Conditions: Neoplasms
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 21
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to determine the maximum tolerated dose (MTD)/optimal biological dose (OBD) of BI 905681 given as an intravenous infusion and to determine the recommended dose and dosing schedule for further trials in the development of BI 905681. The MTD will be defined based on the frequency of patients experiencing dose-limiting toxicities (DLTs) during the MTD/DLT 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 (PK) profile of BI 905681.

Detailed description:
Study was opened to recruitment until 29-Oct-2021, however from 15-Apr-2021 no patient was recruited.

Arms:
arm 1: Subjects received an intravenous infusion of 1.0 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. arm 2: Subjects received an intravenous infusion of 2.5 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. arm 3: Subjects received an intravenous infusion of 5.0 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. arm 4: Subjects received an intravenous infusion of 7.0 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. arm 5: Subjects received an intravenous infusion of 8.5 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met.

Interventions: intervention 1: BI 905681
Intervention descriptions: intervention 1: Infusion

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c29037963-02
EudraCT No.:
EU Trial No:
2019-003490-25
BI Trial No.:
1424-0001
BI Investigational 
Product(s):
BI 905681
Title:
An open-label, Phase I trial to determine the maximum-tolerated 
dose and investigate safety, pharmacokinetics and efficacy of 
BI 905681 administered intravenously in patients with advanced 
solid tumours
Lay Title:
A trial to find the safe dose for BI 905681 in patients with 
incurable tumours or tumours that have spread
Clinical Phase:
Phase I
Clinical Trial Leader
Phone: 
 / Fax:
Team Member 
Medicine 
Phone.: 
 / Fax: 
Coordinating 
Investigator:
Status:
Final Protocol (revised protocol [based on global amendment 1])
Version and Date:
Version: 2.0
Date: 15 November 2019
Page 1 of 94
Proprietary confidential information.
2019 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 905681
Protocol date
28 August 2019
Revision date
15 November 2019
Trial number
1424-0001
Title of trial:
An open-label, Phase I trial to determine the maximum-tolerated dose 
and investigate safety, pharmacokinetics and efficacy of BI 905681 
administered intravenously in patients with advanced solid tumours
Coordinating 
Investigator
Trial site(s):
5 sites
Clinical phase:
Phase I
Objective(s):
The primary objective of this trial is to determine the maximum 
tolerated dose (MTD)/optimal biological dose (OBD) of BI 905681 
given as an intravenous infusion and to determine the recommended 
dose and dosing schedule for further trials in the development of 
BI 905681. The MTD will be defined based on the frequency of 
patients experiencing dose-limiting toxicities (DLTs) during the 
MTD/DLT 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 (PK) profile of BI 905681.
 
Methodology:
This is a Phase I, open-label, non-randomised study of BI 905681 
administered intravenously as a single agent. 
The trial aims to test two different dosing schedules for BI 905681 
(Schedule A: q3w in a 3-week cycle and Schedule B:q2w in a 4-week 
cycle) 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.


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Number of patients 
entered: 
It is anticipated that approximately 60 patients (30 per dosing 
schedule) will be enrolled in the trial.
Diagnosis :
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.
in- and exclusion 
criteria
Inclusion 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. 

Patients (only those who harbour a historically confirmed RNF43 
mutation or R-spondin fusion) willing to undergo mandatory 
tumour biopsy at the time points specified in the protocol.

Eastern Cooperative Oncology Group Score of 0 or 1 (R01-0787).

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

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 


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of the investigator

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 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 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 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 4 months after the last 
dose of BI 905681. A list of contraception methods meeting these 
criteria is provided in the patient information.
Exclusion criteria

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

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

Osteoporosis ≥ CTCAE Grade 2

Chronic corticosteroid use, except as permitted for the 
maintenance therapy of brain metastases (see Exclusion Criterion 
13)

Osteoporotic compression fracture within 12 months prior to 
informed consent which is clinically significant in the opinion of 
the investigator.

Patient who must or wishes to continue the intake of restricted 
medications or any drug considered likely to interfere with the 
safe conduct of the trial.

Previous treatment in this trial.

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.

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 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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efficacy of the test drug.

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.

Active alcohol or drug abuse in the opinion of the investigator.

Patient unwilling or unable to comply with the protocol.

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.

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.

History of Grade 3 hypersensitivity reactions (including cytokine 
release syndrome) to monoclonal antibodies.

History of allergy to kanamycin or similar class drugs (including 
streptomycin, gentamicin, amikacin, tobramycin and neomycin).
Test product(s):
BI 905681
Dose :
Increasing doses of BI 905681 starting at 1.0 mg/kg/q3w. Dose 
escalation will be guided by a Bayesian logistic regression model 
(BLRM) with overdose control until the MTD/OBD is reached.
Mode of 
administration:
Intravenous infusion
Duration of 
treatment:
Administration will continue until progression of disease (PD),  
unacceptable toxicity
Endpoints
The primary endpoints of the trial are:

The MTD/OBD of BI 905681. The MTD will be assessed based 
on the number of patients experiencing DLTs, graded according 
to Common Terminology Criteria for Adverse Events (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

Number of patients experiencing adverse events (AEs) during the 
entire treatment period
The secondary endpoints of the trial are:

The following PK parameters of BI 905681 will be evaluated after 
the first administration of BI 905681 (if feasible):
o
Cmax: maximum measured concentration of BI 905681 
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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Safety criteria:
Adverse events (AEs) according to CTCAE Version 5, incidence of 
DLTs for determination of the MTD/OBD, results of physical 
examinations, laboratory evaluations, vital signs, and 
electrocardiograms (ECGs).
Statistical methods:
The trial will be performed as an open-label study. The objective of 
the design is to determine the MTD of BI 905681 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. Separate MTDs will be determined for Schedule A 
and Schedule B.


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FLOW CHART: BI 905681 (REFMAL 638) SCHEDULE A TRIAL 
ASSESSMENTS
Schedule A Flow 
Chart
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***
±72 
hrs
Day 
2†
±1 
day
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) b
X
X
Xb
X
Safety laboratory 
blood tests and 
urinalysisc
X
X
X
X
X
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 
assessmenth
X
Repeated if clinically indicated
Height
X
Weight
X
X
X
Tumour Assessmenti
X
Every 6 weeks (± 7 days) from start of treatment until documented 
progression
Tumour Biopsy
Xj
Xj
Blood sample for bone 
biomarkersk
Xk
X
Blood samples for 
cytokine release testing
Xl
Xl
Blood samples for 
pharmacokineticsm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Blood sample for anti-
drug antibodies 
(ADAs)
X
X
X
Assess eligibility for 
further treatment
Xn
BI 905681 Infusiono
X


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Schedule A Flow 
Chart
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***
±72 
hrs
Day 
2†
±1 
day
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
Adverse events
X
X
X
X
X
X
X
Concomitant Therapies
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.
** 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, Eastern Cooperative Oncology Group (ECOG)
performance status, vital signs, ECG, safety laboratory blood tests, urinalysis, pregnancy test, weight) do 
not need to be performed if done within 3 calendar days (during the Screening visit) and in the opinion of 
the investigator a repeat assessment 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.
†Cycle 2 only
a
Vital signs measurement on day of infusion as specified in Section 5.2.2
b
ECG required on Day 8 of Cycle 1,but not on Day 8 of Cycle 2 and subsequent cycles.
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 at Screening, on Day 1 of every third cycle (i.e. Cycle 3 Day 1, Cycle 6 Day 1)
and at the EOT.
f
Pregnancy test is only required for women of childbearing potential. 
g
Bone densitometry at the EOT visit is not required if bone densitometry has been performed within the 
previous 4 weeks.
h
Ophthalmologic assessment will be performed for all patients at Screening visit and if the patient develops 
visual symptoms during the trial. The following assessments should be performed: BCVA, colour fundus 
photography, and spectral domain optical coherence tomography (SD-OCT) (see Section 5.2.5.4).
i
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. 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.
j
Pre- and on-treatment tumour biopsy collections for biomarker analyses are mandatory from all patients 
who have a historically confirmed RNF43 mutation or R-spondin fusion entering the trial from Cohort 2 A 
total of 2 tumour biopsies are required. The first tumour biopsy may be obtained any time prior to the first 
dose. For a fresh baseline sample a minimum of 2 core needle biopsies or 1 punch biopsy must be taken 
between Screening and the day before first treatment with BI 905681. An archival sample, from the most 
recent relapse, will be acceptable as the pre-treatment biopsy, if taken within 6 months of trial start. A 
second tumour biopsy sample (two core-needle biopsies or 1 punch biopsy, preferably from the same 


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lesion) will be obtained 24 hours after Cycle 2 infusion (the on-treatment biopsy time point may be 
adapted based on PK analysis).See Section 5.4.1.
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 and the EOT visit.
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 905681 and for 3 hours following subsequent administrations if the previous administrations were well-
tolerated.


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FLOW CHART: BI 905681 (REFMAL 638) SCHEDULE B TRIAL 
ASSESSMENTS
Schedule B
Flow Chart
Trial Period
Screeni
ng
Treatment Cycles*(1 Cycle = 28 Days)
End of 
Treatment 
(EOT)
Follow-
up**
Timing
1-28 
days
prior to 
first 
dose
Day 
1***
±72 
hrs
Day 
2†
±1 
day
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) b
X
X
Xb
Xb
X
Safety laboratory 
blood tests and 
urinalysisc
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 
assessmenth
X
Repeated if clinically indicated
Height
X
Weight
X
X
X
X
Tumour 
Assessmenti
X
Every 8 weeks (± 7 days) from start of treatment until documented progression
Tumour Biopsy
Xj
Xj
Blood sample for 
bone biomarkersk
Xk
X
Blood samples for 
cytokine release 
testing
Xl
Xl
Xl
Blood samples for 
pharmacokineticsm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Blood sample for 
anti-drug antibodies 
(ADAs)
X
Xn
X
X


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Schedule B
Flow Chart
Trial Period
Screeni
ng
Treatment Cycles*(1 Cycle = 28 Days)
End of 
Treatment 
(EOT)
Follow-
up**
Timing
1-28 
days
prior to 
first 
dose
Day 
1***
±72 
hrs
Day 
2†
±1 
day
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
Assess eligibility 
for further treatment
Xo
Xo
BI 905681 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.
** 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.
† Cycle 2 only
a
Vital signs measurement on day of infusion and as specified in Section 5.2.2.
b
ECG required on Day 8 and 15 of Cycle 1, but not on Day 8 and 15 of Cycle 2 and subsequent cycles.
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 at Screening, on Day 1 of every third cycle (i.e. Cycle 3 Day 1, Cycle 6 Day 1)
and at the EOT.
f
Pregnancy test is only required for women of childbearing potential.
g
Bone densitometry at the EOT visit is not required if bone densitometry has been performed within the 
previous 4 weeks.
h
Ophthalmologic assessment will be performed for all patients at Screening visit and if the patient develops 
visual symptoms during the trial. The following assessments should be performed: BCVA, colour fundus 
photography, SD-OCT (see Section 5.2.5.4).
i
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.
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.
j
Pre- and on-treatment tumour biopsy collections for biomarker analyses are mandatory from all patients 
who have a historically confirmed RNF43 mutation or R-spondin fusion entering the trial from Cohort 2 A 
total of 2 tumour biopsies are required. The first tumour biopsy may be obtained any time prior to the first 
dose. For a fresh baseline sample a minimum of 2 core needle biopsies or 1 punch biopsy must be taken 


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between Screening and the day before first treatment with BI 905681. An archival sample, from the most 
recent relapse, will be acceptable as the pre-treatment biopsy, if taken within 6 months of trial start. A 
second tumour biopsy sample (two core-needle biopsies or 1 punch biopsy, preferably from the same 
lesion) will be obtained 24 hours after Cycle 2 infusion (the on-treatment biopsy time point may be 
adapted based on PK analysis). See Section 5.4.1.
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 and the EOT visit.
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 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 10.2.
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 905681 and for 3 hours following subsequent administrations if the previous administrations were well-
tolerated.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART: BI 905681 (REFMAL 638) SCHEDULE A TRIAL ASSESSMENTS..7
FLOW CHART: BI 905681 (REFMAL 638) SCHEDULE B TRIAL ASSESSMENTS 10
TABLE OF CONTENTS ......................................................................................................13
ABBREVIATIONS................................................................................................................17
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................19
1.2.1
Pharmacology......................................................................................................19
1.2.2
Pharmacokinetics................................................................................................20
1.2.3
Toxicology............................................................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................22
1.4
BENEFIT - RISK ASSESSMENT.....................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........25
2.1.1
Objectives.............................................................................................................25
2.1.2
Primary endpoint(s)............................................................................................25
2.1.3
Secondary endpoint(s) ........................................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................27
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................27
3.1.1
Trial Stopping Rules...........................................................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................29
3.3
SELECTION OF TRIAL POPULATION .......................................................30
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Withdrawal of patients from therapy or assessments .....................................32
3.3.4.1
Withdrawal from trial treatment ...........................................................................33
3.3.4.2
Withdrawal of consent for trial participation........................................................33
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................34
4.
TREATMENTS...................................................................................................35
4.1
INVESTIGATIONAL TREATMENTS ...........................................................35
4.1.1
Identity of the Investigational Medicinal Products..........................................35
4.1.2
Selection of doses in the trial..............................................................................35


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4.1.2.1
Starting dose for Schedule A ................................................................................35
4.1.3
Dose-escalation scheme.......................................................................................37
4.1.4
Starting Dose for Schedule B .............................................................................37
4.1.5
Method of assigning patients to treatment groups...........................................38
4.1.6
Drug assignment and administration of doses for each patient......................38
4.1.6.1
Re-treatment criteria .............................................................................................38
4.1.6.2
Management of infusion-related reactions............................................................39
4.1.6.3
Management of Cytokine Release Syndrome (CRS)............................................40
4.1.6.4
Management of bone toxicity ...............................................................................40
4.1.6.5
Management of retinal toxicity.............................................................................41
4.1.6.6
General management of toxicities.........................................................................41
4.1.6.7
Dose Reduction.....................................................................................................42
4.1.7
Definition of dose-limiting toxicity ....................................................................43
4.1.8
Blinding and procedures for unblinding...........................................................44
4.1.9
Packaging, labelling, and re-supply...................................................................44
4.1.10
Storage conditions...............................................................................................44
4.1.11
Drug accountability.............................................................................................44
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................45
4.2.1
Other treatments and emergency procedures..................................................45
4.2.2
Restrictions ..........................................................................................................45
4.2.2.1
Restrictions regarding concomitant treatment ......................................................45
4.2.2.2
Restrictions on diet and life style..........................................................................45
4.2.2.3
Restrictions regarding women of childbearing potential......................................46
4.3
TREATMENT COMPLIANCE........................................................................46
5.
ASSESSMENTS..................................................................................................47
5.1
ASSESSMENT OF EFFICACY........................................................................47
5.2
ASSESSMENT OF SAFETY.............................................................................47
5.2.1
Physical examination ..........................................................................................48
5.2.2
Vital signs.............................................................................................................48
5.2.3
Safety laboratory parameters ............................................................................48
5.2.4
Electrocardiogram ..............................................................................................49
5.2.5
Other safety parameters.....................................................................................50
5.2.5.1
Safety biomarkers for bone resorption..................................................................50
5.2.5.2
Bone densitometry ................................................................................................50
5.2.5.3
Testing for Cytokine Release................................................................................50
5.2.5.4
Ophthalmologic Assessment.................................................................................51
5.2.6
Assessment of adverse events.............................................................................51
5.2.6.1
Definitions of AEs ................................................................................................51
5.2.6.2
Adverse event collection and reporting ................................................................55
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................57
5.3.1
Assessment of pharmacokinetics .......................................................................57
5.3.2
Methods of sample collection .............................................................................57
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................57


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5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................58
5.4.1
Methods of sample collection .............................................................................58
5.5
OTHER ASSESSMENTS...................................................................................59
5.5.1
ADA assessments.................................................................................................59
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................60
6.
INVESTIGATIONAL PLAN.............................................................................61
6.1
VISIT SCHEDULE.............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................61
6.2.1
Screening and run-in period(s)..........................................................................61
6.2.1.1
Screening Period ...................................................................................................61
6.2.1.2
Baseline Conditions ..............................................................................................62
6.2.1.3
Medical History.....................................................................................................62
6.2.1.4
Concomitant therapies...........................................................................................62
6.2.2
Treatment period(s)............................................................................................62
6.2.3
Follow up period and trial completion..............................................................62
6.2.3.1
End-of-treatment visit ...........................................................................................62
6.2.3.2
Follow-up visit......................................................................................................63
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................64
7.1
STATISTICAL DESIGN - MODEL.................................................................64
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................67
7.3
PLANNED ANALYSES.....................................................................................67
7.3.1
Primary endpoint analyses.................................................................................68
7.3.2
Secondary endpoint analyses .............................................................................68
7.3.4
Safety analyses.....................................................................................................68
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................69
7.4
INTERIM ANALYSES ......................................................................................71
7.5
HANDLING OF MISSING DATA ...................................................................71
7.6
RANDOMISATION ...........................................................................................71
7.7
DETERMINATION OF SAMPLE SIZE .........................................................71
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........72
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................72
8.2
DATA QUALITY ASSURANCE ......................................................................73
8.3
RECORDS...........................................................................................................73
8.3.1
Source documents ...............................................................................................73
8.3.2
Direct access to source data and documents.....................................................74
8.3.3
Storage period of records ...................................................................................74
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................75
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........75


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8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................75
8.6
TRIAL MILESTONES.......................................................................................75
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................76
9.
REFERENCES....................................................................................................79
9.1
PUBLISHED REFERENCES............................................................................79
9.2
UNPUBLISHED REFERENCES......................................................................81
10.
APPENDICES.....................................................................................................82
10.1
PHARMACOKINETIC ANALYSES...............................................................82
10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA AND 
CYTOKINE BLOOD SAMPLING AND ECG ASSESSMENT....................84
10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS .................................................................................88
10.4
ECOG PERFORMANCE STATUS..................................................................92
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................93
11.1
GLOBAL AMENDMENT 1 ..............................................................................93


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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine transaminase
ANC
Absolute neutrophil count
AST
Aspartate transaminase
AUC
Area under the Curve
BAP
Bone Alkaline Phosphatase
ß-CTX
Beta- Carboxy-terminal Telopeptide 
BI
Boehringer Ingelheim
BLQ
Below the limit of quantification
BCVA
Best Corrected Visual Acuity
BLRM
Bayesian logistic regression model
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
Clearance
CR
Complete Response
CRA
Clinical Research Associate
CRC
Colorectal Cancer
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract research organization
CRS
Cytokine release syndrome
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DCR
Disease control rate
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EDTA
Ethylendiaminetetracetic Acid
EMA
European Medicines Agency
EOT
End of Treatment
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
GLP
Good Laboratory Practice
HED
Human Equivalent Dose
HIV
Human Immunodeficiency Virus
HNSTD
Highest non-severely toxic dose
HSA
Human Serum Albumin
IB
Investigator’s Brochure


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ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
LDH
Lactate Dehydrogenase
LPDD
Last Patient Drug Discontinuation
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMTV
Mouse Mammary Tumour Virus
MRSD
Maximum recommended starting dose
MST
Medical Sub Team
MTD
Maximum tolerated dose
NCA
Non-compartmental analysis
NOAEL
No-observed-adverse-effect level
NSCLC
Non-small cell lung cancer
OBD
Optimal biological dose
ORR
Objective response rate
P1NP
N-terminal Propeptide of Type 1 Procollagen
PD
Progressive disease
PDc
Pharmacodynamics
PFS
Progression Free Survival
PK
Pharmacokinetics
p.o.
per os (oral)
PR
Partial Response
q2w/q3w
Every 2 weeks/ every 3 weeks
RDE
Recommended Dose for Expansion
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RNF
Ring Finger Protein
RP2D
Recommended Phase 2 dose
RSD
Recommended Starting Dose
SAE
Serious Adverse Event
SD
Stable Disease
SD-OCT
Spectral domain optical coherence tomography
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
TK
Toxicokinetic
TNBC
Triple Negative Breast Cancer
TRACP
Tartrate-resistant Acid Phosphatase
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Despite the recent advancements in 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 
β-catenin and expression of β-catenin dependent genes that promote cancer cell proliferation 
and resistance to chemotherapy/immunotherapy. An antagonistic paratopic antibody that 
binds LRP5 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 an LRP5 antagonist may constitute a valid therapeutic option against cancer
and supports testing of BI 905681 in humans with the objective to improve patients’ 
outcome. The first step in clinical development is this first in human trial to define the safety 
profile of BI 905681 and the Maximum tolerated dose (MTD)/ Optimal Biological Dose 
(OBD)for further development.
The most recent and more detailed information is available in the current Investigator’s 
Brochure (IB) (c27125909-01).
1.2
DRUG PROFILE
1.2.1
Pharmacology
BI 905681 is a new biological entity consisting of three modules: two modules (bi-paratopic) 
binding to distinct epitopes of LRP5 and one module binding to human serum albumin (HSA)
for half-life extension. The three modules are 
connected by two peptide linkers. 
BI 905681 binds to LRP5 and blocks binding of Wnt ligands to the co-receptor complex, 
leading to inhibition of Wnt/β-catenin signaling.
The Wnt ligands, which bind to LRP5 and Frizzled receptor leading to activation of 
downstream signaling, can be divided into Wnt1class and Wnt3a class, each requiring 
different domains of LRP5 for signaling (R17-1851). In particular, BI 905681 
antagonistically binds to these different domains of LRP5 receptor (bi-paratopic binding), 
thereby blocking Wnt signaling mediated by both Wnt1 and Wnt3a class ligands, leading to:

Inhibition of LRP5 phosphorylation,

Activation of β-catenin degradation complex formed by APC/Axin/GSK3,


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
Blockade of β-catenin nuclear translocation and binding to the TCF transcription factors, 
and

Inhibition of transcription of Wnt/-catenin target genes.
Blockade of LRP5 phosphorylation and inhibition of transcription of Wnt/-catenin target 
genes (Axin2 and Notum), can be monitored in vivo as direct and indirect biomarkers for 
selective pathway engagement, respectively, in a Wnt driven tumor xenograft tissue 
(n00267727). Inhibition of Wnt target gene expression in tumor cells is necessary but not 
sufficient for antitumor efficacy (in vitro and in vivo), indicating that it represents a 
pharmacodynamic (PDc) biomarker, but not a biomarker of response to treatment with BI 
905681. In mice PDc biomarker modulation can be monitored in vivo using skin as surrogate 
tissue via detection of Axin2 and Notum gene expression (n00267728).
LRP5 and LRP6 mediated Wnt pathway activation is regulated by the E3 ligase RNF43 and 
the secreted R-spondin proteins. RNF43 inhibits Wnt pathway activation by inducing the 
degradation of the Frizzled/LRP5 or LRP6 receptor complex via endocytosis. The RNF43 
gene has been found to be frequently mutated/ inactivated in a subset of colorectal cancer 
(CRC) and pancreatic ductal adenocarcinoma samples (R17-1850). Furthermore, in a separate 
study, activating R-spondin fusion transcripts, leading to aberrantly inactivating RNF43 
mutations have been shown to enhance ligand dependent Wnt signaling in vitro by increasing 
the abundance of Frizzled receptors on the cell surface.
Nonclinical proof of concept (inhibition of Wnt/β-catenin signaling and efficacy) was 
demonstrated with BI 905681 in mechanistic Wnt-driven and disease-relevant models 
harbouring RNF43 mutations. In particular, BI 905681 demonstrated effective blockade of 
ligand-dependent Wnt signaling in in vitro (RNF43 mutant pancreatic cancer cell lines and 
RNF43 mutant CRC patient-derived organoids) and in vivo models (Wnt driven breast cancer
xenograft), as detected by reduction of Axin2 expression (and Notum gene expression in the 
in vivo model). Furthermore, BI 905681 demonstrated in vitro inhibition of cell viability and 
potent in vivo anti-tumor activity in the cancer models mentioned above. In contrast, BI 
905681 did not block Wnt signaling (i.e. lack of inhibition of Axin2 expression) nor affect 
cell viability in RNF43 wild type pancreatic cancer cell and RNF43 wild type CRC patient 
derived organoid models, supporting the proposed patient enrichment biomarker strategy 
(n00267725, n00267729).
1.2.2
Pharmacokinetics
The pharmacokinetics (PK) for BI 905681 were investigated in the cynomolgus monkey in a 
single dose PK and immunogenicity study and a repeat dose toxicokinetic (TK) and 
immunogenicity study. BI 905681 demonstrated dose-proportional increases in Cmax and 
AUC with increasing dose levels in these studies. Human i.v. PK for BI 905681 was 
predicted using single species scaling from cynomolgus monkey to human using a Dedrick 
plot. The PK curves were fitted using a 2-compartment model.
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 905681 is 
1.4 mg/kg i.v. q1w. Alternatively, a less frequent dosing schedule can be chosen while 
keeping the Cplasma trough level constant, e.g. 3.5 mg/kg i.v. q2w or 6.6 mg/kg i.v. q3w.


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1.2.3
Toxicology
The toxicity profile for BI 905681 has been assessed in repeat dose toxicity studies in
monkeys and mice, an in vitro cytokine release assay, and an in vitro hemocompatibility 
study. The 4-week Good Laboratory Practice (GLP) repeat dose study in monkeys included 
safety pharmacology (cardiovascular, respiratory, and neurological function) and 
immunotoxicology endpoints. 
A traditional tissue cross reactivity (TCR) study on cryosections of normal human tissues 
using immunohistochemistry was not conducted with BI 905681 due to the high nonspecific 
background staining of non-target-expressing cell types or non-cellular elements (e.g. 
interstitial matrix). However, a target tissue distribution study was conducted to determine the 
distribution of LRP5 in formalin-fixed, paraffin embedded human tissues. LRP5 staining was 
present in the stomach, small intestine, large intestine, salivary gland, endocrine pancreas, 
thyroid, kidney, ureter, urinary bladder, uterus, fallopian tube, placenta, testis, breast tissue, 
and brain. LRP5 staining was generally comparable between humans and cynomolgus 
monkeys.
The ready-to-use solution of BI 905681 (10 mg/mL in 25 mM acetate, 230 mM trehalose 
dihydrate, 0.05% (w/v) polysorbate 20, pH 5.5) demonstrated no hemolytic potential in 
human whole blood.
In repeat dose toxicity studies in monkeys, no mortality was observed. Once weekly 
intravenous administration of BI 905681 for up to 4 weeks (total 5 doses) and up to 150 
mg/kg/dose in the cynomolgus monkey was well tolerated and resulted in no adverse findings 
in any of the parameters examined. In the 4-week repeat dose toxicity study, there were non-
adverse trends for or slight decreases in bone formation markers (bone specific alkaline 
phosphatase (BAP) and/or procollagen type 1 amino-terminal propeptide (P1NP)) as a result 
of Wnt signaling inhibition by BI 905681, but no changes in bone resorption markers (β-
Carboxy-terminal Telopeptide (β- CTx) and TRACP-5b) or microscopic correlates. The 
potential effect on bone mass can be monitored by serum bone biomarkers and bone 
densitometry assessment during the clinical development. 
In addition, the implementation of an ophthalmologic monitoring plan is recommended if the 
patient displays visual symptoms during BI 905681 treatment.
The no-observed-adverse-effect level (NOAEL) was determined to be 150 mg/kg/dose q1w, 
and this dose is also considered as the highest non-severely toxic dose (HNSTD) in the 4-
week monkey study. At 150 mg/kg/dose q1w, the steady state mean exposures were 5,290 
g/mL (Cmax) and 498,000 g•h/mL (AUC0-168h). These exposures are 88X, 50X, and 31X 
(Cmax), or 73X, 46X, and 29X (AUC0-168h) to the estimated exposure at a 1.4 mg/kg q1w, 3.5 
mg/kg q2w, and 6.6 mg/kg q3w therapeutic dose, respectively.
Collectively, the nonclinical package of pharmacology, pharmacokinetics, safety studies and 
data support the administration of BI 905681 to patients with advanced cancers. To date, no 
clinical trials have been conducted with BI 905681.


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For a more detailed description of the BI 905681 profile please refer to the current IB.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on the pre-clinical studies summarized in the previous section, the observed anti-
tumour activity and safety profile warrant clinical testing of BI 905681 monotherapy in 
patients with advanced solid tumours. The therapeutic benefit or specific adverse events in 
patients cannot always be anticipated during the trial setup. As the trial progresses there may 
be new scientific knowledge about biomarkers and other factors contributing to diseases or 
the action of a drug.
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.
As BI 905681 is a first-in-class compound with no prior testing in humans, the risks of 
treatment have been evaluated based on the expected effects of targeting the Wnt pathway 
(R17-4168) and on the nonclinical toxicology data.
Under normal conditions, 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. In preclinical mouse models (1) specific ablation of LRP5 in 
intestinal cells had no effect on intestinal epithelial cell homeostasis which is attributed to the 
compensatory role of LRP6-mediated Wnt signaling in the mouse intestinal development 
(R17-1470); and (2) specific ablation of LRP5 in mature osteoblasts showed reduced bone 
density, but the phenotype was more pronounced in the absence of both LRP5 and LRP6 with 
the development of severe osteopenia (R18-0131). 
Several compounds targeting the Wnt pathway, but with a different mechanism of action 
compared to BI 905681 which selectively inhibits Wnt ligand dependent pathway activation, 
have been and continue to be studied in clinical trials. These compounds include vantictumab 
(anti-frizzled receptor antibody), ipafricept (frizzled 8 IgG fusion protein), 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 events including nausea, vomiting and diarrhoea were 
documented as frequent drug related adverse reactions (R17-4166, R17-4167, R17-4168, 
R18-1490). In clinical studies of vantictumab, rosmantuzumab, ipafricept 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 


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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.
A 4-week GLP monkey toxicology study revealed that BI 905681 at dose levels up to 150 
mg/kg/dose q1w was very well tolerated with no adverse effects. Slight decreases of bone 
formation biomarkers (BAP and P1NP) were observed and were considered on target related 
effects. These changes were considered non-adverse based on minimal severity and lack of 
histopathology findings in bones. Bone resorption markers were not affected. No other on- or 
off-target effects of BI 905681 have been observed; thus, the no-observed-adverse-effect 
level (NOAEL) or the highest non-severely toxic dose (HNSTD) was determined to be 150 
mg/kg/dose q1w in the monkey, the most relevant toxicology species.
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, and 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 3.1.1 and 4.1.6.4).
Although the nonclinical GLP toxicology study of BI 905681 did not reveal a risk to induce 
cytokine release syndrome (CRS), patients will be monitored and guidelines for management 
of potential cytokine release syndrome are provided and must be followed thoroughly (see 
Section 4.1.6.3).
There were no BI 905681-related abnormal effects on the eyes (ophthalmological and 
microscopic examinations) observed in the 4-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. 
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 colour vision changes) the same 
ophthalmologic assessment will be repeated. Guidelines for management of potential retinal 
toxicity are provided (see Section 4.1.6.5). Monitoring of asymptomatic patients with spectral 
domain optical coherence tomography (SD-OCT) and full ophthalmologic exams is not 
needed based on published literature. The published literature of related competitors do not 
include retinopathy or any other retinal toxicity as drug-related adverse event.
Throughout the study the safety of the participants will be monitored regularly by a Safety 
Monitoring Committee (SMC). 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.


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In summary, the nonclinical safety package and data support the administration of BI 905681 
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
Objectives
The primary objective of this trial is to determine the maximum tolerated dose 
(MTD)/optimal biological dose (OBD) of BI 905681 given as an intravenous infusion and to 
determine the recommended dose and dosing schedule for further trials in the development of 
BI 905681. The MTD will be defined based on the frequency of patients experiencing dose-
limiting toxicities (DLTs) during the MTD/DLT 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 (PK) profile of 
BI 905681.
 
2.1.2
Primary endpoint(s)
The primary endpoints of the trial are:

The MTD/OBD of BI 905681. The MTD will be assessed based on the number of 
patients experiencing DLTs, graded according to Common Terminology Criteria for 
Adverse Events (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

Number of patients experiencing adverse events (AEs) during the entire treatment period
2.1.3
Secondary endpoint(s)
The secondary endpoints of the trial are:

The following PK parameters of BI 905681 will be evaluated after the first administration 
of BI 905681 (if feasible):
o
Cmax: maximum measured concentration of BI 905681 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 905681 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 aims to test two different dosing schedules for BI 905681 (every 3 weeks (q3w) in a 
3-week cycle and every 2 weeks (q2w) in a 4-week cycle) 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/OBD of Schedule A is reached. The 


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starting dose in Schedule B will be determined by the SMC. The SMC will also review 
whether the planned dosing schedule, assessments and sample collection in Schedule B
remain appropriate, and may decide not to pursue testing of another Schedule. 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 905681 
until the MTD/OBD is reached. Dose escalation steps will depend on the observed AEs and 
occurrence of DLTs during the first treatment cycle. However, relevant safety information 
from all treatment cycles will be considered for the determination of the MTD/OBD and 
recommended dose for further development. In each dose cohort a minimum of 2 patients 
will be treated until a first AE of CTCAE Grade ≥2 occurs during the DLT evaluation period 
(the first cycle of treatment), excluding AEs which are clearly related to disease progression 
or concurrent illness. In that case a minimum of 3 patients will be treated at the recruiting 
cohort and subsequent dose cohorts. The SMC may also recommend the size for the next 
dose escalation cohort or recommend expanding the size of the recruiting cohort. 
Starting at dose Cohort 2 the aim is to recruit a minimum of 2 patients with solid tumours 
harbouring the RNF43 mutation or R-spondin fusion. In case fewer than 2 patients
harbouring the RNF43 mutation or R-spondin fusion can be recruited to the current dose 
cohort, additional patients harbouring the RNF43 mutation or R-spondin fusion will be 
recruited as “back-filled” cohorts. Patients included in the “back-filled” cohorts will be 
treated at a dose level below the current dose level being investigated. These patients will be 
used to permit correlation between exposure and PDc effects. The safety data from the “back-
filled” patients will be evaluated additionally in a descriptive manner and provided to the
SMC. 
As soon as all patients enrolled for safety evaluation on a dose level have completed the 
MTD evaluation period, a BLRM with overdose control will be applied using all available 
data (from both the main cohorts and the “back-filled” cohorts) to determine the next 
permitted dose level and evaluate MTD. The overdose risk will then be calculated for each 
preliminary dose level from Table 4.1.3: 1 and dose escalation will be permitted to all doses 
which fulfil the EWOC criterion. Specifications and details of the BLRM are depicted in 
Section 7.1 and Appendix 10.3. 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.
In case an MTD cannot be determined, and pharmacometric modelling and simulation has 
demonstrated that the dose levels reached provide the required exposure over the dosing 
interval, the SMC can decide to stop dose escalation and recommend a dose for further 
clinical development.
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 


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enrolled at a lower dose level. After the criterion for MTD is fulfilled, there will be no further 
dose escalation regardless of the SMC recommendation.
If no DLT is observed, the SMC may decide to declare the Recommended Dose for 
Expansion (RDE) based on PK/pharmacodynamics 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 905681. 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 905681 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/OBD, 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
(CRS) and/or Grade 3 hypersensitivity reaction and/or Grade 3 infusion reaction

One patient experiences a Grade 4 CRS 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 905681 
and the benefit-risk profile of BI 905681 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 905681 
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 GROUP(S)
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 


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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 European Medicines Agency (EMA) guideline 
on small populations (R07-4856) and by the US Food and Drug Administration (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. 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 
whom standard therapy is not appropriate. 
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 v 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. 
3. Patients (only those who harbour a historically confirmed RNF43 mutation or R-
spondin fusion) willing to undergo mandatory tumour biopsy at the time points 
specified in the protocol.
4. Eastern Cooperative Oncology Group (ECOG) Score of 0 or 1 (R01-0787).
5. Adequate organ function defined as all of the following:


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
Absolute neutrophil count (ANC) ≥1.5 x 109/L; haemoglobin ≥9.0 g/dL; platelets 
≥100 x 109/L without the use of haematopoietic growth factors within 4 weeks of 
start of study medication.

Total bilirubin ≤1.5 x 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 the 
Chronic Kidney Disease Epidemiology Collaboration (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 (ALP) <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)2 must only be 
included after a confirmed menstrual period within the past 4 weeks 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. 
WOCBP and men able to father a child must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that result in a 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 4 months after the last dose of BI 905681. A list of contraception 
methods meeting these criteria is provided in the patient information.
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
                                                
2 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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d) other effectively treated malignancy that is considered cured by local 
treatment
3. Osteoporosis ≥ CTCAE Grade 2
4. Chronic corticosteroid use, except as permitted for the maintenance therapy of brain 
metastases (see Exclusion Criterion 13)
5. Osteoporotic compression fracture within 12 months prior to informed consent which 
is clinically significant in the opinion of the investigator.
6. Patient who must or wishes to continue the intake of restricted medications 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.
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 Grade 3 hypersensitivity reactions (including cytokine release syndrome) 
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
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and electronic case report form (eCRF).


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3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

Has radiological (or clinical) documentation of progressive disease on the current 
treatment.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported. Patients who 
withdraw from treatment prior to disease progression should be encouraged to return for full 
EOT and follow-up assessments as outlined in the Flow Chart. In particular, a follow-up visit 
should be performed wherever possible to ensure all adverse events are adequately followed 
up. 
During the MTD evaluation period, patients withdrawn for a reason other than having a DLT 
or patients who miss more than one visit will be replaced after discussion between the 
sponsor and the Investigator if the information that needed to be collected during that visit is 
not available and makes the patient non-evaluable for the PK analyses or safety parameters 
(including evaluation for DLTs).
Patients who come off trial due to a DLT will not be replaced.
If a patient should become pregnant during the trial, the treatment with BI 905681 must 
immediately be stopped. The patient will be followed up until delivery or termination of 
pregnancy (see Section 5.2.6.2 for information on pregnancy forms). The data of the patient 
will be collected and reported in the eCRF until the last patient’s last visit and any events 
occurring thereafter will be reported in the BI drug safety database as described in Section 
5.2.6.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.


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This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial

Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial

Completion of treatment by all patients and the sponsor determines that sufficient data 
have been collected.  
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Description of test product BI 905681 solution for infusion:
Substance:
BI 905681
Pharmaceutical formulation:
Solution for infusion
Dilution in 0.9% sodium chloride 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 Days 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 estimation of the recommended starting dose (RSD) was made on the basis of the ICH 
Guidance for Industry “S9 Nonclinical Evaluation for Anticancer Pharmaceuticals” (R11-
5034).
Two approaches were taken to calculate the starting dose: (1) use of the HNSTD level 
determined in the 4-week repeat dose toxicity study in the monkey, the most relevant 
toxicology species and (2) use of the minimal efficacious dose level determined using an 
EC50 value from the in vivo pharmacology study (Wnt driven breast cancer xenograft model). 
An approach using the STD10 (a severely toxic dose that causes death or irreversible severe 
toxicity in 10% of rodents) from the 2-week non-GLP mouse study was not feasible due to 
morbidity and mortality that was likely a result of anti-drug antibody (ADA) immune 
complex-related hypersensitivity reactions. The lowest starting dose of 1.0 mg/kg BI 905681 
was selected and is expected to be an adequate and safe starting dose.  
Approach 1 (use of HNSTD level in the 4-week repeat dose toxicity study in the monkey): 
The RSD is calculated to be 8.1 mg/kg.


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In the 4-week GLP repeat dose toxicity study, the NOAEL was determined to be 
150 mg/kg/dose q1w (highest dose tested) and this dose is also considered as the HNSTD 
based on lack of overt toxicities.
  
Step 1: Determination of the HNSTD in the repeat dose toxicity study if non-rodent is the 
most appropriate species (4-week GLP study in the monkey)
Monkey: 
HNSTD = 150 mg/kg 
Step 2: Conversion of 1/6th animal HNSTD to Human Equivalent Dose (HED)
Monkey:
1/6th HNSTD = 25 mg/kg 
Conversion factor from monkey dose to HED: 0.324 (based on body surface area 
scaling factor for the drug molecular weight (43.2 kDa <100 kDa)
HED = 25 mg/kg x 0.324 = 8.1 mg/kg 
Approach 2 (use of minimal efficacious dose level determined using an EC50 value from the 
in vivo pharmacology model): The RSD is calculated to be 1.0 mg/kg.
A Wnt driven breast cancer xenograft model has been used as a mechanistic in vivo model to 
test the anti-tumor activity of BI 905681. BI 905681 was administered at doses of 50, 15 or 5 
mg/kg by i.v. injection twice per week. The significant tumor regression was achieved at 15 
or 50 mg/kg (regression in 7/7 animals) and treatments at these dose levels were well 
tolerated with no overt clinical signs or significant change in body weight. A dose-dependent 
pharmacodynamics modulation (inhibition of Axin2 and Notum gene expression) was 
detected at the end of the efficacy study in tumor tissues. In addition, a PK-PDc time-course 
experiment performed in the same xenograft model revealed that full pathway modulation 
(measured by Axin2 down regulation) was achieved up to 48 hours after single dose 
administration of 15 mg/kg, which corresponded to plasma concentrations higher than 715 
nM. Since continuous inhibition of the Wnt pathway is desired, this threshold is considered as 
the EC90 value of the concentration-effect relationship (in terms of human equivalent Ctrough). 
According to the formula [ECF = (F ÷ (100 - F)) x EC50], and the EC50 of 79.4 nM was 
calculated which is considered appropriate to determine a starting dose in humans. By 
simulation of the human PK profile using predicted PK parameters, a human dose of 1.0 
mg/kg was estimated to provide a Ctrough concentration of 77.3 nM at steady state (assuming 
steady state is reached after 9 weeks), based on a once every three week (q3w) dosing 
schedule.
The RSD of BI 905681 is 1.0 mg/kg administered via i.v. infusion, which is the lowest 
starting dose determined by using the EC50 value from the in vivo pharmacology model 
(Approach 2). This dose is expected to be a safe staring dose that has minimal pharmacologic 
effects and is 8-fold below the RSD determined using the HNSTD from the 4-week repeat 
dose toxicity study in monkeys.
At the 1.0 mg/kg starting dose, the human exposure is predicted to be Cmax of 21.8 μg/mL and 
AUC0-168h of 1,900 μg•h/mL. The steady state combined males and females Cmax and 
AUC0-168h at the NOAEL, 150 mg/kg/dose from the 4-week toxicity study in monkeys are 
5,290 μg/mL and 498,000 μg•h/mL, respectively. The safety margins are 243X and 262X for 


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Cmax and AUC0-168h, respectively. Thus, it is considered that the starting dose of 1.0 mg/kg is 
a conservative starting dose that should assure the safety of patients in the initial clinical trial, 
while allowing the potential for benefit. The estimated exposure multiples versus the 
exposures at the monkey NOAEL are shown in Table 4.1.2.1:1. For further details please 
refer to the IB. 
Table 4.1.2.1:1
Recommended starting dose (1.0 mg/kg) and estimated exposure 
multiples versus exposures at the monkey NOAEL
Cmax
at the 
monkey 
NOAEL
(g/mL)
Estimated Cmax
at 1.0 mg/kg 
(g/mL)
Exposure 
Multiple vs 
Monkey 
NOAEL 
Cmax
†
AUC0-168h 
at the monkey 
NOAEL
g•h/mL
Estimated AUC0-168h
at 1.0 mg/kg
g•h/mL
Exposure 
Multiple vs 
Monkey 
NOAEL 
AUC0-168h
†
5,290
21.8
243X
498,000
1,900
262X
† Exposure multiple = Cmax or AUC0-168h at the NOAEL in monkeys ÷ estimated Cmax or AUC0-168h at 1.0mg/kg in 
humans; To calculate the exposure multiples, AUC0-168h at 1.0 mg/kg was estimated from q3w dosing schedule
4.1.3
Dose-escalation scheme
Table 4.1.3: 1 Provisional (Example Only) dose levels for escalation in Schedule A
Dose Level
Proposed dose
Increment from previous dose
1
1.0 mg/kg/q3w
Starting dose
2
2.5 mg/kg/q3w
150%
3
4.5 mg/kg/q3w
80%
4
6.5 mg/kg/q3w
44.4%
5
8.5 mg/kg/q3w
30.8%
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 to be made. 
Dose escalation will continue until identification of the MTD/OBD, safety concerns arise, or 
the trial is terminated for other reasons. The absolute maximum clinical dose must not exceed 
1120 mg/dose.
4.1.4
Starting Dose for Schedule B
After determination of the MTD/OBD 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, and may decide not to 


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pursue testing of this schedule. 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 3.1). The absolute maximum 
clinical dose must not exceed 1120 mg/dose.
4.1.5
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 slot. Medication will be assigned via Interactive 
Response Technology (IRT) for each treatment cycle. Each medication vial will have a 
unique medication number.
4.1.6
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.
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 905681 will be given as an i.v. 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 or 
infusional reactions for at least 6 hours following the end of infusion of BI 905681. 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 905681 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 905681 i.v. infusion.
4.1.6.1
Re-treatment criteria
Before administering a treatment dose the investigator must review the assessments 
performed according to the respective Flow Charts (Schedule A, Table 10.2:1 and Schedule 
B, Table 10.2:2) and assess eligibility to receive further treatment and check that the 
following criteria are met:


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
Absence of disease progression

Drug-related AEs recovered to Grade ≤1 (or baseline if higher than Grade 1)

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 and will be discussed in the SMC (see 
Section 4.1.6.7).
4.1.6.2
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 AEs, including fatality.
If an infusion-related reaction of ≥ CTCAE Grade 3 occurs, study treatment must be 
permanently discontinued.
If symptoms of an infusion-related reaction of CTCAE Grade 2 occur, which do not qualify 
as a DLT, the infusion should be temporarily stopped. Upon recovery, the following guidance 
must be followed:

If more than 50% of the planned dose of BI 905681 was administered, no further 
BI 905681 will be administered until the next scheduled dose.

If less than 50% of the planned dose of BI 905681 was administered due to 
IRR/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. 

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 905681 infusion; the 


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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.
4.1.6.3
Management of Cytokine Release Syndrome (CRS)
Cytokine release syndrome 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 4.1.6.2, clinical manifestations of CRS and other forms of infusion-
related reactions are difficult to distinguish (especially at first occurrence) and require rapid 
diagnosis and immediate management to avoid severe AEs, 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 905681. 
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 administered due to CRS around the time of administration of BI 
905681 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)

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 4.1.6.2).
4.1.6.4
Management of bone toxicity
Patients will be monitored for bone toxicity using regular measurement of serum bone 
biomarkers and bone densitometry. Treatment with vitamin D and/or calcium carbonate is 
recommended in patients with documented pre-existing osteoporosis, per standard of care
and/or investigator’s discretion. 


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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 905681 must be permanently discontinued.
4.1.6.5
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 at baseline, as well as a full retinal 
examination. These assessments have to be performed within 48-72 hours after occurrence. 
Treatment with BI 905681 will be withheld until this ophthalmologic assessment confirms it 
is safe to restart BI 905681.
Treatment with BI 905681 must be discontinued if either of the following are observed:

CTCAE Grade ≥2 retinopathy

Clinically meaningful changes in fundus photography and spectral domain optical 
coherence tomography (SD-OCT) as determined by the examining ophthalmologist
4.1.6.6
General management of toxicities
Toxicities not covered within Sections 4.1.6.2, 4.1.6.3, 4.1.6.4 and 4.1.6.5 will be handled 
according to the instructions in Table 4.1.6.6: 1


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Table 4.1.6.6: 1 Management of toxicity
Event
First occurrence
Second occurrence
Grade 4 non-
haematological 
toxicity which is 
related to 
BI 905681
Permanently discontinue treatment
Start supportive measures according to 
standards of the institution
Not applicable
Haematological 
toxicity fulfilling 
criteria for DLT 
Hold BI 905681 treatment until recovery to 
Grade ≤1 or baseline; start supportive 
measures according to standards of the 
institution (e.g., granulocyte-colony 
stimulating factor [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 905681 
treatment at a lower dose - see Section 4.1.6.7
Permanently discontinue BI 905681
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 
Hold BI 905681 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 905681 
treatment at a lower dose - see Section 4.1.6.7
Permanently discontinue BI 905681
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 905681 
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.
Same as for first occurrence
4.1.6.7
Dose Reduction
In the event of a DLT which meets certain criteria the patient may continue therapy at a 
reduced dose (see Table 4.1.6.6: 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 4.1.6.1). The patient will re-commence treatment at a reduced dose of BI 905681; 
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 


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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.
4.1.7
Definition of dose-limiting toxicity
Dose-limiting toxicities (DLTs) will be recorded throughout the trial. Any DLT must be 
reported to the 
 Medical Monitor by the Investigator or designee within 24 
hours of first knowledge, and to the 
as an
AESI (as described in Section 5.2.6.1). All DLTs will be agreed upon between the Sponsor, 
the Study Chair, the 
 Medical Monitor, and the Investigators after review of the 
data from each cohort. Only DLTs starting in the first cycle of BI 905681 are necessary for 
dose-escalation decisions made by the SMC. DLT information from later cycles will be taken 
into consideration if available.
All relevant safety information (including DLTs) together with data on target engagement 
will be considered when selecting the recommended doses for the expansion cohorts.
Severity of AEs will be graded according to CTCAE Version 5.0. Any of the following AEs 
will be classified as DLTs following review by the Investigators and the 
 
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

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


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-
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.
4.1.8
Blinding and procedures for unblinding
Not applicable.
4.1.9
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.
4.1.10
Storage conditions
BI 905681 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 local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.11
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)/Independent Ethics Committee (IEC),

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g., competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,


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
Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator 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 use by 
each patient, and the return to the sponsor or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational 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 clinical trial 
protocol (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 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 other mandatory treatments to be used or special emergency procedures to be 
followed in this trial.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant therapy, with reasons for the treatment, must be recorded in the eCRF during 
the Screening and treatment periods, starting at the date of signature of informed consent and 
ending after the residual effect period (REP) a period of 42 days after the last dose of trial 
medication. After REP, only concomitant therapy indicated for treatment of a related AE has 
to be reported. If a new anti-cancer treatment is started, it will be documented in the CRF, on 
a separate page of follow-up therapy, different from the concomitant therapies pages.
4.2.2.2
Restrictions on diet and life style
The usual restrictions on diet and life style that were already applicable for a given patient 
before entry into the trial, according to his/her medical condition, have to be continued.


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4.2.2.3
Restrictions regarding women of childbearing potential 
Due to the advanced stage of disease of Phase I trial patient populations and the high medical 
need, females of childbearing potential can be included in this trial provided that they agree 
to use a highly-effective contraception method. These are methods of birth control per the 
International Council for Harmonisation (ICH) M3 (R2) that result in a failure rate of less 
than 1% per year when used consistently and correctly.
Highly-effective methods of contraception include:

Oral, injected, or implanted hormonal methods of contraception, or

Intrauterine device or intrauterine system, or

‘Double-barrier’ methods of contraception: Male condom in combination with female 
diaphragm/cervical cap plus spermicidal foam/gel/film/cream.
Details of these contraception methods are described in the patient information in the ICF.
Women of childbearing potential must follow these methods during the trial and for at least 
6 months after the end of the trial treatment. Although use of a contraceptive pill is 
considered a highly-effective method of birth control, women of childbearing potential taking 
a contraceptive pill must use an additional barrier method for the entire duration of the trial 
treatment intake and for 6 months after the end of the trial treatment intake.
Male patients with partners of childbearing potential must agree to use condoms and ensure 
their partner is using an additional highly-effective method of birth control, during the trial 
and until at least 6 months after the end of the trial treatment.
4.3
TREATMENT COMPLIANCE
BI 905681 will be administered by i.v. infusion at the sites by the Investigator and/or trained 
site personnel, and dosing will be recorded in the eCRF. Therefore, actual dosing is expected 
to precisely follow the prescribed drug regimen. Missed or interrupted doses will be recorded 
in the eCRF with the associated reasons. The method of collecting dosing information assures 
that total exposure can be calculated programmatically taking into account any missing doses.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The 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). 
The baseline imaging must have been performed within 4 weeks prior to treatment with the 
trial medication and the Investigator will record the target and non-target lesions in the eCRF. 
The same method of assessment and the same technique must be used to characterise each 
reported lesion at baseline and during treatment. Lesions in previously irradiated areas may 
not be considered measurable at baseline unless the lesions occurred after irradiation. 
Tumour assessment will be performed at the time points indicated in the respective Flow 
Charts (Schedule A, Table 10.2:1 and Schedule B, Table 10.2:2) Wherever possible the 
assessment schedule should not be changed, but if there is an interruption or delay of
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 will 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
The safety of BI 905681 will be assessed by a descriptive analysis of incidence and severity 
of AEs graded according to CTCAE (Version 5.0), the incidence of DLTs, laboratory data, 
and results of physical examination. Safety will be assessed in a descriptive way without 
confirmatory analysis.
Dose-limiting toxicities observed during the MTD evaluation period (first 3 weeks of
Schedule A or first 4 weeks of Schedule B) will be considered for MTD determination. 
However, DLTs observed in all treatment cycles will be considered for determining a 
recommended Phase 2 dose (RP2D). The BLRM model will be re-run including the DLT 
information from all cycles. Based on both estimates, the recommended dose for further 
development will be selected. At regular intervals, all available safety data including AEs 
qualifying as DLTs will be submitted to the SMC. The SMC will independently assess this 
information and provide recommendations for trial conduct and dose escalation. If there are 
too few or no DLTs for BLRM guided dose selection, PK and/or biomarker data will be taken 
into consideration for RP2D determination.


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5.2.1
Physical examination
A physical examination will be performed at the time points specified in the Flow Charts.
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, body weight and the evaluation of the ECOG performance score (see 
Appendix 10.4) will be performed at the time points specified in the Flow Charts.
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 Flow Charts.
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)

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 Flow Chart.


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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 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 AE.
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 (25-hydroxy 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 time points indicated in the Flow Charts and 
in Appendix 10.2. 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.


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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 AEs 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-CTX and
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
upon.
When a blood sample for bone biomarkers is required, it will be obtained prior to 
administration of trial medication, before 9:00 am, 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 Flow Chart according to 
standard institutional 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.
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 upon.
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 905681. 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 905681 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 905681
administration. Cytokine measurements will be performed in conjunction with each infusion 


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at the time points specified in Appendix 10.2.
In addition to the scheduled cytokine measurements, ferritin will be measured at baseline 
(Cycle 1 Day 1). If a clinically manifested CRS occurs at any time point, 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 Appendix 10.2, and in the Laboratory Manual.
5.2.5.4
Ophthalmologic Assessment
Ophthalmologic assessment will be performed for all patients at Screening. This will require 
a visit to the opthamologist. 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 meters. The BCVA score is the number of letters read correctly by
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 Heidelberg, 
Zeiss or Topcon equipment will be used.
The same ophthalmologic assessments will be repeated within 48-72 hours 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. Treatment with BI 905681 will be 
withheld until this ophthalmologic assessment confirms it is safe to restart BI 905681.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event


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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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of pre-existing conditions (for the underlying disease adhere to chapter 
“Exemptions to SAE reporting” in Section 5.2.6.2) 
Changes in vital signs, ECG, physical examination, laboratory test results and other 
safety parameters included in Section 5.2.5, if they are judged clinically relevant by 
the investigator.
If such abnormalities already exist prior to trial inclusion they will be considered as baseline 
conditions and should be collected in the eCRF.
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,
-
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. 
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above. A copy of the latest list of “Always Serious AEs” will be provided upon 
request. These events should always be reported as SAEs as described in Section 5.2.6.2.
Every 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 


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reported as described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to 
sponsor and timelines”.
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
within the same timeframe that applies to SAEs, please see ‘AE reporting to sponsor and 
timelines.’
For this trial, the following events will be 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)

an elevation of AST and/or ALT >3 times ULN combined with an elevation of total 
bilirubin >2 times ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 times ULN
For patients with abnormal liver function at baseline (AST and/or ALT > ULN)

an elevation of AST and/or ALT ≥5 times ULN combined with an elevation of total 
bilirubin ≥2 times ULN measured in the same blood draw sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 times ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “Potential DILI checklist” provided in 
the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results (i.e., 
ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the Potential DILI checklist should be 
followed.
Dose Limiting Toxicity
Any medical event fulfilling the criteria of DLT (see Section 4.1.7) 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


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
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 4.1.6.2.
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 4.1.6.3.
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 AEs should be classified and recorded in the CRF according to the CTCAE
v5.0.
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

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)


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
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 any occurrence of cancer and 
trial treatment related SAEs and trial treatment related AESIs of which the 
investigator may become aware of by any means of communication, e.g. phone call. 
Those AEs should be reported on the BI SAE form (see Section 5.2.6.2), but not on
the eCRF. 
Vital Status Data Collection 
For patients who discontinue trial medication prematurely and agree to be contacted further 
but do not agree to physical visits: should be followed up, and from withdrawal from trial 
treatment until the individual patient’s end of the trial the investigator must report all 
deaths/fatal AEs regardless of relationship, and trial treatment related SAEs and trial 
treatment related AESIs the investigator becomes aware of. 
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 secure e-mail connection or via fax 


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immediately (within 24 hours) to the 
:

Secure email (
 SAE mailbox: 
 or 

Fax (
fax number): 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the 
upfront via telephone by calling the 
phone number 
(
). This does not replace the requirement to complete and fax the BI SAE 
form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been  assessed as “chronic” or “stable”, or no 
further information can be obtained.
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. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
Exemptions to SAE reporting
The outcome “disease progression” is used to assess trial endpoints for the analysis of efficacy. It 
will be recorded on the appropriate page of the eCRF. Only if it meets standard seriousness 
criteria (see ‘Serious adverse event’ definition) it will also be recorded on the AE page in the 
eCRF and on the BI SAE form and SAE reporting process will be followed. 
Clinical symptoms and/or signs of PD will be recorded on the AE page in the eCRF. If signs and 
symptoms of disease progression of the patient's underlying malignancy meet standard 


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seriousness criteria, they will additionally be reported on the BI SAE form and SAE reporting 
procedures will be followed.
Exempted events are monitored at appropriate intervals throughout the study at SMC 
meetings.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
If data allow, the PK parameters of BI 905681 mentioned as secondary endpoints will be 
evaluated using non-compartmental analysis (NCA) methods according to the current BI 
internal and
Standard Operation Procedures (SOPs).
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.
5.3.2
Methods of sample collection
For quantification of analyte serum concentrations, samples will be drawn at the time points 
listed in the respective Flow Charts (Schedule A, Table 10.2:1 and Schedule B, Table 10.2:2).
If collected from an arm, it is essential to collect blood from the arm that is opposite to the 
arm used for infusion in order to avoid artificially high or low drug concentration 
determinations. Further details on sample characteristics, processing, handling, and shipment 
are provided in the Laboratory Manual. After completion of the trial, serum samples may be 
used for further methodological investigations, e.g. stability testing. However, only data 
related to the analyte or bioanalytical assay will be generated by these additional 
investigations. The trial samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final trial report has been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a PK/PDc relationship is planned.


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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 PK-PDc 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 BIOMARKER(S)
The evaluation of several biomarkers will be performed in an exploratory manner as a 
means of identifying whether, for example, pharmacodynamics modulation is achieved 
during the dose escalation part of the trial. Where consent is given, tumour samples will be 
obtained as detailed below. Tumor sampling must only be performed for patients who 
have undergone screening assessments, have a historically confirmed RNF43 mutation or 
R-spondin fusion, and are expected to be eligible for treatment in the trial. The following 
exploratory biomarkers are planned to be examined in tumor biopsies attained during the
trial:

Pharmacodynamics modulation of genes associated with Wnt signaling including 
but not limited to AXIN2 mRNA expression.

Tumour microenvironment changes induced by BI 905681 intervention, as 
determined by an analysis of an immune-oncology-related panel of genes. 

-catenin staining pattern using immunohistochemistry.

Genomic profiling of tumour samples implementing next generation sequencing.

Immune oncology related targets including but not limited to CD8 and PDL1.
The aforementioned analysis will be undertaken should enough formalin-fixed and 
paraffin-embedded (FFPE) material be available. 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. Until then, samples will be stored at 
Boehringer Ingelheim or 
.
5.4.1
Methods of sample collection
Biopsies should be taken according to the Flow Chart. Pre- and on-treatment tumour 
biopsy (where feasible, from the same lesion) collections for biomarker analyses will be 
mandatory from all patients who have a historically confirmed RNF43 mutation or 
R-spondin fusion entering the trial starting from Cohort 2. Where mandatory, an archival 
sample (25 x 4-5μm-sections), from the most recent relapse, will be acceptable as the pre-
treatment biopsy, if taken within 6 months of trial start. Otherwise a pre-treatment fresh 
tumour biopsy must be taken and formalin fixed paraffin embedded (FFPE) and stored at 
room temperature. On-treatment samples must also be FFPE and stored at room 
temperature until shipped. Detailed instructions for sampling, handling, and shipment of 
samples are provided in the laboratory manual, but in short:


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
For a fresh baseline sample a minimum of 2 core needle biopsies or 1 punch 
biopsy must be taken between screening and the day before first treatment with 
BI 905681. An archival sample, from the most recent relapse, will be acceptable as 
the pre-treatment biopsy (25 x 4-5μm-sections), if taken within 6 months of trial 
start.

Two core-needle biopsies (preferably from the same lesion) 24 hours after Cycle 2
infusion (the on-treatment biopsy time point may be adapted based on PK 
analysis).
All samples must be adequately labelled by the trial site personnel. Details about tumour 
tissue, labelling of tubes, storage, and shipment (frequency and addresses) will be 
provided in the laboratory manual. 
As medical knowledge in this field is constantly evolving, other tissue/blood biomarkers that 
may become relevant as predictive markers of treatment response may also be explored via 
available tissues/blood or acquisition of additional tumour tissues/blood. The list of 
biomarkers planned to be studied during the trial may change based on new information in 
the literature or early analyses.
5.5
OTHER ASSESSMENTS
5.5.1
ADA assessments
For ADA assessment, samples will be drawn at the time points listed in the respective Flow 
Charts (Schedule A, Table 10.2:1 and Schedule B, Table 10.2:2).
Details on sample collection, characteristics, processing, handling, and shipment are provided 
in the Laboratory Manual. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the final trial report has been signed.
Note that for some disease indications, it may be necessary to use serum samples collected 
prior to administration of test article in order to assess the performance of the ADA assay. 
Such use of pre-dose samples will not compromise the collection of valid ADA data for those 
pre-dose samples.
 


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5.6
APPROPRIATENESS OF MEASUREMENTS
All assessments have been planned in accordance with traditional oncology Phase I trial 
methodology.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and exclusion criteria for the part they are participating in and 
who have signed a written ICF, are eligible for participation in the trial. Patients will visit the 
clinical site at the time points specified in Schedule A Flow Chart and Schedule B Flow Chart
specific to each part. If a patient misses a scheduled visit, and reports to the Investigator 
between the missed visit and the next scheduled visit, the assessments for the missed visit 
must be done with the actual date and the reason must be given for the delayed visit. The next 
visit must then take place at the scheduled time after the first administration of the trial drug 
in the respective treatment cycle.
Once the decision is made for any reason for a patient to stop the treatment with BI 905681, 
an EOT visit must occur as soon as possible (no later than 7 days after stopping treatment). 
After the EOT visit, the patient must undergo a follow-up safety evaluation 42 (+7) days after 
the last administration of trial therapy.
The trial will be conducted according to the principles of GCP.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The procedures required at each trial visit in both portions of the trial are presented in 
Schedule A Flow Chart and Schedule B Flow Chart of this protocol. The key procedures 
required include:

PK samples throughout the trial

Reporting of all AEs occurring after the ICF has been signed

Baseline and on-treatment blood biomarker and immunogenicity assessments

Tumour biopsy biomarker assessments

Tumour assessments (based on computed tomography [CT] / positron emission 
tomography [PET] and/or magnetic resonance imaging [MRI] scan) according to RECIST 
Version 1.1 must be performed once every 2 cycles (meaning every 6 weeks for Schedule 
A and every 8 weeks for Schedule B if there are no delays in cycles but as close as 
possible to the end of the second of the 2 cycles of treatment if there was a delay) after 
the start of BI 905681.
6.2.1
Screening and run-in period(s)
6.2.1.1
Screening Period
The Screening period may run over a period of 28 days (period within the trial and before the 
first intake of BI 905681). For the detailed description of the tests to be performed during this 
period and their timing, please refer to Schedule A Flow Chart and Schedule B Flow Chart.


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6.2.1.2
Baseline Conditions
Demographics (sex, birth date, race, and ethnicity where allowed), information on tobacco 
and alcohol use, and baseline conditions will be collected during the Screening visit.
6.2.1.3
Medical History
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumour site will 
be reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumour, (lymph) 
node, metastasis (TNM) classification will be provided as obtained at diagnosis and at trial 
screening. Previous surgeries will be reported.
Previously administered chemotherapy, vaccine therapy, antibodies therapy, kanamycin or 
similar class drugs (including streptomycin, gentamicin, amikacin, tobramycin and 
neomycin), immune therapy, and hormone therapy will be reported, including start and end 
dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
line of treatment will be recorded, if known.
6.2.1.4
Concomitant therapies
Relevant concomitant diagnoses and/or therapies present at trial entry and/or during 
Screening and relevant to the patient’s safety during the trial as judged by the Investigator 
will be recorded in the eCRF (see Section 4.2.2 for details on concomitant medications). 
Post-trial therapy for advanced or metastatic disease will also be documented.
6.2.2
Treatment period(s)
Please refer to Schedule A Flow Chart and Schedule B Flow Chart for a detailed presentation 
of each visit during the treatment period.
6.2.3
Follow up period and trial completion
6.2.3.1
End-of-treatment visit
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason, as soon as possible, but no later than 7 days after permanent discontinuation of the 
trial medication or when the Investigator decided with the patient to permanently discontinue 
the trial medication or became aware that the trial medication had been terminated.
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.


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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 905681 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* = 
4.5 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 posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33] without skipping any 
dose level. Applying the EWOC criterion it should be unlikely (<25% posterior probability) 
that the DLT rate at that dose will exceed 0.33. 
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 recommend 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 905681.


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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 1.0 mg/kg/q3w would equal 0.02, and the 
median DLT rate at the highest dose of 8.5 mg/kg/q3w would equal 0.1. This yields 
 = (-2.701,-0.233). 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 1.0 mg/kg/q3w would equal 
0.09, and the median DLT at the highest dose of 8.5 mg/kg/q3w would equal 0.40. 
These assumptions yield 	 = (-0.973,-0.115). 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 1.0 mg/kg/q3w would equal 
0.01, and the median DLT at the highest dose of 8.5 mg/kg/q3w would equal 0.02. 
These assumptions yield  = (-4.101,-1.113), i.e. basically a flat curve. The standard 
deviations and correlations were set to , = 5, ,		 = 0.01, therefore almost fixing 


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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.
A summary of the prior distribution is provided in Table 7.1.1. Additionally, the prior 
probabilities of DLTs at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1: 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 1.8 patients. A detailed evaluation of the model using hypothetical data scenarios and 
operating characteristics is provided in the statistical appendix (see Appendix 10.3).
Table 7.1: 1 Summary of prior distribution
Prior Component
Mixture Weight
Mean Vector
SD Vector
Correlation
1: Weakly inf.
0.9
-2.701,-0.233
2.000, 1.000
0.000
2: High Tox
0.05
-0.973,-0.115
2.000, 1.000
0.000
3: Low Tox
0.05
-4.101,-1.113
5.000, 0.010
0.000
Table 7.1: 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%
1
0.853
0.075
0.072
0.081
0.162
<0.001
0.014
0.637
2.5
0.780
0.106
0.114
0.118
0.191
<0.001
0.034
0.742
4.5
0.685
0.138
0.177
0.165
0.221
0.001
0.065
0.826
6.5
0.601
0.155
0.244
0.214
0.256
0.001
0.099
0.900
8.5
0.544
0.161
0.295
0.254
0.283
0.001
0.130
0.953
Doses printed in boldface meet the overdose criterion (P (overdose) < 0.25)


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Figure 7.1: 1: Prior medians and 95% credible intervals
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. 
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 for this trial.
7.3
PLANNED ANALYSES
For the determination of the MTD, only MTD-evaluable patients will be considered. For 
other analyses of efficacy and safety endpoints, all patients in the treated set (i.e., patients 


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treated with at least one dose of trial medication) will be included in the analysis. Any other 
analysis sets will be defined in the Trial Statistical Analysis Plan (TSAP).
No per protocol set will be used in the analysis. However, important protocol violations will 
be summarised with details specified in the TSAP.
7.3.1
Primary endpoint analyses
In order to identify the MTD of the trial, the number of patients with DLTs at each dose level 
during the MTD evaluation period (first three weeks for Schedule A and the first 4 weeks for 
Schedule B) must be presented. Patients who discontinue during the first treatment course for 
reasons other than a DLT will be excluded from the determination of the MTD.
In addition, the number of patients with DLTs that occurred during the entire treatment 
period will be summarised at each dose level. The BLRM will be rerun to re-evaluate the 
MTD and RP2D together with all relevant data collected during the study.
7.3.2
Secondary endpoint analyses
All secondary endpoints will be analysed descriptively.
Details on statistical inference for PK parameters, e.g., dose proportionality using Cmax and 
AUC etc., and all other secondary endpoints analysis will be specified in the TSAP.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the 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.’


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of 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.
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 current BI and 
 SOPs.
All patients in the treated set who received at least one dose of BI 905681 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, they 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 


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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: N, 
arithmetic mean, standard deviation, minimum, median, maximum, arithmetic coefficient of 
variation, geometric mean, and geometric coefficient of variation. For the PK parameters in 
addition to the previous descriptive statistics P10, Q1, Q3, and P90 will be also calculated. 
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 values as well as the descriptive 
statistics will be reported with three significant digits in the clinical trial report.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4
INTERIM ANALYSES
No formal interim analysis is planned.
The sponsor will continuously monitor safety. The dose-escalation design dictates that the 
sponsor and the SMC perform regular safety evaluations. These evaluations will be unblinded 
to dose.
If considered necessary, as soon as the MTD is determined, an evaluation of the safety 
aspects will be performed. Results of this evaluation will be documented and archived. If 
applicable, such an analysis will be defined in more detail in the TSAP.
7.5
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory 
values will be imputed by the respective values from the Screening visit. No other 
imputations will be performed on missing data although every effort will be made to obtain 
complete information on all AEs, with particular emphasis on potential DLTs.
7.6
RANDOMISATION
No randomisation will be performed.
7.7
DETERMINATION OF SAMPLE SIZE
The actual number of patients will depend on the number of dose cohorts and the cohort sizes 
actually tested. Given the pre-specified possible dose levels and the number of patients per 
dose level, simulation studies show a range (refer to Table 10.3:3) of 3 to 51 patients is 
needed to assess five dose levels for Schedule A. Assuming Schedule B has a starting dose of 
1.0 mg/kg/q2w, a similar range of patients is required to assess the dose levels. Taken into 
account the number of patients recruited into the “back-filled” cohorts, around 30 patients are 
needed for each schedule. In total, the estimated sample size for the dose escalation phase 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 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 finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator 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 must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.


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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
Case report forms for individual patients will be provided by the sponsor. For drug 
accountability, refer to Section 4.1.11.
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 CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
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 CRF, data must be derived from source documents, for example:


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
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/consented)

Dates of patient’s visits, including administration of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g., medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
 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 CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g., FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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:
will retain 
trial documents according to contractual agreements with the Sponsor.
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.


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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 
prematurely). Individual investigators will be notified of Suspected Unexpected Serious 
Adverse Reactions (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.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A contract research organisation,
, is responsible for 
project management, medical management, site management, data management, site 
regulatory document management, management of the Trial Master File, some aspects of 
safety management and reporting, medical writing, and medical monitoring.
A Safety Monitoring Committee (SMC) will be established. Members of the SMC will 
include:

 Medical Monitor for the trial, or delegate

Principal Investigators, or delegates, from each investigational site

BI Safety Physician, or delegate

BI Clinical Program Leader, or delegate, responsible for the project.

BI TSTAT

BI TCPK, according to agenda
The BI Safety Physician (or delegate), BI Clinical Program Leader (or delegate) should 
always attend the SMC to discuss safety issues.
The 
Medical Monitor, or delegate, should always be 
present at the SMC. Other BI and non-BI subject matter experts may also be invited, as 
appropriate. The SMC documentation for this trial will define the exact membership and who 
should be present for decisions to be made.


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The SMC will be responsible for assessing the progress of the clinical trial, including making 
safety and efficacy assessments at specified intervals, making dose-escalation decisions for 
BI 905681, making decisions on the next cohort size, and recommending to the Sponsor 
whether to continue, modify, or stop the trial. Minutes from these meetings will be prepared 
and circulated to the trial team and each investigator for comment prior to finalisation.
The tasks and responsibilities of the SMC will be documented. The SMC will maintain 
written records of all its meetings.
Relevant documentation on the participating investigators and other important participants, 
including their curricula vitae, will be filed in an ISF.
The statistical analysis 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 and 
 SOPs as agreed upon and 
documented. A list of responsible persons and relevant local information can be found in the 
ISF.
A central laboratory service and an Interactive Response Technology (IRT) vendor will be 
used in this trial for development of shipment orders and assignment of trial medication.
Details will be provided in the IRT Manual and Central Laboratory Manual, available in the 
ISF.
The 
 Study Chair is responsible for coordinating investigators at the different 
sites participating in this trial. Tasks and responsibilities are defined in a contract.
The organisation of the trial in the participating countries will be performed by 
 
 with which the responsibilities and tasks will have been agreed and 
a written contract filed before initiation of the clinical trial.
A central laboratory service will be used in this trial. Details will be provided in the Central 
Laboratory Manual, available in the ISF.
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 an 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, and

ensure appropriate training and information of Local Clinical Monitors (CML), CRAs, 
and investigators of participating countries.


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The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
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.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 1982; 5:649-655.
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 Jan;45(2):228-47.
R11-5034
Guidance for industry: S9 nonclinical evaluation for anticancer 
pharmaceuticals (ICH, March 2010). 
Website.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInforma
tion/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.
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 
2006;127(3):469-480.


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R17-1470
Zhong Z, Baker JJ, Zylstra-Diegel CR, Williams BO. Lrp5 and Lrp6 play 
compensatory roles in mouse intestinal development J. Cell. Biochem. 
2011; 113: 31–38.
R17-1850
Giannakis M, Hodis E, Mu XJ, et al. RNF43 is frequently mutated in
colorectal and endometrial cancers. Nature Genet 2014;46(12):1264-1266.
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
R18-0131
Regard JB, Zhong Z, Williams BO, Yang Y. Wnt signaling in bone 
development and disease: making stronger bone with Wnts. Cold Spring 
Harbor Perspectives in Biology 2012; 4:1-17.
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, Peachey NS, 
and Nathans J. Norrin, Frizzled-4, and Lrp5 Signaling in Endothelial Cells 
Controls a Genetic Program for Retinal Vascularization. Cell 2009; 
139:285-298.
R18-1475
Hackam AS. Critical Review: The Wnt Signaling Pathway in Retinal 
Degenerations. Life 2005; 57:381-388.


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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.
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
c27125909-01 
BI 905681 Investigator’s Brochure.
n00267725
Effects of the LRP5 specific antagonist BI 905681 on viability of RNF43 
mutant pancreatic cancer cell lines
n00267727
Assessment of efficacy, tolerability and PD biomarker modulation by BI
905681 in MMTV-Wnt1 tumor-bearing BomTac:NMRI-Foxn1nu mice
n00267728
Assessment of pharmacodynamics biomarker in skin tissue in tumor
bearing BomTac:NMRI-Foxn1nu mice treated with BI 905681
n00267729
Effects of the LRP5 specific antagonist BI 905681 on viability of RNF43 
mutant CRC patient derived organoids


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10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
If data allow and if scientifically reasonable, the following pharmacokinetic parameters 
of BI 905681 will be evaluated using non compartmental analysis methods according to 
the current internal BI and 
 SOPs.
After the first doses (before steady state is achieved):

Cmax (maximum measured serum concentration of BI 905681 in serum).

 

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).
 
 
 
 


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If deemed necessary, further appropriate pharmacokinetic parameters might be calculated.
Blood sampling time points for PK, ADA, cytokines and ferritin are given in Appendix 10.2.


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10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ADA AND 
CYTOKINE BLOOD SAMPLING AND ECG ASSESSMENT 
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 
905681
ADA
Cytokines
ECG
Tumour 
Biopsy
Any time before 1st infusion
X
1 and 2
1
Before start of BI 905681 infusion
-0:05
X
X
Xa
Xb
Start of BI 905681 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 (±5 
min)
1:30c
X
3h after the end of infusion (±10 min)
4:00c
X
X
7h after the end of infusion (±15 min)
8:00c
X
X
2
24h after start of infusion (±1 hr)
24:00
X
X
Xg
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 905681 infusion
-0:05
X
X
X
Xb
Start of BI 905681 infusion
0:00
End of infusion  
1:00c
Xe
Immediately after end of infusionf
1:00c
Xf
Xf
3h after the end of infusion (±10 min)
4:00c
X
7h after the end of infusion (±15 min)
8:00c
O
2
24h after start of infusion (±1 hr)
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 905681 infusion
-0:05
X
X
X
Xb
Start of BI 905681 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 


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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.
g
Only required in Cycle 2. The on-treatment biopsy time point may be adapted based on PK analysis.


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Table 10.2: 2 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 905681 ADA
Cytokines
ECG
Tumour 
Biopsy
Any time before 1st infusion
X
1 and 2
1
Before start of BI 905681 infusion
-0:05
X
X
Xa
Xb
Start of BI 905681 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 (±5 
min)
1:30c
X
3h after the end of infusion (±10 
min)
4:00c
X
X
7h after the end of infusion (±15 
min)
8:00c
X
X
2
24h after start of infusion (±1 hr)
24:00
X
X
Xh
4
48:00-96:00  
72:00
X
8
144:00-192:00   
168:00
X
Xd
15
Before start of BI 905681 infusion
335:55
X
X
X
Xb,d
Start of BI 905681 infusion
336:00
End of infusion
337:00c
Immediately after end of infusione
337:00c
Xf
Xf
3h after the end of infusion (±10 
min)
340:00c
X
7h after the end of infusion (±15 
min)
344:00c
X
16
24h after start of infusion (±1 hr)
360:00
X
X
22
480:00-528:00   
504:00
X


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Table 10.2: 2 (cont.) 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 905681 ADA Cytokines
ECG
Tumour 
Biopsy
3 and 4
1
Before start of BI 905681 
infusion
-0:05
X
X
X
Xb
Start of BI 905681 infusion
0:00
End of infusion  
1:00c
Xe
Immediately after end of 
infusione
1:00c
Xf
Xf
3h after the end of infusion (±10 
min)
4:00c
X
7h after the end of infusion (±15 
min)
8:00c
O
2
24h after start of infusion (±1 hr)
24:00
O
8
144:00-192:00  
168:00
X
15
Before start of BI 905681 
infusion
335:55
X
X
Start of BI 905681 infusion
336:00
End of infusion 
337:00c
Immediately after end of 
infusione
337:00c
Xf
3h after the end of infusion (±10 
min)
340:00c
X
7h after the end of infusion (±15 
min)
344:00c
O
16
24h after start of infusion (±1 hr)
360:00
O
22
480:00-528:00  
504:00
X
Cycle 5 
onwards
11
1
Before start of BI 905681 
infusion
-0:05
X
X
X
Xb
Start of BI 905681 infusion
0:00
1
Before start of BI 905681 
infusion
335:55
Xg
X
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 cycle1 
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
h
Only required in Cycle 2


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10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
DATA SCENARIOS
A BLRM with overdose control will be used to guide dose escalation in this study. After 
patients in each cohort have completed at least one cycle of treatment, the prior distribution 
will be updated through Gibbs sampling procedures with the accumulated DLT data from the 
MTD evaluation period (first three weeks of Schedule A and first four weeks of Schedule B). 
Posterior probabilities for the rate of DLTs will be summarised from BLRM. Selection of the 
next dose will be based on these probabilities as well as on other safety laboratory and PK 
data.
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 10.3:1.  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, 
not shown in the Table 10.3:1, 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.
For example, scenario 1 corresponds to the case where no DLT is observed at the first two 
dose levels, then the next permitted dose is 4.5 mg/kg/q3w. 
In scenarios 2 to 6, it is assumed that no DLT is observed until the dose level of 4.5 
mg/kg/q3w. Scenarios 3 to 6 focus on the case where the dose level of 6.5 mg/kg/q3w is 
identified as the MTD. To be more specific, in scenario 3, when 1 DLT is observed at 4.5 
mg/kg/q3w, the next dose permitted by the model is the same dose level and we enroll 3 more 
patients at 4.5 mg/kg/q3w in scenario 4 and observed no DLT. In this case, the model advises 
to escalate to the next dose level of 6.5 mg/kg/q3w. Assuming 1 DLT is then observed at 6.5 
mg/kg/q3w, which is demonstrated in scenario 5, the model proposed to stay at dose level of 
6.5 mg/kg/q3w and enroll 3 more patients. Finally in scenario 6, assuming 1 additional DLT 
is observed, the criteria for MTD are met and 6.5 mg/kg/q3w is claimed to be the MTD.
In cases when DLT is not observed until the predicted efficacious dose 6.5 mg/kg/q3w, the 
adaptive feature of the model is fully illustrated in scenarios 7 to 10. Despite the fact that no 
DLTs were observed in the first three cohorts with 9 patients in total, the model reacts 
immediately to the data observed at 6.5 mg/kg/q3w and advises to stay at current dose in 
scenario with 1 observed DLT in scenario 8 and de-escalate with 2 observed DLTs in 
scenario 10. Further in scenario 9, one additional DLT is observed at 6.5mg/kg/q3w, the 
criteria of MTD are met and we claim MTD at 6.5 mg/kg/q3w.


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Table 10.3:1 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
1
2.5
0
0
0.007
4.5
0.861
0.097
0.042
2
1
2.5
4.5
0
0
2
0.433
2.5
0.622
0.299
0.079
3
1
2.5
4.5
0
0
1
0.116
4.5
0.601
0.283
0.116
4
1
2.5
4.5
4.5
0
0
1
0
0.042
6.5
0.568
0.262
0.170
5
1
2.5
4.5
4.5
6.5
0
0
1
0
1
0.212
6.5
0.407
0.381
0.212
6
1
2.5
4.5
4.5
6.5
6.5
0
0
1
0
1
1
0.246
6.5
0.284
0.471
0.246
7
1
2.5
4.5
0
0
0
0.012
6.5
0.842
0.100
0.057
8
1
2.5
4.5
6.5
0
0
0
1
0.131
6.5
0.598
0.271
0.131
9
1
2.5
4.5
6.5
0
0
0
2
0.179
6.5
0.422
0.399
0.179
10
1
2.5
4.5
6.5
0
0
0
2
0.477
4.5
0.542
0.362
0.096


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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 characteristics of the model, we assume 5 true dose-toxicity scenarios. 
As is shown in Table 10.3: 2, 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: High toxicity values are assumed corresponding to the respective dose levels
- Scenario 3: 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.
- Scenario 6: Extremely high toxicity values are assumed corresponding to the respective 
dose levels
Table 10.3: 2 Assumed true dose-toxicity scenarios (Schedule A)
P(DLT)
Dose (mg/kg/q3w)
Scenario
1
2.5
4.5
6.5
8.5
1 (Prior)
0.081
0.118
0.165
0.214
0.254
2 (High Tox)
0.110
0.260
0.400
0.480
0.550
3 (Low Tox)
0.010
0.035
0.070
0.110
0.180
4 (Non-Logistic)
0.020
0.090
0.220
0.280
0.350
5 (Low-High)
0.030
0.080
0.160
0.350
0.470
6 (Extremely High Tox)
0.280
0.380
0.430
0.470
0.510
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 10.3: 3.


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Table 10.3: 3 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
21.0
72.0
0.0
7
16.15
(3 – 33)
2.54
(1 – 8)
2
25.3
39.3
21.8
13.6
13.89
(3 – 39)
3.52
(1 – 12)
3
19.2
80.8
0
0
18.16
(9 – 51)
1.76
(1 – 7)
4
27.8
42.2
29.5
0.5
16.45
(3 – 36)
2.86
(1 – 11)
5
19.9
44.8
34.2
1.1
18.19
(3 – 45)
3.53
(1 – 10)
6
0
20.7
20.9
58.4
8.87
(3 – 30)
2.94
(1 – 11)
Scenario 1 reflects the case that the true dose-toxicity is aligned with prior means, 72.0% 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 (13.6%) 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 
(80.8%). Since none of the pre-defined dose levels has a true DLT rate in the overdose range, 
none of the trials (0%) are stopped prematurely.
In scenarios 4 and 5, 42.2% and 44.8% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range, respectively.
In scenario 6 (extremely high-toxicity scenario), a majority of trials (58.4%) stopped 
prematurely.
The mean patient numbers range from 8.87 patients (extremely high-toxicity scenario) to 
18.19 patients (low-high scenario) and the maximum number of patients was 51. Therefore, 
the patient numbers are as expected and increase when moving away from the extremely 
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.


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10.4
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
R01-0787


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
15 November 2019
EudraCT number
EU number
2019-003490-25
BI Trial number
1424-0001
BI Investigational 
Product(s)
BI 905681
Title of protocol
An open-label, Phase I trial to determine the maximum-
tolerated dose and investigate safety, pharmacokinetics and 
efficacy of BI 905681 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
Section to be changed
FLOW CHART: BI 905681 (REFMAL 638) SCHEDULE A 
TRIAL ASSESSMENTS
Description of change
The Follow-Up blood sample for bone biomarkers was 
removed. 
Footnote k stating that Bone biomarkers will be assessed on 
Cycle 1 Day 1, Cycle 2 Day 1 and then on Day 1 of every 
odd-numbered cycle and the EOT visit was correct.
Rationale for change
Flow Chart was revised to correct an error in the original 
version of the CTP. 
Section to be changed
FLOW CHART: BI 905681 (REFMAL 638) SCHEDULE B
TRIAL ASSESSMENTS
Description of change
The Follow-Up blood sample for bone biomarkers was 
removed. 
Footnote k stating that Bone biomarkers will be assessed on 
Cycle 1 Day 1, Cycle 2 Day 1 and then on Day 1 of every 
odd-numbered cycle and the EOT visit was correct.
Rationale for change
Flow Chart was revised to correct an error in the original 
version of the CTP. 


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Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
After the criterion for MTD is fulfilled, there will be no 
further dose escalation regardless of the SMC 
recommendation. The SMC may recommend stopping 
further dose escalation after the criterion for MTD is fulfilled. 
Additional patients may be included to confirm this MTD 
estimate (and to further evaluate PK/PDc), i.e. to confirm that 
the EWOC criterion is still fulfilled.
Rationale for change
Text was revised to ensure that if the MTD criterion is 
fulfilled, there is no further dose escalation regardless of the 
SMC recommendation. 
Section to be changed
Table 4.1.1
Description of change
Dilution in 5% glucose 0.9% sodium chloride is required
Rationale for change
Text was revised to correct an error in the original version of 
the CTP.
Section to be changed
Section 4.1.3 and Section 4.1.4
Description of change
The absolute maximum clinical dose must not exceed 1120 
mg/dose. 
Rationale for change
Text was revised to ensure that the specifications for host cell 
DNA and endotoxins stay within the recommended limits for 
the provisional dose levels for Schedule B. 
Section to be changed
Section 4.1.4 Starting Dose for Schedule B
Description of change
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 who will also review whether the planned 
dosing schedule, assessments and sample collection in 
Schedule B remain appropriate, and may decide not to pursue 
testing of this schedule.
Rationale for change
Text was revised to include specific details on the provisional 
starting dose of Schedule B in relation to the Schedule A 
MTD.  
Section to be changed
Section 7.1
Description of change
The BLRM recommended dose for the next dose level is the 
level with the posterior probability of the DLT rate falling in 
the target interval [0.16, 0.33] among the doses fulfilling 
EWOCwithout skipping any dose level.
Rationale for change
The text was revised to clarify that no dose levels would be 
skipped. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29037963
2.0
clinical-trial-protocol-revision-01
An open-label, Phase I trial to determine the maximum-tolerated dose and investigate
safety, pharmacokinetics and efficacy of BI 905681 administered intravenously in
patients with advanced solid tumours
Approval-Clinical Program 
15 Nov 2019 09:28 CET
Author-Clinical Trial Leader
15 Nov 2019 09:47 CET
Author-Clinical Pharmacokineticist
15 Nov 2019 09:55 CET
Approval-Therapeutic Area 
15 Nov 2019 14:11 CET
Author-Trial Statistician
15 Nov 2019 17:13 CET
Approval-Clinical Trial Leader
15 Nov 2019 17:15 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29037963
2.0

SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35271141-01
BI Trial No.:
1424-0001
Title:
An open-label, Phase I trial to determine the maximum-tolerated 
dose and investigate safety, pharmacokinetics and efficacy of 
BI 905681 administered intravenously in patients with advanced 
solid tumours.
Investigational
Product(s):
BI 905681
Responsible trial 
statistician(s):
   Phone: 
   
Date of statistical 
analysis plan:
17 JAN 2022 SIGNED 
Version:
1
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINT(S).......................................................................................................7
5.1
PRIMARY ENDPOINT(S) ..................................................................................7
5.2
SECONDARY ENDPOINT(S) ............................................................................7
5.2.1
Key secondary endpoint(s)...................................................................................7
5.2.2
Secondary endpoint(s) ..........................................................................................7
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENT(S)................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED...........................................................................11
6.5
POOLING OF CENTRES .................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................12
7.
PLANNED ANALYSIS......................................................................................14
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........14
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................14
7.3
TREATMENT COMPLIANCE........................................................................14
7.4
PRIMARY ENDPOINT(S) ................................................................................15
7.4.1
Primary analysis of the primary endpoint(s) ...................................................15
 
7.5
SECONDARY ENDPOINT(S) ..........................................................................15
7.5.1
Key secondary endpoint(s).................................................................................15
7.5.2
(Other) Secondary endpoint(s) ..........................................................................15


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7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................19
7.8.2
Laboratory data ..................................................................................................19
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG......................................................................................................................20
7.8.5
Others...................................................................................................................20
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............21
9. 
REFERENCES....................................................................................................22
11.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Dose levels for escalation in Schedule A .........................................................10
Table 6.1: 2
Definition of treatment periods.........................................................................11
Table 11: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary
Term
Definition / description
AE
BI
Adverse Event
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
CR
Complete Response
CRF
Case Report Form
CTC
Common Terminology Criteria
CTh
Concomitant Therapy
CTP
Clinical Trial Protocol
DBL
Databaselock
DCR
Disease Control Rate
DEC
Dose Escalation Committee
DLT
Dose Limiting Toxicity
EOT
End Of Text
EWOC
Escalation With Overdose Control
ICH
International Conference On Harmonisation
IPD
Important Protocol Deviation
MQRM
Medical Quality Review Meeting
MTD
Maximum Tolerated Dose
MTDS
MTD evaluation set
OBD
OR
ORR
Optimal Biologic Dose
Objective Response
Objective Response rate
PD
Protocol Deviation
PK
Pharmacokinetics
PKS
PK set
PR
Partial Response
PT
Preferred Term
REP
Residual Effect Period
RPM
Report Planning Meeting


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Term
Definition / description
ScS
Screened Set
SD
Stable Disease
STD
Standard Deviation
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 
3.
INTRODUCTION
As per (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 enrollment issues, the trial will be terminated early without determination of the 
maximum tolerated dose (MTD)/optimal biologic dose (OBD) as per protocol. Only schedule 
A has been investigated in the trial. The early termination does not have an impact on the 
planned endpoints.
 
 
 
 
 
 
 
 
5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoints of the trial are:

The MTD/OBD of BI 905681. 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 905681 will be evaluated after the 
first administration of BI 905681 (if feasible), ie. in Cycle 1:
o
Cmax: maximum measured concentration of BI 905681 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 905681 1.0 mg/kg every three weeks. The trial has been terminated before 
the start of schedule B. Dose escalation decisions will be made by a Dose Escalation 
Committee (DEC) 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
1.0 mg/kg/q3w
Starting dose
2
2.5 mg/kg/q3w
150%
3
5.0 mg/kg/q3w
100%
4
7.0 mg/kg/q3w
40%
5
8.5 mg/kg/q3w 
21.4%
The data will be presented for all dose cohorts separately and in total over all dose cohorts. 
DLTs occurring during the MTD evaluation period (during the first treatment cycle) 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, +1 day 
whichever comes first, 
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.
The initial dose of trial medication assigned at the beginning of the first treatment cycle will 
be used as the label of the analysing 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 Databaselock (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.

Screened Set (ScS): includes all patients who have signed the informed consent form 
and will be used for patient disposition.


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
Treated Set (TS): includes all patients who received at least one infusion of BI 
905681. 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. 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 center/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).
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 
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 


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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 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 Section 5.4 of this TSAP. 


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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 after coding according to the current version of MedDRA at 
the database lock. In addition, AEs will be tabulated by preferred terms only. The SoC will be 
sorted alphabetically. In tables displaying AEs by preferred terms, this will be sorted by 
descending frequency of AEs in the “Total” BI 905681 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 
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:


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
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 assessements will be listed for all timepoints.
7.8.5
Others
Patients ophthalmologic assessments will be listed. 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 
17-JAN-22
None
This is the final TSAP