905677, but no changes in bone resorption markers (CTX
and TRAcP) or any microscopic correlates. However, there may be adverse effects on the 
bone mass, especially osteoporosis, after long-term treatment in humans.
In an in vitro cytokine release assay, a potential for BI 905677 to induce cytokine release was 
identified in 2 of 11 whole blood samples from healthy human donors.
IL-2 and IL-10 levels were not elevated with BI 905677 treatment for any of the 
donors. Elevations of IL-6, IL-8, TNF-α and IFN-γ were observed in 2 of 11 donors at the 
two highest concentrations of BI 905677 (10 and 30 mg/mL). Among 4 cytokines, releases 
of TNF-α and IFN-γ (up to 619X vs Avastin negative control; up to 31X vs OKT3 or 
EX79969 positive control) were more pronounced than those of IL-6 and IL-8 (up to 6.6X vs 
Avastin negative control; up to 6X vs OKT3 or EX79969 positive control). Levels of these 
cytokines at the two lowest concentrations (0.3 and 3 μg/mL) were below the levels of the 
Avastin negative control. These two donor samples were confirmed to be negative for pre-
existing anti-drug antibodies for BI 905677, indicating that cytokine release responses in two 
donors are not related to pre-existing anti-drug antibodies.
No abnormal findings were identified in the eye by ophthalmological and microscopic 
evaluations and no alopecia was observed in monkeys at any dose levels tested in the 6-week 
repeat dose study.
For a more detailed description of the BI 905677 profile please refer to the current 
Investigator’s Brochure (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on the pre-clinical studies summarised in the previous section, the observed anti-
tumour activity and safety profile warrant clinical testing of BI 905677. This study is the 
first-in-man study to determine the MTD and the safety profile of BI 905677 monotherapy in 
patients with advanced solid tumours. It is hoped that this trial will provide the foundation of 
a clinical development program which will ultimately benefit many cancer patients.
1.4
BENEFIT - RISK ASSESSMENT
Most patients with locally advanced or metastatic tumours will succumb to their disease. 
Thus, there is a substantial need for novel therapeutic strategies to improve the outcome for 
patients with advanced or metastatic malignancies.


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As BI 905677 is a first-in-class compound, which has not been tested in humans before, the 
risks of treatment have been evaluated based on the expected effects of targeting the Wnt 
pathway (R17-1468) and on the nonclinical toxicology data.
In normal cells, Wnt signaling, mediated by both LRP5 and LRP6 co-receptors, is required 
for (1) homeostasis of intestinal epithelial stem cells, located in the crypts of the small and 
large intestines; (2) skeletal development and homeostasis (promotion of osteoblast 
differentiation from progenitors and osteocyte survival); (3) retinal angiogenesis and 
regulation of retinal endothelial cell differentiation  (R17-1468, R18-0131, R18-1474, R18-
1475) and (4) establishment of the hair follicle by activating bulge stem cells to progress 
toward hair formation. Thus, it is anticipated that potential on-target adverse events may
occur in the gastrointestinal tract, bone, hair follicle, and eye (retina) when the Wnt signaling 
pathway is inhibited by BI 905677.
Several compounds targeting the Wnt pathway, but with a different mechanism of action 
compared to BI 905677 which selectively inhibits Wnt ligand dependent pathway activation, 
have been studied in clinical trials. These compounds include vantictumab (anti-frizzled 
receptor antibody), ipafricept (anti-frizzled 8 receptor antibody), rosmantuzumab (anti-
RSPO3 antibody), Wnt-974 (cysteine palmitoyltransferase porcupine inhibitor) and ETC-159 
(a selective small molecule porcupine inhibitor). Dysgeusia, fatigue, decreased appetite and 
gastrointestinal adverse reactions including nausea, vomiting and diarrhea were documented 
as frequent drug related adverse reactions (R17-4166, R17-4167, R17-4168, R18-1490). In 
clinical studies of vantictumab, rosmantuzumab, ipraficept and ETC-159, bone toxicity was 
observed, consisting of changes in bone markers (increase in β-Carboxy-terminal Telopeptide 
(β –CTX) and/or decrease in procollagen type 1 amino-terminal propeptide (P1NP)), decrease 
in bone density as determined by bone densitometry, and fragility fractures that occurred late 
in the course of therapy (R17-4166, R17-4167, R18-1420, R18-1421, R18-1490, R18-1494). 
To date, cytokine release syndrome and retinopathy have not been reported in any of these 
clinical studies.
Since the results of the 6-week GLP toxicology study in monkeys indicated that animals 
given high dose levels in a less frequent dosing schedule showed better tolerability, lesser 
magnitude of the gastrointestinal tract injury, and better reversibility as compared to the 
frequent schedules at low dose levels, in this study less frequent dosing schedules have been 
chosen to mitigate the gastrointestinal toxicity in the clinic. Gastrointestinal adverse events 
are common with many conventional anti-cancer therapies, and can be managed and 
indirectly monitored in the clinic (e.g., emesis, diarrhea/liquid stool, abdominal pain, and 
body weight loss). In this study, monitoring and supportive measures such as anti-emetics, 
anti-motility agents and stopping/dose modification criteria (see Section 4.1.4) will be 
implemented to reduce the frequency and guide the management of severe gastrointestinal 
AEs.
It is anticipated that there may be adverse effects on the bone mass; thus, in this study 
potential AEs and symptoms (e.g. bone pain, back pain, reduced height, pathologicand 
pathologic fractures) will be monitored using regular monitoring of serum bone biomarkers 
and bone densitometry. In patients with documented pre-existing osteoporosis, treatment with 
vitamin D and/or calcium carbonate is recommended. Management guidelines and stopping 
rules for bone toxicity are provided (see Sections 3.3.1 and 4.1.4.4).


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Another safety aspect for BI 905677 administration is a potential to induce cytokine release 
as was observed in 2 of 11 whole blood samples from healthy human donors. Therefore, 
guidelines for monitoring and management of potential cytokine release syndrome are
provided and must be followed thoroughly (see Section 4.1.4.3).
There were no BI 905677-related abnormal effects on the eyes (ophthalmological and 
microscopic examinations) observed in the 6-week repeat dose study in monkeys. Based on 
the published reports of a potential risk of retinal toxicity as a result of Wnt pathway 
inhibition, an ophthalmologic status assessment will be performed at baseline in all patients
(section 5.2.5.4). In case of occurrence of visual symptoms (e.g. loss in visual acuity, blurred 
or distorted vision, floating specks or cobwebs, night vision changes or color vision changes) 
the same ophthalmologic assessment will be repeated. Guidelines for management of 
potential retinal toxicity are provided (see Section 4.1.4.5).
Throughout the study the safety of the participants will be monitored regularly by a Safety 
Monitoring Committee (SMC) (See Section 8.7). The assessments planned in this study are 
standard for oncology patients.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients’
safety, see also Section 5.2.6, adverse events of special interest.
In summary, the nonclinical safety package and data support the administration of BI 905677
to patients with advanced or metastatic cancer, although close monitoring of all adverse 
events with a focus on potential on-target adverse events is warranted. Given the unmet 
medical need of these patients, there is a case for potential benefit offered by this novel mode 
of action with 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 to determine the maximum tolerated dose (MTD) of 
BI 905677 given as an intravenous infusion and to determine the recommended dose and 
dosing schedule for further trials in the development of BI 905677. The MTD will be defined 
based on the frequency of patients experiencing DLTs during the MTD evaluation period, 
which is defined as the first cycle of treatment. Separate MTDs will be determined for 
Schedule A and Schedule B.
The secondary objective of the trial is:

To determine the pharmacokinetic profile of BI 905677
2.1.2
Primary endpoints
The primary endpoints of the trial are;

The maximum tolerated dose (MTD) of BI 905677 which will be assessed based on 
the number of patients experiencing Dose Limiting Toxicities (DLTs), graded 
according to CTCAE Version 5.0, in the first cycle of treatment (3 weeks in Schedule 
A and 4 weeks in Schedule B). The MTD is defined as the highest dose with less than 
25% risk of the true DLT rate being equal to or above 33%. Separate MTDs will be 
determined for Schedule A and Schedule B. For the definition of DLTs, refer to 
Section 5.2.7 and for more information on how the MTD will be determined, refer to 
Section 7. 

Number of patients experiencing adverse events (AEs) during the entire treatment 
period.
2.1.3
Secondary endpoints
The secondary endpoints of the trial are:

The following PK parameters of BI 905677 will be evaluated after the first
administration of BI 905677 (if feasible):
o
Cmax: maximum measured concentration of BI 905677 in serum after first 
infusion
o
AUC0-tz: area under the serum concentration-time curve over the time interval
from 0 to the last measured time point (tz)


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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 study of BI 905677 administered intravenously
as a single agent. 
Figure 3.1: 1 Trial Design
The design of the trial allows an escalation of dose with intensive safety monitoring to ensure 
the safety of the patients. 
A Bayesian logistic regression model (BLRM) with overdose control (R13-4803) will be 
used to determine the MTD estimate. The BLRM estimates the MTD by updating estimates 
of the probability of observing a DLT for each dose level. At any time in the trial, it will not 
be permitted to escalate to a dose which does not fulfil the escalation with overdose control 
(EWOC) principle (for further details refer to Section 7).
The trial will test two different dosing schedules for BI 905677 with two separate BLRM 
models; in Schedule A the cycles will be 3 weeks in duration and in Schedule B the cycles 
will be 4 weeks in duration. Recruitment into each dosing schedule will occur sequentially.
Recruitment into Schedule B will start after the MTD of Schedule A is reached. Within each 
treatment cohort, patients will be treated at least 72 hours apart to allow adequate monitoring 
for CRS and implementation of preventive measures if required.
In each schedule, successive cohorts of patients will receive increasing doses of BI 905677
until the MTD is reached. Incremental dose increases in successive cohorts will be no more 


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than 100% of the previous dose level and all cohorts will include at least 3 patients. Three
patients will be treated per dose cohort until a first AE of CTCAE Grade ≥2 occurs during 
the DLT evaluation period (the first cycle of treatment), excluding adverse events which are 
clearly related to disease progression or concurrent illness. Then, additional patients have to 
be entered at this dose and subsequent dose escalations will be restricted to a maximum of 
50% from the previous dose until MTD is reached. A Safety Monitoring Committee (SMC, 
see Section 8.7) may also recommend the size for the next dose escalation cohort or 
recommend expanding the size of the recruiting cohort.
After all patients in a cohort have either experienced a DLT or have been observed for at least 
one cycle without experiencing a DLT, the Bayesian model will be updated with the newly 
accumulated data. The overdose risk will then be calculated for each potential dose and dose 
escalation will be permitted to all doses which fulfil the EWOC criterion. At the end of each 
dose level, based on the model and on additional information (PK, pharmacodynamics, 
patient profiles), 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 be 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 will be 
enrolled at a lower dose level.
The SMC may recommend stopping further dose escalation after the criterion for MTD 
(Section 7) is fulfilled. Further patients may be included to confirm this MTD estimate, i.e. to 
confirm that the EWOC criterion is still fulfilled. If no DLT is observed, the SMC may 
decide to declare the Recommended Dose for Expansion (RDE) based on 
PK/Pharmacodynamic endpoints and overall safety profile. Any DLTs occurring after the 
start of the second cycle will be considered for the evaluation of the RDE for BI 905677. The 
SMC can declare any dose fulfilling the EWOC criterion as the RDE, independent of the 
MTD estimate.
Patients will continue to receive treatment with BI 905677 until disease progression (PD) 
according to RECIST or until another reason requiring termination of treatment (see Section 
3.3.4).
After completion of the dose escalation and determination of the MTD/RDE, a protocol 
amendment is planned to add expansion cohorts to the trial.
3.1.1
Trial Stopping Rules
All safety information will be carefully analysed by the sponsor. Enrollment will be 
temporarily stopped if one of the following conditions is met;

> 20% of patients treated in the trial develop grade 3 osteoporosis or another bone-
related DLT

≥ 2 patients treated in the trial develop a serious pathologic fracture

> 20% of patients at a certain dose level experience a grade 3 Cytokine Release 
Syndrome and/or grade 3 hypersensitivity reaction and/or grade 3 infusion reaction


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
One patient experiences a grade 4 Cytokine Release Syndrome and/or grade 4 
hypersensitivity reaction and/or grade 4 infusion reaction
If this occurs, the SMC will conduct an in-depth analysis of the safety profile of BI 905677 
and the benefit-risk profile of BI 905677 will be re-assessed. This assessment will be used to 
determine if the study should be continued as planned, permanently discontinued or whether 
the study should continue with modification to the protocol to adequately mitigate patient risk 
and to ensure that the benefit-risk assessment for continued investigation of BI 905677 
remains positive. The SMC will also consider and provide guidance for the management of 
patients who are currently on treatment. The outcome of the analysis and the 
recommendations will be shared with all involved regulatory health authorities prior to a 
planned re-start of enrollment. In case the benefit-risk assessment is no longer considered to 
be positive, the trial will be discontinued.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
Dose escalation and cohort size will be determined based on the recommendation of the 
SMC, guided by a BLRM with overdose control. An EWOC design will increase the chance 
of treating patients at efficacious doses while reducing the risk of overdosing. This design is 
based on practical experience and is an efficient method due to its ability to identify the dose 
with a desired toxicity rate and its allocation of a greater proportion of patients to doses at, or 
close to, that desired dose (R13-4802, R13-4804, R13-4805). The use of Bayesian models for 
Phase I studies has also been advocated by the EMA guideline on small populations (R07-
4856) and by the FDA (R13-4881).
3.3
SELECTION OF TRIAL POPULATION
Patients with advanced, unresectable and/or metastatic solid tumours who are either 
refractory after standard therapy for the disease or for whom standard therapy is not 
appropriate will be eligible. Patients must also have exhausted treatment options known to 
prolong survival for their disease. The trial will be conducted in approximately 5 sites and it 
is anticipated that approximately 60 patients (30 per dosing schedule) will be enrolled in the 
trial. The total number of patients will depend on the number of dose escalations necessary.
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) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
Assessments may be repeated within the screening period if patients do not initially meet the 
inclusion/exclusion criteria. Eligibility must always be assessed using the latest results 
available. In addition re-screening of patients who have previously failed screening will be 
permitted. In this situation patients will be handled as a new patient i.e. sign a new informed 
consent, allocated a new patient number, and undergo full screening assessments. 
3.3.1
Main diagnosis for trial entry
Patients with histologically or cytologically confirmed advanced, unresectable and/or 
metastatic solid tumours who are either refractory after standard therapy for the disease or for 


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whom standard therapy is not appropriate. Patients must also have exhausted treatment 
options known to prolong survival for their disease.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or 
metastatic non-haematologic malignancy. Patient must have measurable or evaluable
lesions (according to RECIST 1.1).
2. Patient who has failed conventional treatment or for whom no therapy of proven efficacy 
exists or who is not eligible for established treatment options. Patient must have 
exhausted treatment options known to prolong survival for their disease.
3. Patient willing to undergo mandatory skin biopsy at the timepoints specified in the 
protocol.
4. Eastern Cooperative Oncology Group score of 0 or 1 (R01-0787).
5. Adequate organ function defined as all of the following:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; haemoglobin ≥ 9.0 g/dL; 
platelets ≥ 100 x 109/L without the use of hematopoietic growth factors within 
4 weeks of start of study medication.

Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except for 
patients with Gilbert’s syndrome: total bilirubin ≤ 3 x ULN or direct bilirubin 
≤1.5 x ULN.

Creatinine ≤ 1.5 x ULN. If creatinine is > 1.5 x ULN, patient is eligible if 
concurrent creatinine clearance ≥ 50 ml/min (measured or calculated by CKD-
EPI formula or Japanese version of CKD-EPI formula for Japanese patients).

Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN if 
no demonstrable liver metastases, or otherwise ≤ 5 x ULN

Alkaline Phosphatase < 5 x ULN
6. Recovered from any previous therapy-related toxicity to ≤ CTCAE Grade 1 at start of 
treatment (except for alopecia and stable sensory neuropathy which must be ≤ CTCAE 
Grade 2).
7. At least 18 years of age at the time of consent or over the legal age of consent in countries 
where that is greater than 18 years.
8. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
9. Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.
10. Male or female patients. Women of childbearing potential (WOCBP)1 must only be 
included after a confirmed menstrual period within the past 4 weeks and a negative 
                                                
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 


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pregnancy test at screening. WOCBP with irregular menstruation may be included after 
two negative pregnancy tests during screening between 2 and 4 weeks apart. WOCBP and 
men who are 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. These methods must be used during the study and 
for at least 6 months after the last dose of BI 905677. A list of contraception methods 
meeting these criteria is provided in the patient information and in Section 4.2.2.3.
3.3.3
Exclusion criteria
1. Major surgery (major according to the investigator’s assessment) performed within 4
weeks prior to first trial treatment or planned within 6 months after screening.
2. Previous or concomitant malignancies other than the one treated in this trial within the 
last 2 years, except;
a) effectively treated non-melanoma skin cancers
b) effectively treated carcinoma in situ of the cervix
c) effectively treated ductal carcinoma in situ
d) other effectively treated malignancy that is considered cured by local treatment
3. Osteoporosis ≥ CTCAE Grade 2
4. Chronic corticosteroid use
5. Osteoporotic compression fracture within 12 months prior to informed consent which is 
clinically significant in the opinion of the investigator.
6. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
7. Previous treatment in this trial.
8. Treatment with a systemic anti-cancer therapy or investigational drug within 28 days or 5 
half-lives (whichever is shorter) of the first treatment with the study medication.
9. Any history of or concomitant condition that, in the opinion of the investigator, would
compromise the patient’s ability to comply with the study or interfere with the evaluation 
of the safety and efficacy of the test drug.
10. Women who are pregnant, nursing, or who plan to become pregnant or nurse during the 
trial or within 6 months after the last dose of study treatment.
11. Active alcohol or drug abuse in the opinion of the investigator.
12. Patient unwilling or unable to comply with the protocol.
13. Presence or history of uncontrolled or symptomatic brain or subdural metastases, unless
considered stable by the investigator and local therapy was completed. Use of 
corticosteroids is allowed if the dose was stable for at least 4 weeks. Inclusion of patients 
with newly identified brain metastasis/es at screening will be allowed if patients are 
asymptomatic. 
                                                                                                                                                       
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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14. Known history of human immunodeficiency virus (HIV) infection or an active hepatitis B 
or C infection which in the opinion of the investigator may interfere with participation in 
the trial.
15. History of severe hypersensitivity reactions to monoclonal antibodies.
16. History of allergy to kanamycin or similar class drugs (including streptomycin, 
gentamicin, amikacin, tobramycin and neomycin).
3.3.4
Withdrawal of patients from therapy or assessments
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal. 
3.3.4.1
Withdrawal from trial treatment
An individual patient must discontinue trial treatment if the patient:

Withdraws consent for study treatment or further study participation, without the need to 
justify the decision.

Has radiological (or clinical) documentation of progressive disease on the current 
treatment (Section 5.1.1). 

Needs to take concomitant medication that is prohibited in this trial (Section 4.2.2)

Is required to stop treatment due to adverse events as described in Section 4.1.4.

Can no longer be treated with trial medication due to pregnancy or for other medical 
reasons (such as adverse events, concomitant diagnoses or concomitant therapies)

Has a significant deviation from the protocol or eligibility criteria. The decision to 
continue or withdraw treatment will be made by the sponsor in agreement with the 
Investigator. 
If a patient withdraws consent to all further trial procedures and follow-up activities, no 
additional study assessments will be completed. This will be documented in the electronic 
case report form (eCRF).
In all other cases, wherever possible, and given the patient’s agreement, patients who 
withdraw from treatment prior to disease progression should be encouraged to return for full 
EOT and follow-up assessments as outlined in the Flowchart and Section 6.2.3. In particular, 
a follow-up visit should be performed wherever possible to ensure all adverse events are 
adequately followed up. For all patients the reason for withdrawal from treatment (e.g. 
adverse events) must be recorded in the eCRF. These data will be included in the trial 
database and reported.
Patients who withdraw for a reason other than DLT before completing the first treatment 
cycle, or who do not receive the full planned dose in the first treatment cycle without DLT, or 
who miss more than one visit during their first treatment cycle will be replaced. 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.


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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 becomes pregnant during the trial, the treatment with BI 905677 must be stopped 
immediately. The patient will be followed up until delivery or termination of pregnancy. The 
data of the patient will be collected and reported in the eCRF.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing 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 Product
Table 4.1.1: 1
BI 905677
Substance:
BI 905677
Pharmaceutical 
formulation:
Solution for infusion
Dilution in 5% Glucose is required
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/mL (10 mL vial)
Posology:
Schedule A; Infusion on Day 1 of each cycle (1 cycle = 21 days)
Schedule B; Infusion on Day 1 and 15 of each cycle (1 cycle = 28 
days)
Route of 
administration:
i.v.
4.1.2
Selection of doses in the trial
4.1.2.1
Starting Dose for Schedule A
The nonclinical safety package and data support the administration of BI 905677 to patients 
with advanced cancers. The maximum recommended starting dose (MRSD) was made on the 
basis of the US FDA Guidance for Industry “S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals” [R11-5034]. Two approaches were taken to calculate the starting dose: (1) 
use of the lowest EC20 value determined in the in vitro cytokine release assay and (2) use of 
the highest non-severely-toxic dose (HNSTD) level determined in the 6-week repeat dose 
toxicology study in the monkey, the most relevant toxicology species. The lowest starting 
dose of 0.05 mg/kg BI 905677 was selected and is expected to be an adequate and safe 
starting dose.
Approach 1 (use of EC20 value): The MRSD is calculated to be 0.09 mg/kg/dose.
In an in vitro cytokine release assay [n00254050], whole blood samples from eleven healthy 
human donors were incubated for 24 hours with various concentrations of BI 905677 (0.3, 3, 
10, and 30 mg/mL). Releases of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-
8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-
γ) were measured.


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IL-2 and IL-10 levels were not elevated with BI 905677 treatment for any of the donors.
Elevations of IL-6, IL-8, TNF-α and IFN-γ were observed in 2 of 11 donors at the two 
highest concentrations of BI 905677 (10 and 30 mg/mL). Levels of these cytokines at 0.3 and 
3 μg/mL were below the levels of the Avastin negative control.
The EC20 values for the 4 responding cytokines (IL-6, IL-8, TNF-α, and IFN-γ) were 
calculated using the mean cytokine values obtained at 4 different concentrations of BI
905677 (0.3, 3, 10, and 30 mg/mL) from the two donors with cytokine release [n00259622]. 
A human dose that is estimated to result in a Cmax equivalent to the EC20 was then calculated 
with the assumption of linear pharmacokinetics (Table 4.1.2.1: 1).
The calculated EC20 values are similar for 4 cytokines of two donors (see Table 4.1.2.1: 1). 
The lowest EC20 is 0.5 µg/mL for IL-8 and TNF-α in one donor (1465M). A human dose of 
0.09 mg/kg is predicted to have a Cmax of 0.5 µg/mL.
Table 4.1.2.1:1
Summary of Predicted Human Dose at EC20 values for Four 
Cytokines in Two Positive Human Donors
Cytokine
Positive Human Donor (1437F)
Positive Human Donor (1465M)
EC20
(g/mL)
Predicted Human Dose
(mg/kg)
EC20
(g/mL)
Predicted Human Dose
(mg/kg)
IL-6
1.1
0.20
0.8
0.14
IL-8
0.9
0.16
0.5
0.09
IFN
1.1
0.20
0.9
0.16
TNF
1.1
0.20
0.5
0.09
The lowest EC20 and predicted human dose is in bold.
Approach 2 (use of HNSTD level): The MRSD is calculated to be 0.05 mg/kg/dose.
Step 1:
Determination of HNSTD (Highest Non-Severely Toxic Dose) in the repeat 
dose toxicity study if non-rodent is the most appropriate species (6-week GLP 
study in the monkey)
Monkey:
HNSTD = 1 mg/kg/dose q1w
Step 2:
Conversion of 1/6th animal HNSTD to Human Equivalent Dose (HED)
Monkey:
1/6th HNSTD = 0.17 mg/kg/dose q1w
Conversion factor from monkey dose to HED: 0.324 (based on body surface
area scaling factor for the drug molecular weight < 100 kDa)
HED = 0.17 mg/kg/dose x 0.324 = 0.055 mg/kg/dose q1w
HED = 3.3 mg/dose q1w (60 kg human body weight)
The selected starting dose of 0.05 mg/kg/dose is 22x or 66x below the predicted efficacious 
human dose of 1.1 mg/kg/dose q1w or 3.3 mg/kg/dose q3w, respectively. The estimated 
exposures in humans at 0.05 mg/kg are 0.28 g/mL Cmax and 14.82 g•h/mL AUC0-168h and 
these exposures are 42X (Cmax) and 20X (AUC0-168h) below the exposures achieved at the 
NOAEL/HNSTD determined in the 6-week monkey study (steady state mean males and 
females combined exposure of 11.8 g/mL Cmax and 299 g•h/mL AUC0-168h at 1 mg/kg/dose 
q1w).


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Considering the key dose limiting toxicities are the gastrointestinal toxicity and potential 
cytokine releases which can be managed and closely monitored in the clinic, the starting dose 
of 0.05 mg/kg is considered to be adequately safe. For further details please refer to the 
Investigator’s Brochure (c16307316).
At the end of each treatment cohort, BI will convene a meeting with the SMC members. At 
the dose escalation meeting, the clinical course (safety information including both DLTs and 
all CTCAE Grade >= 2 toxicity data during the DLT evaluation period, and all available PK 
data) for each patient in the current dose cohort will be described in detail. Updated safety 
data on other ongoing patients, including data beyond the DLT evaluation period, will be 
discussed as well. Based on that, a decision on the next dose level to be tested is made. Dose 
escalation will continue until identification of the MTD, safety concerns arise, or the trial is 
terminated for other reasons.
4.1.2.2
Starting Dose for Schedule B
After determination of the MTD in Schedule A, Schedule B will commence. The starting 
dose in Schedule B will be determined by the SMC, and will not exceed 30% of the MTD 
from Schedule A. The SMC will also review whether the planned dosing schedule, 
assessments and sample collection in Schedule B remain appropriate. Schedule B will utilise 
its own BLRM and prior distribution will be derived from data in Schedule A.
The dose levels and cohort sizes in Schedule B will be decided by the SMC, following the 
same process and rules as for Schedule A (described in Section 4.1.2.1). 
Based on the observations of safety and tolerability in Schedule B (dosing every 2 weeks), 
the SMC may decide to reduce the dosing frequency in Schedule B to once every 4 weeks
and the provisional dose levels and a new BLRM will be specified. If this occurs it will be 
documented in the CTMF, investigators will be informed in writing and the information for 
patients will be updated. The following activities/assessments on Day 15 of each cycle will 
not be performed; Physical Examination, weight, blood sample for anti-drug antibodies 
(ADAs), BI 905677 infusion.
4.1.3
Method of assigning patients to treatment groups
At any time during the trial, a single dose cohort will be open for recruitment and each patient 
will be allocated to the next available cohort. Medication will be assigned via Interactive 
Response Technology (IRT) for each treatment cycle. Each medication vial will have a 
unique medication number.
4.1.4
Drug assignment and administration of doses for each patient
The study drug will be prepared and handled according to the ‘Clinical Supplies Handling 
Instruction’ which will be filed in the ISF. Upon notification that a patient will be treated in 
the study, the pharmacy will prepare the study drug at the assigned dosage for administration 
to the patient.


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The Cycle 1 Day 1 dose will be calculated using the Cycle 1 Day 1 weight as the reference 
weight. If the patient’s weight changes by ≤ 5% compared to the reference weight, the dose 
(in mg) may remain the same for subsequent cycles. If the weight changes by > 5% the dose 
will be recalculated and the new weight will be used as the reference weight.
BI 905677 will be given as an intra-venous infusion by authorised site staff in a specialised 
unit where emergency care can be provided (e.g. intensive care unit available, medical 
personnel trained in advanced life support). The expected infusion time is approximately 60
minutes. Patients must remain under observation for potential signs and symptoms of 
cytokine release for at least 6 hours following the end of infusion of BI 905677. If no signs or 
symptoms are observed during the first three administrations the duration of observation may 
be reduced to 3 hours for subsequent administrations. For patients who require systemic 
steroids around the time of administration of BI 905677 or during the post-treatment 
monitoring period, hospitalisation and monitoring for at least 24 hours is mandatory.
Appropriate drugs and medical equipment to treat anaphylactic reactions must be 
immediately available and study personnel must be trained to recognise and treat 
anaphylaxis.
No routine premedication will be required for BI 905677 i.v. infusion.
4.1.4.1
Re-treatment criteria
Before administering a treatment dose the investigator must review the assessments 
performed according to the Flowchart and assess eligibility to receive further treatment and 
check that the following criteria are met;
o
Absence of disease progression
o
Drug related AEs recovered to Grade ≤ 1 (or baseline if higher than Grade 1)
o
For AEs that do not require a treatment interruption, a toxicity of CTCAE Grade 2
(e.g. hypophosphatemia, anorexia, neuropathy) may be acceptable, provided the 
investigator considers it safe for the patient to continue treatment
If the criteria for re-treatment are not met, the patient should be evaluated and the next dose 
of treatment may be delayed until the criteria are met. For patients on Schedule A the dose 
may be delayed for up to 14 days. For patients on Schedule B, the dose may be delayed for 
up to 7 days. Dose reduction may be appropriate (see Section 4.1.4.7).
4.1.4.2
Management of infusion-related reactions
Infusion-related reactions involve the immune system; however, they can have different 
mechanisms. Some are allergic in nature and are usually mediated by immunoglobulin E 
while others are not classical allergic reactions (so-called anaphylactoid reactions e.g. caused 
by cytokine release). Although infusional reactions can be allergic or nonallergic, clinical 
symptoms are difficult to distinguish and require rapid assessment and immediate 
management to avoid severe adverse events, including fatality.
If an infusion-related reaction of ≥ CTCAE Grade 3 occurs, study treatment must be 
permanently discontinued.


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If symptoms of an infusion-related reaction of CTCAE Grade 2 occur, which do not qualify 
as DLT according to Section 5.2.7, the infusion should be temporarily stopped. Upon 
recovery, the following guidance must be followed;

If more than 50% of the planned dose of BI 905677 was administered, no further 
BI 905677 will be administered until the next scheduled dose.

If less than 50% of the planned dose of BI 905677 was administered due to CRS, a 
further dose of 50% of the intended total dose may be administered on the 
following day and after recovery to baseline for at least 24 hours.

During the first re-exposure patients should be hospitalised for at least 24 hours
and closely monitored during the first re-exposure. 

Premedication must be used for all subsequent treatment infusions. The 
recommended premedication is:
o
Acetaminophen/Paracetamol 650 mg - 1000 mg p.o., or equivalent
o
Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.
o
Glucocorticoid i.v., equivalent to prednisolone 50-100 mg 

The infusion rate for further treatment cycles may be adapted according to 
Investigator decision, but any adaption of the infusion rate must be agreed with the 
sponsor.
If infusion reactions and/or hypersensitivity reactions occur in a substantial proportion of 
treated patients without premedication, the SMC may decide that all future patients treated in 
the study must receive premedication (as described above) prior to BI 905677 infusion; the 
dosage and schedule of premedication will be aligned and will take into account any local 
clinical standards. Such a decision will be communicated to all investigators in writing.
4.1.4.3
Management of Cytokine Release Syndrome (CRS)
CRS is a disorder characterised by fever, tachypnea, headache, tachycardia, hypotension, 
rash, and/or hypoxia caused by the release of cytokines. As outlined above in section 4.1.4.2,
clinical manifestations of CRS and other forms of infusion related reactions are difficult to 
distinguish (especially at first occurence) and require rapid diagnosis and immediate 
management to avoid severe adverse events, including fatality.
Patients will be closely monitored for potential signs and symptoms of CRS (e.g. 
hypotension, rash, tachypnea, hypoxia, tachycardia, fever, nausea, fatigue, headache, 
myalgias and malaise). Patients must remain under observation for potential signs and 
symptoms of cytokine release for at least 6 hours following the end of infusion of BI 905677. 
If no signs or symptoms are observed during the first three administrations patients the 
duration of observation may be reduced to 3 hours for subsequent administrations. For 
patients who require systemic steroids around the time of administration of BI 905677 or 
during the post-treatment monitoring period, hospitalisation and monitoring for at least 24 
hours is mandatory.
Body temperature, pulse rate and blood pressure will be measured prior to the start of 
infusion, every 30 minutes (± 10 minutes) during the infusion, and then at the following 
regular intervals during the post-treatment observation period;

every 30 minutes (± 10 minutes) during the first 3 hours after end of infusion

every hour (± 10 minutes) between 3-6 hours after end of infusion (if relevant)


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
every 4-8 hours from 6 hours after end of infusion until observation ends (if relevant)
In case of suspected or confirmed CRS, patients will be appropriately treated according to 
best medical judgement based on institutional standards and/or publications (e.g. R16-2323). 
Supportive therapy including antipyretics, intravenous fluids, and low dose vasopressors may 
be used. In patients who do not respond to this, corticosteroids and/or interleukin 6 receptor 
antagonists (R15-0031, R18-1685, R18-1686) may be required and patients should be 
monitored closely, preferably in an intensive care unit.
In the event of CTCAE ≥ Grade 3 CRS study treatment must be permanently discontinued.
In the event of CTCAE Grade 2 CRS the guidance for handling a CTCAE Grade 2 infusion-
related reaction must be followed (section 4.1.4.2).
4.1.4.4
Management of bone toxicity
Patients will be monitored for bone toxicity using regular measurement of serum bone 
biomarkers (section 5.2.5.1) and bone densitometry (section 5.2.5.2). Treatment with vitamin 
D and/or calcium carbonate is recommended in patients with documented pre-existing
osteoporosis. 
In case of a β-CTX increase of ≥ 50% or a P1NP decrease of ≥ 50%, zoledronic acid or 
another bisphosphonate will be initiated according to the standards of the institution. In case 
of a pathological fracture of any grade, BI 905677 must be permanently discontinued.
4.1.4.5
Management of retinal toxicity
Visual symptoms (e.g.loss in visual acuity, blurred or distorted vision, floating specks or 
cobwebs, night vision changes or color vision changes) during study treatment will trigger the 
same ophthalmologic assessments as performed as baseline as well as a full retinal 
examination (see also section 5.2.5.4).
Treatment with BI 905677 must be discontinued if either of the following are observed:

CTCAE grade ≥ 2 retinopathy

Clinically meaningful changes in fundus photography and SD-OCT as determined by 
the examining ophthalmologist
4.1.4.6
General management of toxicities
Toxicities not covered within sections 4.1.4.2, 4.1.4.3, 4.1.4.4 and 4.1.4.5 will be handled 
according to the instructions in table 4.1.4.6:1  For the definition of a DLT, refer to Section 
5.2.7.
Table 4.1.4.6: 1 Management of toxicity
Event
First occurrence
Second occurrence
Grade 4 non-
haematological 

Permanently discontinue 
treatment
Not applicable


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toxicity which is 
related to BI 
905677

Start supportive measures 
according to standards of the 
institution
Haematological 
toxicity 
fulfilling criteria 
for DLT (see 
Section 5.2.7)

Hold BI 905677 treatment until 
recovery to Grade ≤ 1 or 
baseline; start supportive 
measures according to 
standards of the institution 
(e.g. G-CSF, antibiotics, 
platelet transfusion)

Perform complete blood count 
at least twice per week until 
improvement to a lower grade

Patient may be eligible to 
continue BI 905677 treatment 
at a lower dose - see section 
4.1.4.7

Permanently 
discontinue BI 905677

Start supportive 
measures according to 
standards of the 
institution (e.g. G-CSF, 
antibiotics, platelet 
transfusion)

Perform complete 
blood count at least 
twice per week until 
improvement to a 
lower grade
Non-
haematological 
toxicity Grade 
<4 fulfilling the 
criteria for DLT 
(see Section 
5.2.7)

Hold BI 905677 treatment until 
recovery to Grade ≤ 1 or 
baseline; start supportive 
measures according to 
standards of the institution 
(e.g. anti-emetics, loperamide 
and/or other conventional anti-
diarrheals)

Patient may be eligible to 
continue BI 905677 treatment 
at a lower dose - see section 
4.1.4.7

Permanently 
discontinue BI 905677

Start supportive 
measures according to 
standards of the 
institution
Toxicity which 
does not meet 
DLT criteria e.g.
nausea, 
vomiting, 
diarrhoea ≤ 
Grade 2

Start supportive measures 
according to standards of the 
institution (e.g. anti-emetics, 
loperamide and/or other 
conventional anti-diarrheals)

If event is Grade ≥ 2, hold 
BI 905677 treatment until 
recovery to Grade ≤ 1. A 
toxicity of CTCAE Grade 2 
(e.g. hypophosphatemia, 
anorexia, neuropathy) may be 
acceptable, provided the 
investigator considers it safe 
for the patient to continue 
treatment.

As for first occurence


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4.1.4.7
Dose Reduction
In the event of a DLT which meets certain criteria the patient may continue therapy at a 
reduced dose (see Table 4.1.4.6: 1 for criteria). Patients may continue therapy only after 
recovery from the DLT to grade ≤ 1 or baseline and when re-treatment criteria are met
(Section 4.1.4.1). The patient will re-commence treatment at a reduced dose of BI 905677; 
the dose will be one dose level down (according to the BLRM for the relevant treatment 
schedule) from the previous dose administered to the patient. 
A maximum of one dose reduction will be allowed for an individual patient during the whole 
trial and a subsequent dose increase will not be allowed. A dose reduction to a level below 
the trial starting dose is not allowed. In the event of a second occurrence of toxicity requiring 
dose reduction, the patient must permanently discontinue treatment.
4.1.5
Blinding and procedures for unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational product will be provided by BI or a designated Contract Research 
Organisation (CRO). It will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT 
system, which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
BI 905677 will be kept in its original packaging and in a secure limited access storage area 
according to the storage instructions as provided 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 sponsor must be contacted immediately.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / ethics 
committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 


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The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the 
administration to 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 product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. 
At the time of return to the sponsor at the end of the trial, the investigator / pharmacist / 
investigational drug storage manager must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Rescue medications to reverse the actions of BI 905677 are not available. Potential adverse 
events should be treated symptomatically and must be recorded. Concomitant medications or 
therapy to provide adequate supportive care may be given as clinically necessary. 
Radiotherapy for local symptom control of non-target lesions may be allowed if agreed 
between the investigator and sponsor.
All concomitant therapy, including pre-medication, anaesthetic agents, vitamins, 
homeopathic/herbal remedies and nutritional supplements must be recorded in the eCRF 
during the screening and treatment period, starting from the date of signature of informed 
consent, and ending at the EOT visit. Between the EOT visit and the individual patient’s end 
of trial, only concomitant therapy indicated for treatment of an AE has to be reported.
Concomitant therapies used as pre-medication prior to infusion of BI 905677 will be 
indicated in the eCRF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The use of prophylactic haematopoietic growth factors (e.g. G-CSF) is prohibited in cycle 1.
No experimental anti-cancer treatment and/or standard chemo-, immunotherapy, hormone 
treatment, or radiotherapy (other than described in Section 4.2.1) is allowed concomitantly 
with the administration of study treatment. 


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4.2.2.2
Restrictions on diet and life style
There are no restrictions on diet and lifestyle.
4.2.2.3
Restrictions regarding women and men of childbearing potential 
Women of childbearing potential (for the definition please refer to Section 3.3.2) and men 
able to father a child must use two medically approved methods of birth control throughout 
the trial, and for a period of at least 6 months after last trial drug intake. They must use one 
barrier method, i.e. condom or occlusive cap with spermicide, or vasectomized partner, and 
one highly effective non-barrier method including oral, injected or implanted hormonal 
contraceptives, intrauterine device or system.
Male patients: 
Men whose partner is a woman of childbearing potential must use a condom during the study, 
and for a period of at least 6 months after the last dose of study drug.
Female patients: 
Women of childbearing potential (WOCBP) must use a highly effective method of birth 
control per ICH M3 (R2) that results in a low failure rate of less than 1% per year when used 
consistently and correctly during the study, and for a period of at least 6 months after the last 
dose of study drug.
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm.
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
BI 905677 will be administered as an intravenous infusion at the clinical site under the 
supervision of trained site personnel. Therefore actual dosing is expected to follow the 
protocol. The dose administered will be recorded in the eCRF and any irregularities in dosing 
will also be documented in the eCRF by the investigator or designee.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Tumour assessment
Tumour response will be evaluated according to RECIST Version 1.1 (R09-0262). 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).
Baseline imaging should include imaging of all known or suspected sites of disease using an 
appropriate method. The investigator (or designee) will record the target and non-target 
lesions in the eCRF. Lesions in previously irradiated areas may not be considered measurable 
at baseline unless the lesions occurred after irradiation. The same method of assessment and 
the same imaging technique must be used at each subsequent timepoint to characterise each 
reported lesion throughout treatment and during follow-up.
Tumour assessment will be performed at the timepoints indicated in the Flowchart. Wherever 
possible the assessment schedule should not be changed, but if there is an interruption or 
delay to treatment, alteration of the tumour assessment schedule to align with clinical 
assessments is allowed. Additional unscheduled tumour assessments may be performed at the 
discretion of the Investigator.
Copies of images collected during this study may be sent to a central imaging facility of an 
independent CRO where they will be stored for up to 30 years. During this time, if needed, an 
independent assessment of tumour response using the stored images may be performed but 
individual results will not routinely be reported to investigators and will not influence 
treatment or medical decisions while the patient is participating in this study.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A physical examination will be performed at the timepoints specified in the Flowchart. 
A full physical examination serves as a clinical tumour assessment and should include a 
cardiopulmonary examination, examination of the regional lymph nodes, the abdomen and an 
assessment of the mental and neurological status. Additional symptoms which have not been 
reported during a previous examination should be clarified. Wherever possible the same 
investigator should perform this examination.
Measurement of height (in cm), body weight (in kg) and the evaluation of the ECOG 
performance score (see Appendix 10.5) will be performed at the timepoints specified in the 
Flowchart.
5.2.2
Vital signs
Vital signs (body temperature, blood pressure and pulse rate after 2 minutes of supine rest) 
will be recorded at the time points specified in the Flowchart.


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Body temperature, pulse rate and blood pressure will be measured prior to the start of 
infusion, every 30 minutes (± 10 minutes) during the infusion, and then at the following 
regular intervals during the post-treatment observation period (variable duration; see section 
4.1.4.2 for details);

every 30 minutes (± 10 minutes) during the first 3 hours after end of infusion

every hour (± 10 minutes) between 3-6 hours after end of infusion (if relevant)

every 4-8 hours from 6 hours after end of infusion until observation ends (if relevant)
In case of an infusion-related reaction the investigator should decide whether increased 
monitoring of vital signs is required.
5.2.3
Safety laboratory parameters
Safety laboratory parameters will be analysed at a local laboratory. Safety laboratory 
examinations will include tests as listed in Table 5.2.3:1, and should be obtained at the time 
points specified in the Flowchart.
Table 5.2.3:1
Safety Laboratory Tests
Category
Parameters
Haematology
Red blood cell count (RBC), haemoglobin,
haematocrit, platelet count, reticulocytes, white 
blood cell count ( WBC) with differential 
(neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils)
Coagulation
International Normalized Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Biochemistry
Glucose, sodium, potassium, calcium, phosphate, 
magnesium, chloride, bicarbonate (HCO3), urea, 
creatinine, AST, ALT, alkaline phosphatase, 
lactate dehydrogenase (LDH), bilirubin, total 
protein, albumin. Creatinine clearance, creatine 
phosphokinase, cholesterol and triglycerides if 
indicated.
Immunoglobulins
Serum immunoglobulin levels (IgG, IgM, IgA, 
IgE) and direct antiglobulin test to be measured at 
screening and repeated if an infusion related 
reaction occurs.
Urinalysis
pH, protein, glucose, blood, leucocytes, nitrite; in 
case of pathological finding further evaluation 
should be performed and results documented 
Pregnancy test
β-HCG testing in urine or serum in women of 


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Category
Parameters
childbearing potential (WOCBP)
In case of haematological toxicity of Grade 4, or other haematological AEs fulfilling the 
criteria for DLT, a complete blood count has to be performed at least twice per week until 
improvement to a lower grade. The investigator should complete additional evaluations of 
laboratory tests as clinically indicated. Any abnormal and clinically relevant findings from 
these investigations need to be reported as an Adverse Event.
In case the criteria for possible hepatic injury are fulfilled, a number of additional tests will 
be performed (please see Section 5.2.6.1 and the “DILI Checklist” provided in the study 
portal and the ISF).
In addition to the tests above, a blood test for Vitamin D will be performed at screening, 
every third cycle (Cycle 3 Day 1, Cycle 6 Day 1 etc) and at EOT. This will be analysed at a 
local laboratory.
5.2.4
Electrocardiogram
A 12-lead resting ECG will be performed at the timepoints indicated in the Flowchart and in 
section 10.2 and 10.3. The investigator or a designee will evaluate whether the ECG is 
normal or abnormal and whether it is clinically relevant, if abnormal. ECGs may be repeated 
for quality reasons and the repeated recording used for analysis. 
On Day 15 of Cycle 1 (Schedule B only) and on Day 1 of each cycle from Cycle 2 onwards 
the ECG should be performed prior to treatment and reviewed as part of the assessment of 
eligibility for further treatment.
Additional ECGs may be performed for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record. Clinically relevant abnormal 
findings will be reported either as baseline condition (if identified at the Screening visit) or 
otherwise as adverse events and will be followed up and/or treated as medically appropriate.
5.2.5
Other safety parameters
5.2.5.1
Safety biomarkers for bone resorption
Biomarkers for bone resorption and formation (including, but not limited to, β-Carboxy-
terminal Telopeptide (β-CTX), P1NP) will be assessed in a blood sample at baseline (Cycle 1 
Day 1), at the start of cycle 2 and cycle 3 and then every 2 cycles (every odd-numbered 
cycle) and at EOT. Assessment will be performed in a central laboratory and results will be 
provided to investigators unless local regulations prohibit this. In the event that clinically 
significant changes are observed, these will be discussed within the SMC and appropriate 
action agreed.


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When a blood sample for bone biomarkers is required, it will be obtained prior to 
administration of trial medication, before 9am, and in a fasting state (at least 8 hours since 
last food intake).
5.2.5.2
Bone densitometry
Bone densitometry will be performed at the times indicated in the Flowchart according to 
standard institution practice and bone mineral density will be recorded. In the event that bone 
mineral density changes by >5% from baseline, bone densitometry will be repeated at least 
two months after the change is first observed to determine whether the change has persisted 
and constitutes a DLT (see Section 5.2.7).  
In addition to the above, the SMC will regularly review any reported bone mineral density 
changes of >5% from baseline which have not yet been confirmed after two months and if 
necessary, appropriate action will be agreed.
5.2.5.3
Testing for Cytokine Release
Patients must remain under observation for potential signs and symptoms of cytokine release 
for at least 6 hours following the end of infusion of BI 905677. If no signs or symptoms are 
observed during the first three administrations the duration of observation may be reduced to
3 hours for subsequent administrations. For patients who require systemic steroids around the 
time of administration of BI 905677 or during the post-treatment monitoring period, 
hospitalisation and monitoring for at least 24 hours is mandatory.
Clinical signs and symptoms of cytokine release will be recorded as AEs. In addition, a panel 
of cytokines (including, but not limited to IL-2, IL-6, IL-10, IFN-γ, TNF-α, MCP-1) will be 
measured in peripheral blood in order to monitor release of cytokines after BI 905677
administration. Cytokine measurements will be performed in conjunction with each infusion 
at the timepoints specified in Appendices 10.2 and 10.3.
In addition to the scheduled cytokine measurements, ferritin will be measured at baseline 
(Cycle 1 Day 1). If a clinically manifested cytokine release syndrome occurs at any
timepoint, unscheduled blood sampling for cytokine and ferritin measurement will be 
performed, ideally at the start of symptoms (and before start of corticosteroid treatment) and
48-72 hours after the start of symptoms.
Cytokines and ferritin will be measured in a central lab authorised by Boehringer Ingelheim 
using immunoassay techniques, such as BD Cytometric Bead Array (CBA) and MSD assay. 
Details are specified in Appendices 10.2 and 10.3, and in the Laboratory Manual.
5.2.5.4
Ophthalmologic Assessment
Ophthalmologic assessment will be performed for all patients at the screening visit. The 
following assessments will be performed;

Best corrected visual acuity (BCVA): BCVA will be determined using the 
early treatment diabetic retinopathy study (ETDRS) visual acuity chart starting at a 
test distance of 4 metres. The BCVA score is the number of letters read correctly by 


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the patient. The assessment will be performed by a trained person under standard 
conditions regarding examination room and equipment.

Colour fundus photography: Seven-field or modified 4-field digital fundus 
photographs will be obtained from both eyes by a qualified person. 

Spectral domain optical coherence tomography (SD-OCT): The retinal layers and 
thickness can be visualized and measured by SD-OCT. The assessment will be 
performed by a qualified person, and only 
equipment 
will be used.
The same ophthalmologic assessments will be repeated if the patient develops visual 
symptoms during the trial. If the ophthalmological assessments are repeated, they should be 
performed using the same devices/equipment as used at screening. Additionally, a full retinal 
examination must be performed.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An adverse event (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.
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 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
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. 


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For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the duration between discontinuation of the trial medication and must be 
reported as described in 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 eDC system. These events should 
always be reported as SAEs as described above.
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 above. The sponsor will submit specific AESI 
reports to the regulatory authority in an expedited fashion where required by the authority.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

For patients with normal liver function at baseline (ALT, AST, and bilirubin within 
normal limits at baseline): 
o
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample, and/or 
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN

For patients with abnormal liver function at baseline (AST and/or ALT>ULN) 
o
an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of 
total bilirubin ≥2 fold ULN measured in the same blood draw sample, with the 
exclusion of the causes due to underlying diseases, and/or
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the study 
portal and in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 


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analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Dose Limiting Toxicity
Any medical event fulfilling the criteria of DLT (see Section 5.2.7) should be reported as an 
AESI.
Infusion-related Reactions (including Cytokine Release Syndrome)
The following terms describe those events that are to be considered infusion-related 
reactions. Regardless of grade, these events, when occurring within 72 hours of study drug 
administration, are considered AESIs and must be reported as such;

Allergic reaction

Anaphylaxis

Cytokine-release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions

Any other event which the investigator determines may be a potential infusion-related AE
Treatment of infusion-related reactions and the handling of subsequent trial dosing are 
described in Section 4.1.4.2.
The initial clinical sign of a CRS is fever that can rise to high temperatures and is often 
associated with flu-like symptoms (e.g. nausea, fatigue, headache, myalgias, malaise, chills, 
rigor, tremor, hypoxia, tachypnea, rash, vomiting, diarrhoea, abdominal pain, muscle and 
joint pain, and generalised weakness). CRS symptoms may occur quickly during or after 
administration, or after several hours or days. Patients will be assessed for signs and 
symptoms of CRS and CRS will be reported as an AESI.
Management guidelines and treatment of CRS are described in Section 4.1.4.3.
Retinal toxicity
Any retinal toxicity (Standardised MedDRA Query ‘Retinal Disorder’) will be reported as an 
AESI.
Other AESIs
Based on safety observations during the trial, the SMC may define additional AEs as AESIs. 
If this occurs, investigators will be informed in writing.
Severity of AEs
The severity of adverse events should be classified and recorded in the eCRF according to the 
CTCAE version 5.0 (R18-1357).
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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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 diminished).
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.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files. The 
following must be collected and documented on the appropriate eCRF(s) by the investigator:

From signing the informed consent onwards until the individual patient’s end of trial: all 
AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: the investigator does not need to actively 
monitor the patient for AEs but should only report related SAEs and related AESIs of 
which the investigator may become aware of by any means of communication, e.g. phone 
call. Those AEs should however, not be reported in the eCRF.


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Figure 5.2.6.2: 1
Safety reporting
AE reporting to 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.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the eCRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions (if not 
recorded as a study endpoint; see exemption below).
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
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.


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Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner. 
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.
Exemptions to AE reporting
Disease Progression is recorded to enable analysis of efficacy endpoints. Progression of the 
patient's underlying malignancy will be recorded on the appropriate pages of the eCRF as 
part of efficacy data collection and will not be reported as an AE unless the criteria for
seriousness are met (see ‘Serious adverse event’ definition), in which case SAE reporting 
procedures will be followed.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy (PD), the event must be reported as an SAE 
on the SAE Form and on the eCRF.
Clinical symptoms and/or signs of PD will be recorded as adverse events.
5.2.7
Definition of Dose Limiting Toxicity (DLT)
All DLTs occurring during the first or subsequent treatment cycles should be reported as 
AESIs according to the same timelines as serious AEs. Any of the following AEs will be 
classified as DLTs following review by the SMC and the Medical Monitor, unless 
unequivocally due to underlying malignancy or an extraneous cause;

Schedule A; Any AE which prevents a patient starting Cycle 2 within 14 days of 
completion of Cycle 1

Schedule B; Any AE which prevents a patient starting Cycle 2 within 7 days of 
completion of Cycle 1

Bone mineral density change of >5% from baseline, confirmed at least 2 months after 
initial observation

β-CTX increase of more than two-fold from baseline


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
Grade 3 osteoporosis

CTCAE grade ≥ 2 retinopathy and clinically meaningful changes in fundus 
photography and SD-OCT as determined by the examining ophthalmologist

Any fracture without a history of trauma or as a result of a fall from standing height or 
less

Haematologic toxicities:
-
Grade 4 anaemia
-
Grade 3 anaemia requiring blood transfusion
-
Neutropenia Grade 4 present for >7 days
-
Febrile neutropenia ≥ Grade 3
-
Neutropenia Grade 3 with documented infection
-
Any Grade 3 thrombocytopenia with bleeding or a requirement for platelet 
transfusions
-
Grade 4 thrombocytopenia (platelets <25,000/μL)

Grade 4 vomiting or diarrhoea (irrespective of whether adequately treated)

Any ≥Grade 3 non-haematologic toxicity with the following exceptions:
-
Inadequately treated grade 3 vomiting or diarrhoea persisting for less than 48 
hours after start of adequate treatment
-
Grade 3 vomiting or diarrhoea which persists for less than 48 hours after start of 
adequate treatment
-
Inadequately treated nausea
-
Grade 3 fatigue that persists <7 days
-
Any Grade 3 laboratory abnormality which is not considered clinically relevant by 
the investigator, resolves spontaneously or responds to conventional medical 
intervention
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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Pharmacokinetic profiles of BI 905677 in serum will be investigated after the first and after 
repeated doses. Standard PK parameters as listed in Appendix 10.1 will be calculated, if data 
allow and if scientifically reasonable.
Pharmacokinetic data may additionally be analysed using a population pharmacokinetic 
approach. Modelling and simulation activities will be planned and documented separately 
according to internal and external guidelines and SOPs.
Exploratory pharmacokinetic analyses can be performed as necessary for SMC decisions, but 
are not expected to be done more frequently than every second SMC meeting and do require 
sufficient lead time to collect samples, measure BI 905677 serum concentrations, analyse 
data and prepare meaningful outputs. The final exploratory analysis will be performed at the 
earliest after the cohort at MTD of treatment Schedule B completed the first treatment cycle.


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For the purpose of these exploratory analyses, PK serum samples obtained up to at least 24 
hours after drug administration will be used. A scientifically sound subset of the PK 
parameters listed in Appendix 10.1 will be calculated which may include Cmax, AUC and t1/2, 
if these parameters can be reliably determined from the available samples and serum 
concentration time profiles. In contrast to the final PK analysis, the exploratory analyses will
be based on planned sampling times rather than on actual times; no supplementary subject
information, e.g. on AEs or concomitant medication, will be used in these analyses, and the 
outputs will not be validated. Minor discrepancies between exploratory and final results may 
therefore occur.
5.3.2
Methods of sample collection
The timepoints for collection of PK samples are given in Appendices 10.2 and 10.3. Details 
of the sample collection, preparation, storage and shipment are described in the laboratory 
manual.
After completion of the trial, the samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final study 
report has been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a pharmacokinetic/pharmacodynamic relationship is planned.
Correlation between drug concentration and response may be made if adequate data are 
available. In addition, exploratory correlation may also be made between drug concentration 
and AEs.
Data may also be used to develop pharmacokinetic/pharmacodynamic models, if feasible. 
Modelling and simulation activities will be planned and documented separately according to 
internal and external guidelines and SOPs.
5.4
ASSESSMENT OF BIOMARKERS
This section refers to exploratory biomarkers. Established biomarkers of safety are described 
and discussed in Section 5.2. All biomarkers will be assessed in a central laboratory at BI or a 
by a designated CRO.
5.4.1
Biomarker analysis
 
 
 


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detailed below. Baseline sampling must only be performed for patients who have undergone 
screening assessments and are expected to be eligible for treatment in the trial.
All samples are expected to be exhausted during the course of investigative analysis. Should 
this not be the case, samples might also be used for assay validation and concordance testing. 
Remaining samples will be disposed of at the latest 5 years after the end of the trial. Until 
then, samples will be stored at Boehringer Ingelheim or a designated CRO.
 
Pre-treatment and on-treatment skin biopsies will be obtained at the time points indicated in 
the Flowchart. Skin biopsy will be performed for all patients in the relevant schedule who 
start treatment after at least one of the following criteria has been met within the schedule;

A Grade 2 AE has been observed (excluding toxicities which are clearly 
related to disease progression or concurrent illness)

Dose escalation has reached a dose level ≥ 0.8 mg/kg
Data obtained from the analysis of skin biopsies will not be disclosed to patients because the 
analysis is exploratory. If consent is withdrawn, all samples and the data that had already 
been collected up to the time of withdrawal of consent will still be used.
5.4.1.1
Methods of sample collection for skin biopsies
Skin biopsies (6 mm punch) will be performed pre-treatment and on treatment 48-96 hours
after infusion of Cycle 2. The exact timing of this sample may be modified based on the 
observations from the first patients in the trial. If this happens it will be documented in the 
CTMF, communicated to investigators in writing and the information given to new patients 
will be updated.
A 6 mm punch biopsy is to be obtained using the investigator’s standard procedure. Upon 
attaining the skin biopsy the specimen should be immediately transferred to
 tube 
and stored overnight in a refrigerator at approximately 2-8°C. The sample must be at the 
bottom of the tube. The next day samples are to be transferred to a freezer (approximately -
20°C, non-self-defrost) and stored until ready to be shipped.
Detailed instructions for sampling, handling, and shipment of samples are provided in the 
ISF/laboratory manual.
5.4.2
Biobanking
No biobanking is planned.
5.5
OTHER ASSESSMENTS
5.5.1
Demographics and history
Demographic information including gender, year of birth and race/ethnicity, as well as 
general medical history and detailed oncological disease history will be collected. This will 
include date of first diagnosis of malignancy, staging and grading information, and details of 
previous treatment for malignancy.


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5.5.2
Sampling for anti-drug antibodies (ADAs)
5.5.2.1
Methods of ADA sample collection
For the determination of anti-drug antibodies (ADA), approximately 3 mL of blood will be 
taken from a forearm vein in a blood drawing tube at those time points specified in the 
Flowchart and in Appendices 10.2 and 10.3.
Details of the sample collection, preparation, storage and shipment are described in the 
laboratory manual.
5.6
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD is based on toxicities graded according to CTCAE version 5.0 (R18-
1357). The CTCAE criteria are commonly used in the assessment of AEs in cancer patients.
RECIST 1.1 (R09-0262) is used for evaluation of response. These criteria are well-
established and scientifically accepted.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients should adhere to the visit schedule as specified in the Flowchart. If treatment 
administration is delayed at any time, the schedule of all subsequent visits/cycles will be 
recalculated based on the actual date of treatment. 
If a patient misses a visit during which there is no treatment administration planned, the visit 
should be rescheduled as soon as possible and the delayed visit documented with the actual 
date and the reason for the delay. The scheduling of subsequent visits must not be altered, so 
if it is not possible to reschedule prior to the next planned visit, the missed visit should be 
skipped.
If a patient is hospitalised for administrative reasons to allow treatment and PK sampling this 
will not be considered an SAE, unless any other criteria for an SAE are fulfilled.
In addition to the scheduled assessments, unscheduled assessments for safety reasons may be 
performed at any time according to clinical need.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Following informed consent, the patient will undergo visit 1/screening assessments as 
indicated in the Flowchart. The assessments must fall within the acceptable Screening visit 
window but do not need to be performed on the same day. Screening assessments may be 
repeated as long as they fall within the Screening visit window. If more than one screening 
assessment is available, the latest assessment prior to the start of treatment must be used to 
assess eligibility. 
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 the 
Screening visit window.
There is no mandatory order of assessments, but the skin biopsy must only be performed on 
patients who are expected to be eligible. When applicable, the pre-treatment/baseline skin 
biopsy must be obtained prior to the first dose.
If the patient meets the eligibility criteria during screening, the first treatment visit should be 
scheduled. Any baseline conditions which are present at the Screening visit should be 
reported in the eCRF. 
Re-screening of patients who have previously failed screening will be permitted. In this 
situation patients will be allocated a new patient number.


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6.2.2
Treatment period
The investigator must perform a final assessment of eligibility when the results of all 
screening assessments are available. If the patient does not meet the eligibility criteria, the 
patient must be recorded as a screen failure.
If a patient is eligible for trial participation, treatment is allocated using IRT. The Cycle 1 
Day 1 assessments as listed in the Flowchart are then performed. Some assessments do not 
need to be repeated if performed within 2 calendar days as part of the Screening visit; see 
Flowchart for details.
Subsequent visits during the treatment period are performed as described in the Flowchart.
Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment 
are met (see Section 3.3.4).
When a blood sample for bone biomarkers is required, it will be obtained prior to 
administration of trial medication, before 9am, and in a fasting state (at least 8 hours since 
last food intake).
6.2.3
Follow up period and trial completion
6.2.3.1
End of treatment visit
After a decision to permanently discontinue treatment within the trial is taken, no further 
administration of study medication should take place and the EOT visit should be performed 
within 7 days of the decision. If the decision to permanently discontinue trial treatment is 
taken during a scheduled visit, the EOT visit should be performed instead of the scheduled 
visit.
The assessments to be performed at the EOT visit are described in the Flowchart. The blood 
sample for bone biomarkers will be obtained before 9am and in a fasting state (at least 8 
hours since last food intake).
6.2.3.2
Follow-up visit
A follow-up visit should be performed 42-49 days after the last administration of trial 
medication. The information collected at this visit should include all new AEs that occurred 
after EOT and a follow-up of AEs ongoing at EOT. Any subsequent anti-cancer therapy
administered between EOT and follow-up should be reported.
Wherever possible the follow-up visit must be performed in person, but if the investigator 
judges appropriate (e.g. in the event the patient is undergoing end-of-life care), follow-up 
information may be collected by telephone.
The follow-up visit marks the completion of the study for the individual patient. After the 
completion of the study the patient will receive standard medical care.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The trial will be performed as an open-label study. The objective of the design is to determine 
the MTD of BI 905677 defined as the highest dose with less than 25% risk of the true DLT 
rate being ≥ 33% (EWOC criterion). The dose-finding in Schedule A and B will be guided by 
Bayesian 2-parameter logistic regression models with overdose control (R13-4803). Separate 
MTDs will be determined for Schedule A and Schedule B.
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* = 
1.1 mg/kg/week 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 summarised 
using the following intervals:
Under dosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM recommended dose for the next dose level 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 50% from cohort to 
cohort, after a Grade ≥2AE is observed in Cycle 1 (excluding adverse events which are 
clearly related to disease progression or concurrent illness).
The MTD may be considered reached if all the following criteria are fulfilled:
1. Next recommended dose = current dose (stabilisation condition)
2. Number of DLTs in study is at least 1.
3. At least 9 patients have been treated in the trial.
and at least one of the following criteria is fulfilled:

The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.5, OR

At least 6 patients have been treated at the MTD.
The SMC may recommend stopping the trial after the criterion for MTD is fulfilled. Further 
patients may be included to confirm this MTD estimate. If no DLT is observed while 
information from the PK profile is considered sufficient, the SMC may recommended a dose 
for further testing. Any DLTs occurring after the start of the second cycle will be considered 
for the evaluation of the recommended dose for further testing for BI 905677.


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Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified.
This prior distribution will be specified as a mixture of three multivariate normal 
distributions, i.e.
а(θ) = a1f1(θ) + a2f2(θ) + a3f3(θ)
with
ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 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 (Schedule A):
For the current trial, no relevant information in the form of human data was available, since 
no trial in a comparable population with comparable dosing schedule has been conducted. To 
support the interpretation of the prior distribution, the highest dose is assumed to be 8.5 
mg/kg/q3w. Therefore, the three mixture components were established as follows:

A weakly informative prior was derived reflecting the a priori assumption that the 
median DLT rate at the starting dose of 0.05 mg/kg/q3w would equal 0.001, and the 
median DLT rate at the highest dose of 8.5 mg/kg/q3w would equal 0.25. This yields 
 = (-2.169, 0.123). The standard deviations were set such that large uncertainty 
about the parameter means is reflected, and the correlation was set to 0, thus yielding 
, = 2, ,		 = 1 and  = 0, respectively. The prior weight  for the first 
component was chosen as 0.9. 

A high-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much more toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 0.05 mg/kg/q3w would 
equal 0.005, and the median DLT at the highest dose of 8.5 mg/kg/q3w would equal 
0.60. These assumptions yield 	 = (-0.644, 0.104). The standard deviations and 
correlations were set identical to the weakly informative prior, i.e. 	, = 2, 	,		 = 1 
and 	 = 0, respectively. The prior weight 	 for the second component was chosen as 
0.05. 

A low-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much less toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 0.05 mg/kg/q3w would 
equal 0.003, and the median DLT at the highest dose of 8.5 mg/kg/q3w would equal 
0.03. These assumptions yield  = (-3.905, -0.790), i.e. basically a flat curve. The 
standard deviations and correlations were set to , = 5, ,		 = 0.01, therefore 
almost fixing the slope parameter to its mean. The correlation was set to 0, i.e.  = 0. 
The prior weight  for the third component was chosen as 0.05.


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A summary of the prior distribution is provided in Table 7.1.1. A detailed evaluation of the 
model using hypothetical data scenarios and operating characteristics is provided in the 
statistical appendix (see Table 10.4: 3).
Table 7.1.1 Summary of prior distribution
Prior Component
Mixture Weight
Mean Vector
SD Vector
Correlation
1: Weakly inf.
0.9
-2.169, 0.123
2.000, 1.000
0.000
2: High Tox
0.05
-0.644, 0.104
2.000, 1.000
0.000
3: Low Tox
0.05
-3.905, -0.790
5.000, 0.010
0.000
Prior derivation (Schedule B):
Schedule B will start after the MTD of Schedule A is reached and prior distribution of 
Schedule B will be derived based on the data observed from Schedule A. The starting dose of 
Schedule B will not exceed 30% of the MTD in Schedule A.
Statistical model assessment:
The model is assessed based on two different metrics: 
Hypothetical data scenarios: for various potential data constellations as they could occur in the 
actual trial, the maximal next doses as allowed by the model and by certain escalation limit are 
investigated. Various data scenarios provide a way to assess the “on-study” behaviour of the 
model. 
Simulated operating characteristics: these illustrate how often a correct dose would be declared as 
MTD by the model for different assumed true dose-toxicity relationships. They can be considered 
as an assessment of the “long-run” behaviour of the model.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. This is an exploratory study where the 
primary objective is the determination of MTD and RDE. All analyses in this trial are 
descriptive and exploratory in nature.
7.3
PLANNED ANALYSES
The primary analysis will be conducted once the MTD of both Schedules A and B or RDE 
are determined.
Only one analysis population will be considered for efficacy and safety analyses: the treated
set. The treated set (TS) will consist of all patients who were treated with any dose of 
BI 905677. Patients will be analysed under the actual treatment received.
The PK set includes all subjects in the TS who provide at least one observation for at least 
one PK endpoint without important protocol violations relevant to the evaluation of PK. It is 
used for analysis of dose proportionality, exploratory food effect and time to steady state.


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No per protocol population will be used for analyses; however protocol violations will be
identified and listed.
7.3.1
Primary endpoint analyses
In order to determine the MTD, the occurrence of a DLT in the first cycle will be assessed on 
an individual patient level. The MTD will be determined as described in Section 7.1.
Based on the data observed in the trial, other models might be considered, either additionally 
or replacing the primary model. For feasibility or other reasons, a different dose might be 
considered as the recommended dose for future development.
The number of patients experiencing AEs during the entire treatment period will be 
summarised by dose level for each schedule.
7.3.2
Secondary endpoint analyses
All secondary endpoints will be analysed descriptively.
Details of the primary endpoint as well as the secondary endpoint analyses will be specified in the 
trial statistical analysis plan (TSAP).
7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. All AEs with an onset between 
start of treatment and end of the residual effect period (REP), a period of 42 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 AEs will concentrate on treatment-emergent adverse 
events, i.e. all AEs occurring between start of treatment and end of the residual effect period. 
AEs that start before first drug intake and deteriorate under treatment will also be considered 
as ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of MedDRA at the 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.


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Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Refer to Appendix 10.1 for pharmacokinetic parameters to be calculated using non-
compartmental analysis (NCA). The derivation of pharmacokinetic parameters is described in 
detail in the BI SOP 
All patients in the treated set who received at least one dose of BI 905677 and provided at 
least one valid serum concentration value will be included in the pharmacokinetic analysis. 
Patients who are considered as not evaluable will be listed with their individual serum
concentrations and individual pharmacokinetic parameters, however, will not be included in 
descriptive statistics for serum concentrations, pharmacokinetic parameters or other statistical 
assessment.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 
If a concentration is only excluded from half-life determination, it will be used for all other 
calculations (e.g. descriptive statistics) and for graphical presentation. If a concentration 
value is excluded from all calculations, it will not be presented graphically or used for the 
calculation of descriptive statistics and parameter determination. However the excluded 
concentration itself will be listed in the clinical trial report associated with an appropriate 
flag.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Noncompartmental pharmacokinetic analyses of the serum
concentration-time data will be performed using a validated software program, e.g. Phoenix 
WinNonlin Version 5.2. Only concentrations within the validated concentration range will be 
used for the calculation of pharmacokinetic parameters. For pre-dose samples, the actual 
sampling time will be set to zero.
Serum concentrations will be plotted graphically versus time for all evaluable patients as 
listed in the drug serum concentration-time tables. For the presentation of the mean profiles, 
the geometric and arithmetic mean and the planned blood sampling times will be used. If the 
actual sampling time deviates significantly from the planned time, the corresponding serum
concentration will be excluded from the calculation of descriptive statistics.
The following descriptive statistics will be calculated for analyte concentrations as well as for 
all pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, P10, Q1, Q3, P90, arithmetic coefficient of variation, geometric mean, and 
geometric coefficient of variation. The data format for descriptive statistics of concentrations 
will be identical with the data format of the respective concentrations. The descriptive 
statistics of pharmacokinetic parameters will be calculated using the individual values with 
the number of decimal places as provided by the evaluation program. Then the individual 


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values as well as the descriptive statistics will be reported with three significant digits in the 
clinical trial report.
Dose proportionality of BI 905677 will be assessed if feasible based on Cmax,ss/AUCτ,ss and 
Cmax, AUC0-. The attainment of steady state will be explored if feasible by plotting trough 
concentrations (Cpre, Cpre,N) against time.
Assessment of dose proportionality:
If necessary, dose proportionality will be explored using the power model that describes the 
functional relationship between the dose and PK endpoints, Cmax, AUC0-∞, Cmax,ss, AUCτ,ss. 
The basic model consists of a regression model applied to log-transformed data. The 
corresponding Analysis of Covariance (ANCOVA) model includes the logarithm of the dose 
as a covariate. Based on the estimate for the slope parameter , a two sided 95% confidence 
interval for the slope will be computed. Perfect dose proportionality would correspond to a 
slope of 1. The assumption of a linear relationship between the log-transformed 
pharmacokinetic endpoint and the log-transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed. The 
model for dose proportionality analysis will be detailed in TSAP.
Attainment of steady state:
If applicable, the statistical model to explore the attainment of steady state using the trough 
concentrations described above for each dose level will be a repeated measures linear model 
on the logarithmic scale including 'subject' as a fixed effect and 'time' as a repeated effect. 
The corresponding model, if all dose levels are analysed simultaneously, will include the log-
transformed 'dose' as a covariate. Both models allow modelling the covariance structure of 
the data. The structure of the covariance matrix generally is not known in advance and will 
therefore be determined on a data-driven basis. The strategy/criteria to determine the final 
structure will be described in the TSAP.
Subsequently, adjusted least square means and two sided 95% confidence intervals will be 
calculated and back transformed by exponentiation. Furthermore pairwise comparisons of the 
log-transformed differences between all subsequent  time points (log(Cpre,i/Cpre,j) = log(Cpre,i) 
- log(Cpre,j) where j>i) will be performed including the calculation of two sided 95% 
confidence intervals using t tests. Comparisons which reveal small p-values will be inspected 
to determine if the relevant differences between time points are resulting from not yet 
attaining steady state. In general, all dose levels will be analysed separately. If there is 
evidence that the patterns (or trend) of the trough concentration profiles are comparable 
across dose levels they will be analysed simultaneously if this is justified. Other analyses, 
such as regression over time may be considered as post-hoc analyses.
To support the analyses of dose proportionality, and attainment of steady state, graphical 
representations of the data might be created. These might include (but are not limited to) 
individual time-courses of trough serum concentrations and the (geometric) mean serum
concentration time profiles.


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7.4
INTERIM ANALYSES
No formal interim analysis is planned.
Interim evaluations will be performed as considered necessary and details will be specified in 
the TSAP. In particular safety evaluations will be performed after each dose cohort by the 
SMC consisting of the investigators and representatives of the sponsor (refer to Section 
3.1.1). Based on this the SMC will recommend the next dose level as well as the 
corresponding cohort size. SMC meeting minutes and outputs provided for these SMC 
meetings will be documented and archived in the clinical trial master file (CTMF).
7.5
HANDLING OF MISSING DATA
Pharmacokinetics:
Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR 
(no valid result), NOA (not analysed) and BLQ (below the limit of quantification) will be 
ignored and not replaced by zero at any time point. Descriptive statistics of concentrations at 
specific time points will be calculated only when at least 2/3 of the individuals have 
concentrations within the validated concentration range.
Pharmacokinetic parameters: 
In the non-compartmental analysis, concentration data identified with NOS, NOR and NOA 
will not be considered. BLQ values of the profile will be ignored. Descriptive statistics of 
parameters will be calculated only when at least 2/3 of the individual parameter estimates of a 
certain parameter are available. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.6
RANDOMISATION
Patients will be assigned, not randomised, into escalating dose cohorts by order of admission 
into the trial.
7.7
DETERMINATION OF SAMPLE SIZE
Simulation studies (refer to Table 10.4: 5) show a range of 3 to 51 patients are needed to 
assess 11 dose levels for Schedule A. Assuming Schedule A has an MTD of 3.3 mg/kg/q3w, 
and Schedule B starts at 0.4 mg/kg/q2w (which is less than 30% of the MTD for Schedule A), 
Schedule B requires a range of 3 to 45 patients. On average, it is around 30 patients for each 
Schedule. In total, the estimated sample size for the trial is around 60 patients.
The replacement of patients is described in Section 3.3.4.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
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.
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 IRB / Independent Ethics Committee (IEC) and competent 
authority (CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The investigator or delegate obtains written consent of the patient’s 
own free will with the informed consent form after confirming that the patient understands 
the contents. The investigator or 
 delegate must sign (or place a seal on) and date the 
informed consent form. If a trial collaborator has given a supplementary explanation, the trial


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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 quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
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 good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail). 
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, will be acceptable.
During the site visit the sponsor’s Clinical Research Associate (CRA) or auditor must be 
granted access to the original patient file (please see Section 8.3.2). The investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted from any copy of the patients’
source documents before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, 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)


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
Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (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 makes the 
patient ineligible for the clinical trial.

Technical information collected on PK sampling days (e.g. PK sampling times, multiple 
vital signs measurements linked with PK sampling) may be collected on trial-specific PK 
logs, which will be considered as source data for related entries in the eCRF and are 
considered part of the ISF.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs 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.


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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, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
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 Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 


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prematurely). Individual investigators will be notified of SUSARs occurring with the trial
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A Safety Monitoring Committee (SMC) composed of participating investigators and 
members of the BI trial team will be established to review individual and aggregated safety  
data at regular intervals to determine the safety profile and risk/benefit ratio and make 
decisions on next dose level/dose escalation/de-escalation/modification/next cohort size.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Local Clinical Monitors (CML), 
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.


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Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central imaging service, and an IRT vendor will be used in this 
trial. Details will be provided in the IRT Manual, Imaging Manual and Central Laboratory 
Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et 
al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982; 5:649-655.
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S.Department 
of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER) 2005.
R07-4856
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on clinical trials in small populations. 
London, 27 July 2006: doc. ref. CHMP/EWP/83561/2005.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009; 45:228-247.
R11-5034
Guidance for industry: S9 nonclinical evaluation for anticancer 
pharmaceuticals (ICH, March 2010). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo
rmation/Guida nces/ucm085389.pdf (access date: 5 December 2011) ; 
Rockville: 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) 2010.
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol. 2013; 71:1107-
1114.
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med. 2008; 27:2420-2439.
R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol. 2007; 
25(31):4982-4986.
R13-4805
Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted 
agents. Plos One. 2012; 7(12):e51039.
R13-4881
FDA’s critical path initiative. U.S. Food and Drug Administration: 2012 
webpage updated 28 December 2012: accessed 8 November 2013. 
http://www.fda.gov/ScienceResearch/Special/Topics/CritialPathInitiative/c
m076689.htm.


Boehringer Ingelheim
02 August 2018
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Page 70 of 94
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001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
R15-0031
Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release 
syndrome associated with novel T cell-engaging therapies. Cancer J 
(Sudbury) 2014. 20(2):119-122.
R15-3504
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence 
worldwide in 2012 (homepage). World Health Organization International 
Agency on Cancer; 2012. http://globocan.iarc.fr/Default.aspx.
R16-2323
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. 
Current concepts in the diagnosis and management of cytokine release 
syndrome. Blood 2014. 124(2):188-195.
R17-1468
Clevers H. Wnt/beta-catenin signaling in development and disease. 
Cell.127(3):469-480 (2006).
R17-1849
Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, 
et al. Recurrent R-spondin fusions in colon cancer. Nature 488 (7413), 660-
4 (2012).
R17-1850
Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, 
Cibulskis K, et al. RNF43 is frequently mutated in colorectal and 
endometrial cancers. Nat Genet 46 (12), 1264- 6 (2014).
R17-1851
Ettenberg SA, Charlat O, Daley MP, Liu S, Vincent KJ, Stuart DD, et al. 
Inhibition of tumorigenesis driven by different Wnt proteins requires 
blockade of distinct ligand-binding regions by LRP6 antibodies. Proc Natl 
Acad Sci U S A 107(35), 15473-8 (2010).
R17-4166
Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, 
et al. A first-in-human phase 1 study of the anti-cancer stem cell agent 
ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with 
advanced solid tumors. Clinical Cancer Research, Author Manuscript 
Published Online First on September 27, 2017, doi: 10.1158/1078-
0432.CCR-17-2157 Clin Cancer Res 2017
R17-4167
Papadopoulos K, Rosen L, Chugh R, Goldman J, Yen YC, Yeung P, et al. 
A phase la study in patients with advanced solid tumors for the human 
monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the 
WNT pathway. ECC 2013, Eur Cancer Cong of the European Cancer 
Organization, the European Society for Medical Oncology, and the 
European Society for Radiation and Oncology (ECCO-ESMO-ESTRO), 
Amsterdam, 27 Sep - 1 Oct 2013 (Poster) 2013
R17-4168
Janku F, Connolly R, LoRusso P, Jonge M de, Vaishampayan U, Rodon J, 
et al. Phase I study of WNT974, a first-in-class porcupine inhibitor, in 
advanced solid tumors.  AACR-NCI-EORTC Int Conf on Molecular 
Targets and Cancer Therapeutics, Boston, 5-9 Nov 2015 (Poster) 2015


Boehringer Ingelheim
02 August 2018
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001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
R18-0131
Regard JB, Zhong Z, Williams BO, Yang Y. Wnt signaling in bone 
development and disease: making stronger bone with Wnts. Cold Spring 
Harb Perspect Biol 2012. 4(12):a007997
R18-1357
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017).https://ctep.cancer.gov/protocolDevelopment/electronic_applications/
docs/CTCAE_v 5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 
(access date: 9 April 2017) ; U.S.Department of Health and Human 
Services, National Institutes of Health, National Cancer Institute 2017
R18-1420
Messersmith W, Cohen SJ, Shahda S, Lenz HJ, Weekes C, Dotan E, et al. 
Phase 1b study of WNT inhibitor vantictumab (VAN, human monoclonal
antibody) with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients (pts) 
with previously untreated stage IV pancreatic cancer (PC). 41st Ann Cong 
of the European Society for Medical Oncology (ESMO), Copenhagen, 7 -
11 Oct 2016 (Poster) 2016
R18-1421
Mita M, Becerra C, Richards D, Mita A, Shagisultanova E, Osborne C, et 
al. Phase 1b study of WNT inhibitor vantictumab (VAN, human 
monoclonal antibody) with paclitaxel (P) in patients (pts) with 1st- to 3rd-
line metastatic HER2-negative breast cancer (BC). 52nd Ann Mtg of the 
American Society of Clinical Oncology (ASCO), Chicago, 3 - 7 Jun 2016 
(Poster) 2016
R18-1474
Ye X, Wang Y, Cahill H, Yu M, Badea TC, Smallwood PM, et al. Norrin, 
Frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic 
program for retinal vascularization. Cell 2009. 139(2):285-298.
R18-1475
Hackam AS. The Wnt signaling pathway in retinal degenerations. IUBMB 
Life 2005. 57(6):381-388.
R18-1490
Ng M, Tan DSP, Subbiah V, Weekes CD, Teneggi V, Diermayr V, et al. 
First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in 
patients with advanced solid tumours. 53rd Ann Mtg of the American 
Society of Clinical Oncology (ASCO), Chicago, 2 - 6 Jun 2017 J Clin 
Oncol 2017. 35(15)(Suppl) Abstr 2584
R18-1494
Bendell J, Eckhardt SG, Hochster HS, Morris VK, Strickler J, Kapoun AM, 
et al. Initial results from a phase 1a/b study of OMP-131R10, a first-in-class 
anti-RSPO3 antibody, in advanced solid tumors and previously treated 
metastatic colorectal cancer (CRC). 28th EORTC-NCI-AACR Symp on 
Molecular Targets and Cancer Therapeutics, Munich, 29 Nov - 2 Dec 2016 
(Poster) 2016
R18-1685
Frey N. Cytokine release syndrome: who is at risk and how to treat. 
Baillieres Best Pract Res Clin Haematol 2017. 30:336-340.


Boehringer Ingelheim
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R18-1686
Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for 
acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ 
Program 2016. 2016(1):567-572.
9.2
UNPUBLISHED REFERENCES
n00254050
BI 905677: Cytokine Release Analysis of Healthy Human Volunteer Blood 
treated in-vitro with BI 905677. BI Study No. 16R151. 25 April 2017.
n00256243  
Effects of the LRP5/LRP6 antagonist BI 905677 on viability of RNF43 
mutant pancreatic cancer cell lines. (report in progress)  
n00256244  
Effects of the LRP5/LRP6 antagonist BI 905677 on viability of RNF43 
mutant CRC patient derived organoids. (report in progress)
n00256247
Assessment of efficacy, tolerability and PD biomarker modulation by BI 
905677 in MMTV-Wnt1 tumor-bearing BomTac:NMRI-Foxn1nu mice. 
(report in progress)
n00256248
Assessment of pharmacodynamics biomarker in skin tissue in non tumor 
bearing BomTac:NMRI-Foxn1nu mice treated with BI 905677. (report in 
progress)
n00259622
BI 905677 Nonclinical Expert Statement: Calculation of EC20 Values for 
In Vitro Cytokine Release from Human PBMCs in Two Responders. 1 
February 2018.
c16307316
BI 905677 Investigator’s Brochure, current version


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10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
If data allow and if scientifically reasonable, the following pharmacokinetic parameters of 
BI 905677 will be evaluated using non compartmental analysis methods according to the 
internal BI SOP 
After the first doses (before steady state is achieved):

Cmax (maximum measured serum concentration of BI 905677 in serum).

AUC0-∞(area under the serum concentration-time curve of the analyte over the time
interval from zero extrapolated to infinity).

AUC0-tz (area under the serum concentration-time curve of the analyte over the time
interval from 0 up to the last quantifiable data point).

AUC0-336 (q2w, area under the serum concentration-time curve over the time interval 
from 0 to 336 h).

AUC0-504 (q3w, area under the serum concentration-time curve over the time interval 
from 0 to 504 h).

%AUCtz-∞(the percentage of the AUC0-∞that is obtained by extrapolation)

AUCt1-t2 (area under the concentration time curve of the analyte in serum over the 
time interval t1 to t2)

tmax (time from dosing to the maximum measured serum concentration).

λz (terminal rate constant in serum)

t1/2 (terminal half-life).

MRTinf (mean residence time after intravenous infusion).

CL (total clearance of the analyte in serum).

Vz (apparent volume of distribution during the terminal phase).

Vss (volume of distribution after intravenous infusion).
After repeated doses, after steady state is achieved (steady state parameters will be 
calculated only, if steady state has been achieved):

Cmax,ss (maximum measured concentration of the analyte in serum at steady state over 
a uniform dosing interval τ)

Cmin,ss (minimum concentration of the analyte in serum at steady state over a uniform

dosing interval τ)

tmin,ss (time to reach minimum serum concentration during the dosing interval τ at 
steady state)

Cavg (average concentration of the analyte in serum at steady state)

Cpre,ss (predose concentration of the analyte in serum at steady state immediately 
before administration of the next dose)

Cpre,N (The predose concentration immediately before administration of the Nth dose 
over the dosing interval τ is taken directly from the observed drug serum
concentration-time data)

AUCτ,ss (area under the concentration-time curve of the analyte in serum at steady 
state over a uniform dosing interval τ)


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
AUCt1-t2,ss (area under the concentration time curve of the analyte in serum over the 
time interval t1 to t2 at steady state)

tmax,ss (time from last dosing to maximum concentration of the analyte in serum at 
steady state)

λz,ss (terminal rate constant in serum at steady state)

t1/2,ss (terminal half-life of the analyte in serum at steady state)

MRTinf,ss (mean residence time of the analyte in the body after intravenous infusion at

steady state)

CLss (total clearance of the analyte in serum at steady state)

Vz,ss (volume of distribution during the terminal phase after multiple intravascular
administrations at steady)

Vss,ss (volume of distribution after multiple intravascular administrations at steady 
state).

RA, Cmax (accumulation ratio based on Cmax)

RA, AUC (accumulation ratio based on AUC0-τ)

Linearity index

PTF (Peak-Trough Fluctuation)
If deemed necessary, further appropriate pharmacokinetic parameters might be calculated. 
Blood sampling time points for PK, ADA,cytokines and ferritin are given in Appendices 10.2
and 10.3.


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10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA AND 
CYTOKINE BLOOD SAMPLING AND ECG ASSESSMENT IN 
SCHEDULE A
Table 10.2: 1
Time schedule for PK, ADA and cytokine blood sampling and ECG 
assessment in Schedule A
Cycle
Day
Time Point 
(hh:min)
CRF Time 
/ planned 
time
PK
BI 905677
ADA
Cytokines
ECG
1 and 2
1
Before start of BI 905677 infusion
-0:05
X
X
Xa
Xb
Start of BI 905677 infusion
0:00
End of infusion
1:00c
Xd,e
Immediately after end of infusione
1:00c
Xf
Xf
0.5h after the end of infusion
1:30c
X
3h after the end of infusion
4:00c
X
X
7h after the end of infusion
8:00c
X
X
2
24h after start of infusion
24:00
X
X
4
48:00-96:00
72:00
X
8
144:00-192:00
168:00
X
Xd
15
288:00-384:00
336:00
X
3 and 4
1
Before start of BI 905677 infusion
-0:05
X
X
X
Xb
Start of BI 905677 infusion
0:00
End of infusion
1:00c
Xe
Immediately after end of infusionf
1:00c
Xf
Xf
3h after the end of infusion
4:00c
X
7h after the end of infusion
8:00c
O
2
24h after start of infusion
24:00
X
8
144:00-192:00
168:00
X
15
288:00-384:00
336:00
X
Cycle 5
onwards
1
Before start of BI 905677 infusion
-0:05
X
X
X
Xb
Start of BI 905677 infusion
0:00
EOT
N/A
N/A
N/A
X
X
X
FU
N/A
N/A
N/A
X
X
O = Optional. To be taken if the patient is already in the clinic.
a
A sample for ferritin testing will collected before the start of infusion on cycle 1 day 1.
b
Pre-dose ECG will be performed within 10 minutes prior to start of infusion.
c
The planned times assume an infusion duration of 60 min. If the infusion duration is shorter or longer, the PK and 
cytokine sample times for the end of infusion sample and all subsequent Day 1 samples should be adjusted 
accordingly (timings calculated from the end of infusion, as indicated in the column ‘Time Point’) and the actual 
times recorded in the eCRF.
d
Only required in Cycle 1
e
End of infusion ECG will be performed within 10 minutes prior to the end of infusion
f
PK sample must be taken within 5 min after the end of infusion. Cytokine sample must be taken within 30 min 
after the end of infusion.


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10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA AND 
CYTOKINE BLOOD SAMPLING AND ECG ASSESSMENT IN 
SCHEDULE B
Table 10.3: 1 Time schedule for PK, ADA and cytokine blood sampling and ECG 
assessment in Schedule B
Cycle
Day
Time Point 
(hh:min)
CRF Time / 
planned 
time
PK
BI 905677
ADA
Cytokines
ECG
1 and 2
1
Before start of BI 905677 infusion
-0:05
X
X
Xa
Xb
Start of BI 905677 infusion
0:00
End of infusion
1:00c
Xd, e
Immediately after end of infusione
1:00c
Xf
Xf
0.5h after the end of infusion
1:30c
X
3h after the end of infusion
4:00c
X
X
7h after the end of infusion
8:00c
X
X
2
24h after start of infusion
24:00
X
X
4
48:00-96:00
72:00
X
8
144:00-192:00
168:00
X
Xd
15
Before start of BI 905677 infusion
335:55
X
X
X
Xb,d
Start of BI 905677 infusion
336:00
End of infusion
337:00c
Immediately after end of infusione
337:00c
Xf
Xf
3h after the end of infusion
340:00c
X
7h after the end of infusion
344:00c
X
16
24h after start of infusion
360:00
X
X
22
480:00-528:00
504:00
X
3 and 4
1
Before start of BI 905677 infusion
-0:05
X
X
X
Xb
Start of BI 905677 infusion
0:00
End of infusion
1:00c
Xe
Immediately after end of infusione
1:00c
Xf
Xf
3h after the end of infusion
4:00c
X
7h after the end of infusion
8:00c
O
2
24h after start of infusion
24:00
O
8
144:00-192:00
168:00
X
15
Before start of BI 905677 infusion
335:55
X
X
Start of BI 905677 infusion
336:00
End of infusion
337:00c
Immediately after end of infusione
337:00c
Xf
3h after the end of infusion
340:00c
X


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Table 10.3:1 – Continued Time Schedule for PK, ADA and cytokine blood sampling and 
ECG assessment in Schedule B
Cycle
Day
Time Point 
(hh:min)
CRF Time / 
planned 
time
PK
BI 905677
ADA
Cytokines
ECG
7h after the end of infusion
344:00c
O
Cycle 3 
and 4 
(cont.)
16
24h after start of infusion
360:00
O
22
480:00-528:00
504:00
X
Cycle 5
onwards
1
Before start of BI 905677 infusion
-0:05
X
X
X
Xb
Start of BI 905677 infusion
0:00
15
Before start of BI 905677 infusion
335:55
Xg
X
Start of BI 905677 infusion
336:00
EOT
N/A
N/A
N/A
X
X
X
FU
N/A
N/A
N/A
X
X
O = Optional. To be taken if the patient is already in the clinic.
a
A sample for ferritin testing will collected before the start of infusion on cycle 1 day 1.
b
Pre-dose ECG will be performed within 10 minutes prior to start of infusion.
c
The planned times assume an infusion duration of 60 min. If the infusion duration is shorter or longer, the PK 
sample times for the end of infusion sample and all subsequent Day 1 samples should be adjusted accordingly
(timings calculated from the end of infusion, as indicated in the column ‘Time Point’) and the actual times 
recorded in the eCRF.
d
Only required in Cycle 1
e
End of infusion ECG will be performed within 10 minutes prior to the end of infusion
f
PK sample must be taken within 5 min after the end of infusion. Cytokine sample must be taken within 30 min 
after the end of infusion.
g
Only required in Cycles 5 and 6


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10.4
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
DATA SCENARIOS
Table 10.4: 1 Provisional dose levels for escalation in Schedule A
Dose level
Proposed dose
Increment from previous dose
1
0.05 mg/kg/q3w
2
0.1 mg/kg/q3w
100%
3
0.2 mg/kg/q3w
100%
4
0.4 mg/kg/q3w
100%
5
0.8 mg/kg/q3w
100%
6
1.6 mg/kg/q3w
100%
7
2.4 mg/kg/q3w
50%
8
3.3 mg/kg/q3w 
(predicted efficacious human dose)
38%
9
4.5 mg/kg/q3w
36%
10
6.2 mg/kg/q3w
38%
11
8.5 mg/kg/q3w
37%
A table of provisional dose levels for escalation in Schedule A is provided (Table 10.4:1) to 
support the simulations of the dose escalation plan. Additionally, the prior probabilities of 
DLTs at different doses, as well as the corresponding probability of under-, targeted and 
overdosing, are shown in Table 10.4: 2. Graphically, the prior medians with accompanying 
95% credible intervals are shown in Figure 10.4: 1. As can be seen from both the table and 
the figure, the prior medians of the DLT probabilities are in line with the prior medians 
derived from the weakly informative prior, and the uncertainty around the medians is large, 
showing the low amount of information this prior provides. This is also supported by the 
prior sample size, i.e., the information contained in the prior. This is approximately equal to 
1.6 patients.
Table 10.4: 2: Prior probabilities of DLT at selected doses
Dose 
Probability of true DLT rate in
Quantiles
[0-0.16)
[0.16-0.33)
[0.33-1]
Mean
SD
2.50%
50%
97.50%
0.05
0.936
0.032
0.032
0.037
0.116
<0.001
0.001
0.400
0.1
0.922
0.039
0.039
0.044
0.127
<0.001
0.002
0.466
0.2
0.903
0.047
0.050
0.055
0.140
<0.001
0.003
0.538
0.4
0.876
0.058
0.065
0.069
0.156
<0.001
0.007
0.617
0.8
0.832
0.078
0.089
0.092
0.177
<0.001
0.015
0.693
1.6
0.76
0.106
0.134
0.129
0.204
<0.001
0.036
0.782
2.4
0.685
0.134
0.182
0.167
0.226
<0.001
0.063
0.836
3.3
0.592
0.162
0.246
0.215
0.250
0.001
0.105
0.882
4.5
0.490
0.172
0.337
0.282
0.288
0.001
0.167
0.948
6.2
0.410
0.161
0.430
0.352
0.321
0.002
0.244
0.987
8.5
0.351
0.147
0.502
0.414
0.344
0.002
0.334
0.998
Doses printed in boldface meet the overdose criterion (P (overdose) < 0.25)


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Figure 10.4: 1:  Prior medians and 95% credible intervals. Note that the following intervals 
are marked by the two dashed lines at 0.16 and 0.33: Under dosing: [0.00, 0.16], Targeted 
toxicity: [0.16, 0.33] and Over toxicity: [0.33, 1.00]
The model was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics.
Hypothetical data scenarios
Hypothetical data scenarios for dosing Schedule A are shown in Table: 10.4: 3.  These 
scenarios reflect potential on-study data constellations and related escalation as allowed by 
the model. 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. The actual dose chosen for the next cohort will be determined by the SMC after 
taking into consideration the recommended dose from the model as well as other relevant 
data from this study.
In scenarios 2 to 10, it is assumed that no DLT is observed until the dose level of 2.4 
mg/kg/q3w, which is one level below the predicted efficacious human dose of 3.3 
mg/kg/q3w. To be more specific, in scenario 7, when 1 DLT is observed at 2.4 mg/kg/q3w, 
the next dose permitted by the model is the same dose level and 3 more patients are enrolled 
at 2.4 mg/kg/q3w in scenario 8 and observed no DLT. In this case, the model advises to 
escalate to the next dose level of 3.3 mg/kg/q3w. Assuming 1 DLT is then observed at 3.3 
mg/kg/q3w, which is demonstrated in scenario 9, the model proposed to stay at dose level of 
3.3 mg/kg/q3w and enroll 3 more patients. Finally in scenario 10, assuming no additional 
DLT is observed, the criteria for MTD are met and MTD is reached at 3.3 mg/kg/q3w.
In extreme cases when DLT is not observed until the reference dose, the adaptive feature of 
the model is fully illustrated in scenarios 11, 12 and 13. Despite the fact that no DLTs were 
observed in the first seven cohorts with 21 patients in total, the model reacts immediately to 


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the data observed at 3.3 mg/kg/q3w and advises to stay at current dose in scenario with 1 
observed DLT in scenario 12 and de-escalate with 2 observed DLTs in scenario 13.
Table 10.4:3 Hypothetical data scenarios for dosing Schedule A
Scenario
Dose
(mg/kg/q3w)
# 
DLT
# 
Pat
Current 
Dose:
P(OD)
Next Dose
(mg/kg/q3w)
Next Dose
P(UD)
P(TD)
P(OD)
1
0.05
0
3
0.003
0.1
0.975
0.019
0.006
2
0.05
0.1
0
0
3
3
0.001
0.2
0.978
0.018
0.004
3
0.05
0.1
0.2
0
0
0
3
3
3
0.001
0.4
0.974
0.022
0.004
4
0.05
0.1
0.2
0.4
0
0
0
0
3
3
3
3
<0.001
0.8
0.965
0.029
0.006
5
0.05
0.1
0.2
0.4
0.8
0
0
0
0
0
3
3
3
3
3
0.001
1.6
0.924
0.060
0.016
6
0.05
0.1
0.2
0.4
0.8
1.6
0
0
0
0
0
0
3
3
3
3
3
3
0.003
2.4
0.899
0.075
0.026
7
0.05
0.1
0.2
0.4
0.8
1.6
2.4
0
0
0
0
0
0
1
3
3
3
3
3
3
3
0.082
2.4
0.663
0.255
0.082
8
0.05
0.1
0.2
0.4
0.8
1.6
2.4
0
0
0
0
0
0
1
3
3
3
3
3
3
6
0.027
3.3
0.586
0.267
0.147


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Table 10.4:3 – Continued Hypothetical data scenarios for dosing Schedule A 
Scenario
Dose
(mg/kg/q3w)
# 
DLT
# 
Pat
Current 
Dose:
P(OD)
Next Dose
(mg/kg/q3w)
Next Dose
P(UD)
P(TD)
P(OD)
9
0.05
0.1
0.2
0.4
0.8
1.6
2.4
3.3
0
0
0
0
0
0
1
1
3
3
3
3
3
3
6
3
0.202
3.3
0.403
0.395
0.202
10
0.05
0.1
0.2
0.4
0.8
1.6
2.4
3.3
0
0
0
0
0
0
1
1
3
3
3
3
3
3
6
6
0.070
3.3
0.586
0.344
0.070
11
0.05
0.1
0.2
0.4
0.8
1.6
2.4
0
0
0
0
0
0
0
3
3
3
3
3
3
3
0.006
3.3
0.855
0.098
0.048
12
0.05
0.1
0.2
0.4
0.8
1.6
2.4
3.3
0
0
0
0
0
0
0
1
3
3
3
3
3
3
3
3
0.017
3.3
0.592
0.291
0.117
13
0.05
0.1
0.2
0.4
0.8
1.6
2.4
3.3
0
0
0
0
0
0
0
2
3
3
3
3
3
3
3
3
0.433
2.4
0.641
0.297
0.062


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Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulation. In order to 
assess the operating scharacteristics of the model, we assume 5 true dose-toxicity scenarios. 
As is shown in Table 10.4: 4, these scenarios reflect a wide range of possible cases as 
follows:
- Scenario 1: The true dose-toxicity relationship is aligned with prior means
- Scenario 2: Very high toxicity values are assumed corresponding to the respective dose 
levels
- Scenario 3: Very low toxicity values are assumed corresponding to the respective dose 
levels
- Scenario 4: A non-logistic dose-toxicity relationship is assumed
- Scenario 5: Low toxicity values followed by high toxicity values are assumed, i.e. a very 
steep dose-toxicity curve is adopted.
Table 10.4: 4 Assumed true dose-toxicity scenarios (Schedule A)
P(DLT)
Dose (mg/kg/q3w)
Scenario
0.05
0.1
0.2
0.4
0.8
1.6
2.4
3.3
4.5
6.2
8.5
1 (Prior)
0.037
0.045
0.055
0.074
0.092
0.129
0.167
0.215
0.282
0.352
0.414
2 (High Tox)
0.110
0.130
0.150
0.170
0.190
0.260
0.320
0.400
0.480
0.550
0.610
3 (Low Tox)
0.020
0.035
0.050
0.070
0.090
0.110
0.150
0.180
0.220
0.250
0.270
4 (Non-
Logistic)
0.040
0.070
0.090
0.140
0.190
0.220
0.250
0.280
0.310
0.350
0.380
5 (Low-High)
0.030
0.050
0.080
0.105
0.130
0.160
0.280
0.350
0.390
0.430
0.470
Bold numbers indicate true DLT rates in the target interval [0.16, 0.33].
For each of these scenarios, 1000 trials were simulated based on dosing Schedule A. 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: 5.


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Table 10.4: 5 Simulated operating characteristics (Schedule A)
Scenario
% of trials declaring an MTD with true DLT rate in
# Patients
# DLT
underdose
Target dose
overdose
STOPPED
Mean
(Min – Max)
Mean
(Min – Max)
1
24.4
60.5
14.5
0.6
23.13
(3 – 48)
3.61
(1 – 12)
2
15.6
70.9
8.2
5.3
19.13
(3 – 45)
4.08
(1 – 12)
3
35.0
64.6
0
0.4
23.78
(3 – 45)
3.24
(1 – 9)
4
15.7
75.6
7.6
1.1
20.51
(3 – 48)
3.66
(1 – 11)
5
30.1
46.4
22.9
0.6
21.80
(3 – 51)
3.95
(1 – 14)
Scenario 1 reflects the case that the true dose-toxicity is aligned with prior means, 60.5% of 
the simulated trials declared a dose as MTD with true DLT rate in the targeted dose range.
In scenario 2 (high-toxicity scenario), the starting dose has a probability of 0.11 to observe 
DLTs in the first cohort. This contributes to the high percentage (5.3%) of all simulated trials 
for which the trial is stopped since none of the doses is considered tolerable anymore. This is 
an expected situation for a high-toxicity scenario.
Scenario 3 (low-toxicity scenario) shows, that even with small toxicity rates the model 
declares MTDs with true DLT rate in the targeted interval in a high percentage of trials 
(64.6%). Since none of the pre-defined dose levels has a true DLT rate in the overdose range, 
only very few trials (0.4%) are stopped prematurely.
In scenarios 4 and 5, 75.6% and 46.4% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range, respectively.
The mean patient numbers range from 19.13 patients (high-toxicity scenario) to 23.78
patients (low-toxicity scenario) and the maximum number of patients was 51. 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 behavior of the model and the 
operating characteristics demonstrate a good precision of MTD determination.
Hypothetic scenarios and operating characteristics for dosing Schedule B will be derived 
once the MTD of Schedule A is determined and updated for each dose cohort. Similarly in 
Schedule B, the actual dose chosen for the next cohort will be determined by the SMC after 
taking into consideration the recommended dose from the model as well as other relevant 
data from this study.


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10.5
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
R01-0787


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
23 May 2018
EudraCT number
2017-002945-31
BI Trial number
1401-0001
BI Investigational Product(s)
BI 905677
Title of protocol
An open-label, Phase I trial to determine the 
maximum-tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 905677 
administered intravenously in patients with 
advanced solid tumours
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
All sections
Description of change
Phase Ib (dose expansion) part of study removed 
throughout the protocol.
Rationale for change
Details of planned dose expansion cannot be 
provided yet and therefore will be added later 
when available.
Section to be changed
All sections
Description of change
Optional tumour biopsy and corresponding blood 
sample for DNA analysis removed throughout the 
protocol.
Rationale for change
A re-evaluation of the benefits and risks of 
obtaining tumour samples led to the conclusion 
that tumour biopsies were no longer required 
during the dose escalation phase. 
Section to be changed
Synopsis and 2.1.2
Description of change
Primary endpoint changed from ‘Number of 
patients experiencing drug-related AEs during the 


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entire treatment period’ to ‘Number of patients 
experiencing AEs during the entire treatment 
period’
Rationale for change
To reflect that all AEs will be taken into 
consideration.
Section to be changed
Synopsis and sections 3.3, 3.3.1 and 3.3.2
Description of change
Added inclusion requirement that patients must 
have exhausted treatment options known to 
prolong survival for their disease.
Rationale for change
To ensure that an appropriate patient population is 
considered for the trial.
Section to be changed
Synopsis and section 4.1.2
Description of change
Starting dose in Schedule B will not be pre-
specified but will be determined using the MTD 
from Schedule A. Separate MTDs will be 
determined for Schedule A and Schedule B.
Rationale for change
Schedule A and B will now be performed 
sequentially so information from Schedule A can 
be used to determine the most appropriate starting 
dose in Schedule B.
Section to be changed
All sections
Description of change
CTCAE updated from version 4.03 to version 5.0 
throughout
Rationale for change
Administrative change to ensure latest version is 
used
Section to be changed
Flowchart and sections 4.1.4.3 and 5.2.2
Description of change
Additional guidance provided on frequency of 
monitoring of vital signs during and after infusion.
Rationale for change
To ensure consistent monitoring of patients in the 
trial.
Section to be changed
Flowchart and section 5.2.3
Description of change
Vitamin D testing added
Rationale for change
Additional safety monitoring
Section to be changed
Flowchart and section 5.2.5.4
Description of change
Ophthalmologic assessments added
Rationale for change
To ensure consistent and adequate monitoring of 
patients for ophthalmologic toxicity.
Section to be changed
Footnote to flowcharts, section 1.2.1, and section 
8.7
Description of change
Correction of spelling and grammatical errors
Rationale for change
Correction


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Section to be changed
Footnote to flowchart and section 5.2.5.1
Description of change
Addition of bone biomarker sample at Cycle 2 
Day 1 in both schedules
Rationale for change
To ensure that early changes to bone biomarkers 
are detected.
Section to be changed
Footnote to flowcharts, section 5.2.5.3, 10.2 and 
10.3
Description of change
Additional of further cytokine sample timepoints
and modification of PK and ADA sampling for 
consistency. Addition of ferritin sampling at 
baseline and when CRS occurs.
Rationale for change
To ensure that adequate data is collected regarding 
the potential of BI 905677 to induce Cytokine 
Release Syndrome.
Section to be changed
Footnote to flowcharts, section 4.1.4 and section 
5.2.5.3
Description of change
Modification to requirements for post-infusion 
monitoring
Rationale for change
To ensure that patients are adequately monitored 
for Cytokine Release Syndrome.
Section to be changed
Abbreviations
Description of change
Addition of various new abbreviations. Removal 
of redundant abbreviations.
Rationale for change
Administrative
Section to be changed
1.2.3
Description of change
Further information added regarding the potential 
of BI 905677 to cause cytokine release syndrome
and to be consistent with updated Investigator 
Brochure.
Rationale for change
To ensure information is available to investigators.
Section to be changed
1.4
Description of change
Further information and references provided 
regarding the expected safety profile of BI 905677 
based on published data from compounds with a 
similar mechanism of action.
Rationale for change
To provide investigators with further information 
regarding the risk:benefit of the trial, the potential 
side effects of treatment and the considerations for 
management of side effects.
Section to be changed
2.1.1, 3.1 and 4.1.2
Description of change
Trial design updated to perform Schedule A and B 


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sequentially.
Rationale for change
Schedule A and B will be performed sequentially 
in order to eliminate bias in the selection of 
patients for each Schedule, to allow the MTD of 
each Schedule to be determined independently and 
to allow the information from Schedule A to 
influence the starting dose in Schedule B.
Section to be changed
2.1.1
Description of change
Trial objectives and endpoints updated to reflect 
deletion of phase Ib dose expansion and separate 
MTDs for Schedule A and Schedule B
Rationale for change
Administrative
Section to be changed
3.1
Description of change
Trial design changed to allow a maximum dose 
increase of 100% between dose cohorts and to 
require at least three patients per dose cohort.
Rationale for change
The dose escalation steps have been made more 
conservative in order to protect patient safety.
Section to be changed
3.1
Description of change
Rationale for gap of 72 hours between patients 
added
Rationale for change
Additional explanation
Section to be changed
3.1.1
Description of change
New section added to describe circumstances 
under which trial would be temporarily stopped to 
re-evaluate risk/benefit ratio.
Rationale for change
To ensure that clear guidance is available to 
investigators and SMC regarding events which 
would necessitate a temporary stop to the trial.
Section to be changed
3.3.2
Description of change
Inclusion criteria 10 changed to add additional 
requirement to include WOCBP only after a 
confirmed menstrual period and a negative 
pregnancy test at screening. WOCBP with 
irregular menstruation may be included after two 
negative pregnancy tests during screening between 
2 and 4 weeks apart. 
Rationale for change
Modified to ensure consistency with 
‘Recommendations related to contraception and 
pregnancy testing in clinical trials’ by the Clinical 
trial Facilitation Group


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Section to be changed
3.3.3
Description of change
Exclusion criteria added to exclude patients with ≥ 
Grade 2 Osteoporosis and patients with chronic 
corticosteroid use.
Rationale for change
To ensure that patients at potentially higher risk of 
toxicity are not included in the trial.
Section to be changed
4.1.2.1
Description of change
Section describing selection of starting dose re-
written.
Rationale for change
To be consistent with the IB.
Section to be changed
4.1.3
Description of change
Section updated to reflect that there is no longer a 
possibility that two dose cohorts in different 
schedules will be open at the same time.
Rationale for change
Updated to be consistent with new trial design
Section to be changed
4.1.2.2
Description of change
Addition of new section to describe how starting 
dose for Schedule B will be determined.
Rationale for change
Method of determining starting dose has changed 
because Schedule A and Schedule B will now be 
performed sequentially.
Section to be changed
4.1.4.1
Description of change
Minor modifications and further guidance added to 
re-treatment criteria and guidelines
Rationale for change
To ensure patients are only re-treated when 
appropriate.
Section to be changed
4.1.4.2
Description of change
Clarification added on identification and handling 
of different grades of infusion-related reaction. 
Rationale for change
Clarification and update to be consistent with new 
guidance on handling of CRS.
Section to be changed
Addition of new section 4.1.4.3
Description of change
Addition of new section 4.1.4.3 to give guidance 
on management of Cytokine Release Syndrome
Rationale for change
To ensure that patients are adequately monitored 
for CRS and that CRS events are adequately 
managed and treated.
Section to be changed
Addition of new section 4.1.4.4
Description of change
Addition of new section 4.1.4.4 to give guidance 
on management of bone toxicity
Rationale for change
To ensure consistent and adequate management of 


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bone toxicity throughout the trial.
Section to be changed
Addition of new section 4.1.4.5
Description of change
Addition of new section 4.1.4.5 to give guidance 
on management of retinal toxicity
Rationale for change
To ensure consistent and adequate management of 
retinal toxicity throughout the trial.
Section to be changed
4.1.4.6
Description of change
Further guidance added for management of Grade 
4 non-haematological toxicity and for situations 
where dose reduction may be considered.
Rationale for change
Further guidance required to ensure consistent 
management of toxicities.
Section to be changed
4.1.4.7
Description of change
Dose reduction will not be decided by the 
investigator but will be restricted to the previous 
dose level tested. Clarification that patients who 
experience a second occurrence of toxicity 
requiring dose reduction must permanently 
discontinue treatment.
Rationale for change
To provide clearer guidance on dose reduction.
Section to be changed
4.2.1
Description of change
Clarification added to indicate that concomitant 
therapies used as pre-medication prior to BI 
905677 infusion will be recorded in the eCRF.
Rationale for change
Clarification
Section to be changed
5.2.4, 10.2 and 10.3
Description of change
Clarification that ECG performed on Day 1 of 
Cycle should be performed within 10 minutes 
prior to start of infusion and end of infusion ECG 
should be performed within 10 minutes prior to 
end of infusion. Addition of three further ECGs.
Rationale for change
Requirement to add further guidance and for 
additional ECGs at anticipated maximal plasma 
concentration.
Section to be changed
5.2.5.2
Description of change
Added requirement to record bone mineral density 
measurements and to repeat bone densitometry 
after at least two months if a change in bone 
mineral density of >5% is observed. Added 
explanation that SMC will regularly review any 
reported changes.
Rationale for change
To ensure that changes in bone density are 


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followed up so that accurate assessment of DLTs 
can be made.
Section to be changed
5.2.5.4
Description of change
Addition of new section on ophthalmologic 
assessment.
Rationale for change
To ensure patients are adequately monitored for 
retinal toxicity.
Section to be changed
5.2.6.1
Description of change
Addition of further details regarding Cytokine 
Release Syndrome and addition of Retinal toxicity 
to the list of Adverse Events of Special Interest
Rationale for change
To ensure that adequate information is captured 
regarding these events and reported to authorities 
where required.
Section to be changed
5.2.6.2
Description of change
Clarification that disease progression is not a study 
endpoint but instead is recorded to enable analysis 
of efficacy endpoints
Rationale for change
Administrative correction
Section to be changed
5.2.7
Description of change
Additional events have been added to the list of 
DLTs and existing DLTs have been clarified.
Rationale for change
To ensure that all potential toxicities of BI 905677 
are accounted for when assessing the tolerability 
of the compound.
Section to be changed
7.1, 7.7 and 10.4
Description of change
Statistical models, derivations and simulations 
updated.
Rationale for change
Updates required due to changes to design of trial.
Section to be changed
8.1
Description of change
Change of formatting to clarify that text is 
applicable for all countries.
Rationale for change
Administrative correction.
Section to be changed
9
Description of change
Addition of new references used in protocol. 
Removal of redundant references. Removal of 
personnel names for unpublished references. 
Updates to references where status has changed.
Rationale for change
Administrative change


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Number of global amendment
2
Date of CTP revision
05 July 2018
EudraCT number
2017-002945-31
BI Trial number
1401-0001
BI Investigational Product(s)
BI 905677
Title of protocol
An open-label, Phase I trial to determine the 
maximum-tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 905677 
administered intravenously in patients with 
advanced solid tumours
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Amendment is neither logistical nor administrative 
but has been classified as non-substantial in 
accordance with relevant legislation
Section to be changed
3.3.3 Exclusion criteria
Description of change
New exclusion criterion added ‘History of allergy 
to kanamycin or similar class drugs (including 
streptomycin, gentamicin, amikacin, tobramycin 
and neomycin).’
Rationale for change
Trace amounts of kanamycin may be present in the 
IMP therefore patients who are known to be at risk 
of allergic reaction will be excluded.
Section to be changed
4.1.4, 4.1.4.3, 5.2.5.3
Description of change
Deletion of ‘6-hour’ from ‘6-hour post-treatment 
monitoring period’
Rationale for change
Administrative correction. The post-treatment 
monitoring period is of variable length.
Section to be changed
4.1.4.6 General management of toxicities
Description of change
Deletion of examples of supportive measures
Rationale for change
Correction of administrative error – examples are 
not relevant and not required
Section to be changed
10.3
Description of change
Reference to footnote changed from ‘c’ to ‘f’
Rationale for change
Correction of administrative error


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Clinical Trial Protocol
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Number of global amendment
3
Date of CTP revision
02 August 2018
EudraCT number
2017-002945-31
BI Trial number
1401-0001
BI Investigational Product(s)
BI 905677
Title of protocol
An open-label, Phase I trial to determine the 
maximum-tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 905677 
administered intravenously in patients with 
advanced solid tumours
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.3.3 Exclusion criteria
Description of change
Women who are pregnant, nursing, or who plan to 
become pregnant during the trial.
Changed to;
Women who are pregnant, nursing, or who plan to 
become pregnant or nurse during the trial or within 
6 months after the last dose of study treatment.
Rationale for change
For consistency with other sections, the exclusion 
criteria is updated to exclude patients who plan to 
become pregnant or nurse within 6 months after 
end of treatment.
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Patients who withdraw for a reason other than 
DLT before completing the first treatment cycle or 
who miss more than one visit during their first 
treatment cycle will be replaced.
Changed to;


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Patients who withdraw for a reason other than 
DLT before completing the first treatment cycle,
or who do not receive the full planned dose in the 
first treatment cycle without DLT, or who miss 
more than one visit during their first treatment 
cycle will be replaced.
Rationale for change
Patients who do not receive the full planned dose 
in the first treatment cycle without DLT will be 
replaced to ensure adequate evaluation of the dose 
level and accurate determination of the MTD.
Section to be changed
Table 4.1.4.6: 1 Management of toxicity 
4.1.4.7 Dose Reduction
Description of change
Clarification of requirements for management of 
toxicity and dose reduction.
Rationale for change
To ensure consistency between table and text.
Section to be changed
4.2.2.1
Description of change
Addition of the following text ‘The use of 
prophylactic haemotopoietic growth factors (e.g. 
G-CSF) prior to treatment is prohibited in cycle 1.’
Rationale for change
To ensure adequate assessment of the 
toxicity/MTD of the study treatment.
Section to be changed
5.2.7
Description of change
Addition of Grade 3 anaemia requiring blood 
transfusion as a DLT
Rationale for change
To ensure adequate assessment of the 
toxicity/MTD of the study treatment.
Section to be changed
5.4.1 Biomarker analysis
Description of change
The following text has been added;
Data obtained from the analysis of skin biopsies 
will not be disclosed to patients because the 
analysis is exploratory. If consent is withdrawn, all
samples and the data that had already been 
collected up to the time of withdrawal of consent 
will still be used.
Rationale for change
Provision of additional information about skin 
biopsies.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18134159
5.0
clinical-trial-protocol-version-04
An open-label, Phase I trial to determine the maximum-tolerated dose and investigate
safety, pharmacokinetics and efficacy of BI 905677 administered intravenously in
patients with advanced solid tumours
Approval-Therapeutic Area 
03 Aug 2018 10:00 CEST
Approval-Clinical Program 
03 Aug 2018 10:32 CEST
Author-Trial Clinical Monitor
03 Aug 2018 11:22 CEST
Author-Trial Clinical
Pharmacokineticist
03 Aug 2018 12:11 CEST
Author-Trial Statistician
03 Aug 2018 15:59 CEST
Verification-Paper Signature
Completion
07 Aug 2018 12:26 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18134159
5.0

SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c38459988-01
BI Trial No.:
1401-0001 
Title:
An open-label, Phase I trial to determine the maximum-tolerated
dose and investigate safety, pharmacokinetics and efficacy of
BI 905677 administered intravenously in patients with advanced
solid tumours
Including Protocol Amendment 3 (Version 4.0, 02-AUG-2018)
Investigational
Product(s):
BI 905677
Responsible trial 
statistician(s):
 
Phone:
   
Date of statistical 
analysis plan:
16 MAY 2022 SIGNED 
Version:
1
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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.
ENDPOINT(S).......................................................................................................8
5.1
PRIMARY ENDPOINT(S) ..................................................................................8
5.2
SECONDARY ENDPOINT(S) ............................................................................8
5.2.1
Key secondary endpoint(s)...................................................................................8
5.2.2
Secondary endpoint(s) ..........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENT(S)................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................13
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................15
7.3
TREATMENT COMPLIANCE........................................................................15
7.4
PRIMARY ENDPOINT(S) ................................................................................16
7.4.1
Primary analysis of the primary endpoint(s) ...................................................16
 
7.5
SECONDARY ENDPOINT(S) ..........................................................................16
7.5.1
Key secondary endpoint(s).................................................................................16
7.5.2
(Other) Secondary endpoint(s) ..........................................................................16


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7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................21
7.8.4
ECG......................................................................................................................21
7.8.5
Others...................................................................................................................22
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............23
9. 
REFERENCES....................................................................................................24
11.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.1: 1
Dose levels for escalation in Schedule A .........................................................11
Table 6.1: 2
Definition of treatment periods.........................................................................12
Table 11: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary
Term
Definition / description
ADA
Anti-Drug Antibodies
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BMI
Body mass index
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
BSA
Body surface area
CR
Complete Response
CTCAE
Common Terminology Criteria for Adverse Events
CTh
Concomitant Therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database lock
DCR
Disease Control Rate
DLT
Dose Limiting Toxicity
eCRF
Electronic Case Report Form
EoT
End Of Text
EWOC
Escalation With Overdose Control
ICH
International Conference On Harmonisation
IPD
Important Protocol Deviation
MedDRA
Medical Dictionary for Drug Regulatory Activities
MQRM
Medical Quality Review Meeting
MTD
Maximum Tolerated Dose
MTDS
MTD evaluation set
OR
Objective Response
PD
Protocol Deviation
PK
Pharmacokinetics
PKS
PK analysis set


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Term
Definition / description
ADA
Anti-Drug Antibodies
PR
Partial Response
PT
Preferred Term
RECIST
Response Evaluation Criteria in Solid Tumors
REP
Residual Effect Period
RPM
Report Planning Meeting
ScS
Screened Set
SD
Stable Disease
STD
Standard Deviation
SMC
Safety Monitoring Committee 
SMQ
Standardised MedDRA Query
SOC
System Organ Class
ToC
Table of Contents
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
WHO DD
World Health Organisation Drug Dictionary 


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3.
INTRODUCTION
As per 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, definition of measurements and variables, planning of sample size, and 
randomization.
Version 9.4 or the latest version will be used for analyses.
R Version 4.0.1 and JAGS Version 4.3.0 or the latest versions will be used for the Bayesian 
Logistic Regression Model (BLRM) analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Due to the decision to discontinue the development of the LRP5&6 program, only schedule A 
has been investigated in the trial. However, the maximum tolerated dose (MTD) in this 
schedule has been determined as per protocol. The planned endpoints to be analyzed were not
changed due to the early termination.
 
 
 
 
 
 
5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoints of the trial are:

The MTD of BI 905677. The MTD will be assessed based on the number of patients 
experiencing dose limiting toxicities (DLTs), graded according to Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0, in the first cycle of treatment (first 3 
weeks of treatment, MTD evaluation period). The MTD is defined as the highest dose 
with less than 25% risk of the true DLT rate being equal to or above 33% as determined 
by the BLRM defined in the CTP. 

Number of patients experiencing adverse events (AEs) during the entire treatment period. 
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
The secondary endpoints of the trial are:

The following Pharmacokinetics (PK) parameters of BI 905677 will be evaluated after the 
first administration of BI 905677 (if feasible), i.e. in Cycle 1:


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o
Cmax: maximum measured concentration of BI 905677 in serum after first 
infusion
o
AUC0-tz: area under the serum concentration-time curve over the time interval 
from 0 to the last measured time point (tz)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
This is an open label, non-randomized, dose escalation phase I study. The starting dose for 
Schedule A is BI 905677 0.05 mg/kg every three weeks. Dose escalation decisions will be
made by a Safety Monitoring Committee (SMC) guided by the BLRM with escalation with 
overdose control (EWOC) criterion. Table 6.1: 1 shows the dose levels that were administered 
in Schedule A. 
Table 6.1: 1
Dose levels for escalation in Schedule A
Cohort
Dose Level
Proposed dose
Increment from previous dose
1
0.05 mg/kg/q3w
Starting dose
2
0.1 mg/kg/q3w
100%
3
0.2 mg/kg/q3w
100%
4
0.4 mg/kg/q3w
100%
5
0.8 mg/kg/q3w 
100%
6
1.6 mg/kg/q3w
100%
7
2.4 mg/kg/q3w
50%
8
3.6 mg/kg/q3w
50%
9
2.8 mg/kg/q3w
-22%
The data will be presented for all dose cohorts separately and in total over all dose cohorts. 
DLTs occurring during the MTD evaluation period (first three weeks of treatment) will be 
presented separately. 
“Analysing treatment” will be used for reporting of treatment-emergent adverse events (AEs) 
and to differentiate between screening, on-treatment, and post-treatment safety data. The 
inequalities start date <= onset date of the AE < end date of the AE will determine whether 
the AE will be assigned to the “analysing treatment” or not. 
The treatment periods of the trial which will be used for the reporting of AEs and safety 
laboratory parameters are given in Table 6.1: 2. Safety data recorded during the Residual 
Effect Period (REP) will be considered as on-treatment. In this trial, the REP is defined as 42 
days. 
If not specified otherwise, all safety tables will be based on the on-treatment period. AEs that 
have an onset date during the screening or post-treatment periods will be displayed in separate 
listings.


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Table 6.1: 2
Definition of treatment periods
Analysing Treatment 
Period
Start Date (including)
Stop Date (excluding)
Screening
Date of informed consent
The date of first trial 
medication administration 
On-treatment
Date of first administration of 
trial medication
Date of last trial 
medication administration 
+ REP*, or death, 
whichever comes first,
+1 day
(e.g., actual on-treatment 
period + REP*)
Post-treatment
Last day of on-treatment period 
+1 day
Date of the last contact 
date or death, or DBL 
date, whichever comes 
first, +1 day
MTD evaluation 
period
Date of first administration of 
trial medication
Date of first 
administration of trial 
medication +21 days
*Note: A 42-day residual effect period (REP) is defined. DBL = database lock. 
The initial dose of trial medication assigned at the beginning of the first treatment cycle will 
be used as the label of the analyzing treatment.
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important if it affects the rights or safety of the study patients, or 
if it can potentially influence the primary outcome measurements in a non-negligible way.
Important Protocol Deviations (IPDs) are stored in the DV domain template (Excel 
spreadsheet). 
If the data show other IPDs, this table will be supplemented accordingly at Medical Quality 
Review Meetings (MQRMs) or Report Planning Meetings (RPMs) or through team review of 
the manual PD log. The final list of IPDs will be confirmed before Database lock (DBL). No 
per protocol set is defined for this phase I study, but patients with an IPD will be identified 
and reported in the Clinical Trial Report (CTR).
6.3
SUBJECT SETS ANALYSED
The following subject sets will be defined.


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
Screened Set (ScS): includes all patients who have signed the informed consent form 
and will be used for patient disposition.

Treated Set (TS): includes all patients who received at least one infusion of BI 
905677. The TS is used for both efficacy and safety analyses, and for summary of 
demographics, baseline characteristics, disease history, and concomitant therapies.

MTD Evaluation Set (MTDS): includes all patients in the TS who were not replaced 
for the MTD determination. The MTD Evaluation Set is used for the primary analyses 
of DLTs and MTD determination. Rules for replacement of patients are defined in the 
CTP Section 3.3.4.1. The list of replaced patients will be provided by the Clinical trial 
leader before DBL and documented in the decision log (2).

PK Analysis Set (PKS): The PK set includes all subjects in the TS who provide at 
least one observation for at least one PK endpoint without important protocol 
violations relevant to the evaluation of PK. The PKS is used for all pharmacokinetic 
analyses. 
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be made to collect complete data at each visit for each patient. Missing 
baseline laboratory values will be imputed by the respective values from the screening visit. 
Potential outliers will be reported and analyzed as observed. If not specified otherwise, 
missing data will not be imputed and remain missing. No other imputations will be performed 
on missing data although every effort will be made to obtain complete information on AEs, 
with particular emphasis on potential DLTs.
Missing or incomplete AE dates will be handled according to the Boehringer Ingelheim (BI) 
guideline (3). Missing data and outliers of PK data will be handled according to the BI 
standards (4) and as specified in Section 7.5 of the CTP.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Visit labels
Study days and visits will be labelled according to the CTP’s flow chart. The visit schedule 
with accompanying details can also be found in the flow charts in the CTP. 
Baseline definition
Unless otherwise specified, baseline is defined as the time point closest to and prior to the 
first administration of study treatment. Note that for some study procedures (e.g. body weight, 
vital signs, laboratory tests) baseline may be the measurement made on the same day the 


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study treatment was started. In such cases these measurements will be assumed to have been 
taken according to the protocol, i.e. prior to the first administration of study treatment. But for 
some measurements, the examination time may also need to be considered, in instances where 
time is recorded in addition to date. If not available, then the values reported at the screening 
visit will be considered.
For laboratory parameters for which not only the examination date but also the sampling time 
was recorded, examination time should be taken into consideration when defining baseline.
That is a laboratory measurement on the same date as the first administration of study 
treatment is considered as baseline if and only if the examination time of this laboratory 
measurement is before the first administration of study treatment. 


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics includes: N / Mean / standard 
deviation [STD] / Min / Median / Max.
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.
If needed, conversion from days to weeks, months and years will be as follows:

Weeks=Days/7

Months=(Days*12)/365.25

Years=Days/365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant therapies (CTh) will be coded according to World Health Organisation Drug 
Dictionary (WHO DD). They will be classified according to the Anatomical, Therapeutic, 
Chemical (ATC) classification system. The third ATC level will be used to categorise CThs 
by therapy type. In situations where a medical product may be used for more than one equally 
important indication, there are often several classification alternatives. As appropriate, 
patients receiving CThs with more than one possible ATC level-three category will be 
counted more than once; footnotes will clarify this possible double counting in tables.
Summaries will be presented for previous and concomitant medications started at baseline and 
for concomitant therapies started after first administration of the trial medication.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. 
Compliance with trial medication will be based on the drug infusion/administered eCRF data 
and calculated as amount of drug infused/administered divided by the amount of drug to be 
infused/administered expressed as a percentage, see calculations below. 
“Per Cycle” compliance to trial medication will be calculated as follows:
(345678 59 :;6< =796>?:/@:4=7=>8?;?: @8 ABCD? 7)
(345678 59 :;6< ED@77?: 85 F? =796>?:/@:4=7=>8?;?: @8 ABCD? 7 )× 100.


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Overall compliance to trial medication will be calculated as mean of the “per cycle” 
compliance. 
The compliance will be based on the total volume infused in mL (eCRF data) compared to 
total volume prepared (eCRF data).
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
In order to identify the MTD of the trial, the number of patients at each dose level that had 
DLT during the MTD evaluation period (first three weeks / first 21 days of treatment for 
Schedule A) will be presented, excluding patients who discontinue during the first treatment 
cycle for reasons other than a DLT. 
The BLRM as described in Section 7.1 of the CTP will be analyzed using the number of 
patients at each dose that had DLTs during the MTD evaluation period among the patients in 
the MTD set. The prior defined in Table 7.1.1 of the CTP will be used for the analysis. The 
resulting posterior distribution of the DLT rates of the doses tested during the trial will be 
summarized using their mean, SD, 2.5% quantile, median, and 97.5% quantile. Additionally, 
the posterior probabilities of the DLT rate lying in the intervals [0, 0.16) (underdosing), [0.16, 
0.33) (target dosing), and [0.33, 1] (overdosing) will be computed and listed for each dose. 
The posterior probabilities of underdosing, target dosing, and overdosing of the tested dose 
levels will additionally be visualized in a bar diagram that further displays which of the dose 
levels satisfy the EWOC criterion. 
In addition, the number of patients with DLTs that occurred during the entire treatment period 
will be summarized at each dose level. 
 
 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Not applicable.
7.5.2
(Other) Secondary endpoint(s)
Descriptive statistics will be presented for Cmax and AUC0-tz . The analysis of standard PK 
parameters and pharmacodynamic analyses will be performed as outlined in Section 7.3.5 of 
the CTP, if applicable and feasible. 


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7.7
EXTENT OF EXPOSURE
Treatment exposure will be primarily summarized by the total on-treatment time and has been 
defined in 
of this TSAP. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. In addition, some displays will be 
based on the MTD evaluation set and the MTD evaluation period.
7.8.1
Adverse Events
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 residual effect period (REP), a period 
of 42 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 
residual effect period. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent.’
The analyses of adverse events (AE) will be descriptive in nature. All analyses of AEs will be 
based on the number of patients with AEs and not on the number of AEs. Frequency of 
patients with AEs will be tabulated by treatment dose, highest CTCAE grade, system organ 
class (SOC) and preferred term (PT) after coding according to the current version of 
MedDRA at the database lock. In addition, AEs will be tabulated by PTs only. The SOC will 
be sorted alphabetically. In tables displaying AEs by PTs, this will be sorted by descending 
frequency of AEs in the “Total” BI 905677 group. 
Summary tables and listings of AEs, SAEs, related AEs, related SAEs, AEs of special 
interest, AEs leading to dose reduction, AEs leading to treatment discontinuation and AEs 
leading to deaths will be provided.
For the analysis of DLTs with regard to the primary endpoint see Section 7.4.1.
7.8.2
Laboratory data
The analysis of laboratory data will be descriptively in nature and will follow standard 
procedures. The analysis of laboratory data will use the same “analyzing treatments” as 


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described for AEs, except for that the baseline laboratory values will be included in the “on 
treatment” period. 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 value will be displayed in the category “Missing CTCAE grade 
at baseline”. 
Descriptive statistics, including change from baseline, frequency of patients with transitions 
relative to the references range, will be provided for laboratory assessments at scheduled 
visits. Data collected during potential unscheduled laboratory assessments will be listed. No 
post-study laboratory values will be considered. CTCAE grade for applicable laboratory 
parameters will be calculated according to CTCAE v5.0. The following outputs will be 
presented:

Baseline, last value and difference from baseline

Worst CTCAE grade experienced during the on-treatment period

Transitions of the CTCAE grade from baseline to the worst lab values, from baseline to 
the last lab values, and from the worst to last values during the on-treatment period

Possible clinically significant laboratory values

Transitions for laboratory values without CTCAE grade based on reference ranges
Note: For calculating the change in CTCAE grade from baseline, patients with a CTCAE 
grade of -9 (no CTCAE grade defined) or CTCAE grade of -5 (overlapping reference ranges) 
will be treated as a CTCAE grade 0 for all analyses. In laboratory listings, the CTCAE grade 
is displayed as -9 and -5, respectively.
For uric acid, hypokalemia, amylase, bicarbonate, eosinophils, glucose (high direction), INR 
of prothrombin time, lipase, methemoglobin, sodium (low direction) the CTCAE grade cannot 
always be assigned by the laboratory parameter itself as two different CTCAE grades have the 
same laboratory constellation, but are distinguished by additional clinical parameter. In this 
case a CTCAE grade of -1 will be assigned. These will not be considered for laboratory 
analyses. In laboratory listings, the CTCAE grade is displayed as -1, respectively.
Patients with hepatic enzyme elevation will be tabulated.
7.8.3
Vital signs
Vital signs and physical examination, at Screening, baseline, during the course of the trial and 
at the end-of-trial evaluation will be listed with regard to possible changes compared to 
findings before start of treatment. 
7.8.4
ECG
ECG data will be collected as described in CTP Section 5.2.4. Clinically significant findings 
in ECG data will be reported under “Adverse events” if applicable and will be analyzed 
accordingly. In addition, patients ECG assessments will be listed for all timepoints. 


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7.8.5
Others
Patients ophthalmologic assessments will be listed. If measured, patients who have a bone 
densitometry assessment with a bone mineral decrease of >5% from baseline will be also 
given in a patient listing.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
Not applicable.


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9. 
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.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) 
Decision Log”, current version, Group “Biostatistics & Data Sciences”.
3.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, 
current version.
4.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics”, current version.
R11-1488
Kenward MG, Roger JH Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 53, 983-997, 1997.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
16-MAY2022
None
This is the final TSAP