Clinical trial NCT05087992
Conditions: Gastrointestinal Cancer, Metastatic
Sponsor: Boehringer Ingelheim
Start date: 2021-11-24; Completion date: 2023-11-14
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is open to adults with advanced colorectal cancer or with advanced pancreatic cancer. The study has 2 parts. In the first part, participants with colorectal cancer get a medicine called BI 905711 combined with chemotherapy and bevacizumab. The purpose of the first part is to find the highest BI 905711 dose participants can tolerate. In the second part, participants with colorectal cancer or pancreatic cancer get BI 905711 combined with chemotherapy. Some participants also get bevacizumab. The second part tests whether BI 905711 makes tumours shrink. Participants get BI 905711, chemotherapy and bevacizumab about every 2 weeks as an infusion into a vein. Participants can stay in the study as long as they benefit from treatment and can tolerate it. The doctors regularly check the health of the participants and note any health problems that could have been caused by the study treatment. The doctors also monitor the size of the tumour.

Detailed description:

Arms: arm 1: Patients with colorectal adenocarcinoma (CRC) received a single administration of 0.6 milligrams (mg) / kilograms (kg) of BI 905711 intravenously on Day 3 of each 14-day cycle. Patients also received FOLFIRI (irinotecan: 180 mg/squaremeters (m2) over 1.5 hours (hrs), leucovorin: 400 mg/m2 (in Japan: levoleucovorin: 200 mg/m2) over 2 hrs, fluorouracil: 400 mg/m2 bolus or 2400 mg/m2 46 hrs continuous infusion) in combination with bevacizumab, 5 mg/kg over 30 minutes (min) intravenously on Day 1 of each 14-day cycle. arm 2: Patients with colorectal adenocarcinoma (CRC) received a single administration of 1.2 mg/kg of BI 905711 intravenously on Day 3 of each 14-day cycle. Patients also received FOLFIRI (irinotecan: 180 mg/m2 over 1.5 hours (hrs), leucovorin: 400 mg/m2 (in Japan: levoleucovorin: 200 mg/m2) over 2 hrs, fluorouracil: 400 mg/m2 bolus or 2400 mg/m2 46 hrs continuous infusion) in combination with bevacizumab, 5 mg/kg over 30 minutes (min) intravenously on Day 1 of each 14-day cycle. arm 3: Patients with colorectal adenocarcinoma (CRC) received FOLFIRI (irinotecan: 180 mg/m2 over 1.5 hours (hrs), leucovorin \[or levoleucovorin\]: 400 mg/m2 (in Japan: levoleucovorin: 200 mg/m2) over 2 hrs, fluorouracil: 400 mg/m2 bolus or 2400 mg/m2 46 hrs continuous infusion) in combination with bevacizumab, 5 mg/kg over 30 minutes (min) intravenously on Day 1 of each 14-day cycle.
Interventions: intervention 1: BI 905711 intervention 2: FOLFIRI intervention 3: Bevacizumab
Intervention descriptions: intervention 1: BI 905711 intervention 2: FOLFIRI intervention 3: Bevacizumab

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (19.0) / Saved on: 03 Nov 2020
Clinical Trial Protocol
 
Document Number:
c35307392-04                         
EudraCT No.
EU Trial No.
2021-003041-37 
BI Trial No.
1412-0003
BI Investigational
Medicinal Product(s)
BI 905711
Title
A phase Ia/Ib, open label, multicentre, dose escalation study of BI 
905711 in combination with chemotherapy followed by expansion 
cohorts in patients with advanced gastrointestinal cancers
Lay Title
A study to find the best dose of BI 905711 in combination with 
chemotherapy and to test whether this dose helps people with 
advanced gastrointestinal cancers.
Clinical Phase
Ia/Ib
Clinical Trial Leader
Telephone: 
 Fax: 
 
Coordinating 
Investigator
Phone:
Current Version and 
Date
Final Version 4
27 APR 2023
Original Protocol 
Date
23 JUN 2021
Page 1 of 134
Proprietary confidential information.
! 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
23 JUN 2021
Revision date
27 APR 2023
BI trial number
1412-0003
Title of trial
A phase Ia/b, open label, multicentre, dose escalation study of BI 
905711 in combination with chemo-therapy followed by expansion 
cohorts in patients with advanced gastrointestinal cancers
Coordinating 
Investigator
Trial site(s)
Multi-centre
Clinical phase
Ia/Ib
Trial rationale
BI 905711 is a tetravalent bispecific antibody targeting both 
TRAILR2 and CDH17 and is designed to selectively induce apoptosis 
in CDH17 expressing tumour cells via CDH17- dependent clustering 
of TRAILR2. The combination of TRAILR2/CDH17 antibody with 
chemotherapy aims to increase the apoptotic signal by the activation 
of both the intrinsic and the extrinsic apoptosis pathways in cancer 
cells. In relevant preclinical GI cancer models including colorectal 
cancer and pancreatic adenocarcinoma, BI 905711 showed efficacy as 
single agent and in combination with chemotherapy agents like 
capecitabine, irinotecan, paclitaxel and oxaliplatin. Moreover, pro-
apoptotic priming with irinotecan followed 24 hours later by BI 
905711 led to a synergistic effect as compared to co-administration 
on the same day (data on file). These data are consistent with 
published data demonstrating that pre-treatment with chemotherapy 
eg. cisplatin and irinotecan, sensitizes cancer cells to TRAILR2 
agonistic antibodies and the sequential administration might 
overcome resistance (see section 1.3 for more details).
The first-in-human trial 1412-0001 is assessing BI 905711 as 
monotherapy in patients with advanced or metastatic GI cancers. In 
Phase Ia, 45 patients (26 with CRC, 19 with non-CRC GI cancers) 
have received BI 905711 (dose range 0.02–4.8 mg/kg). No safety 
concerns or dose-limiting toxicities have been observed to date and 
the MTD was not reached.Based on safety, pharmacokinetic, and 
pharmacodynamic profiles, as well as preliminary antitumor activity 
of BI 905711, three dose levels (0.6 mg/kg, 1.2 mg/kg and 2.4 mg/kg) 
given biweekly or one dose level (0.6 mg/kg) given weekly were 
selected for assessment of BI 905711 monotherapy in 1412-0001 
expansion phase 1b.
Trial objective(s)
Phase Ia:
∀
To determine the maximum tolerated dose (MTD) and the 
recommended dose for expansion (RDE) of BI 905711 in 


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combination with FOLFIRI regimen plus bevacizumab in 
CRC patients based on the frequency of patients experiencing 
dose limiting toxicities (DLT) during the MTD evaluation 
period.
∀
To explore pharmacokinetics/pharmacodynamics, and efficacy 
to guide the determination of a MTD or a potentially effective 
dose in the absence of MTD, of BI 905711 in combination 
with FOLFIRI plus bevacizumab.
Phase Ib
∀
To evaluate the efficacy and safety of BI 905711 in 
combination with FOLFIRI plus bevacizumab in the CRC 
cohort, and define RP2D.
∀
To evaluate the efficacy and safety of BI 905711 in 
combination with FOLFIRI (or Liposomal Irinotecan Plus 5-
FU/Leucovorin) in PDAC cohort, and define RP2D.
Trial endpoints
Primary endpoints:
Phase Ia
∀
Maximum tolerated dose (MTD) defined as the highest dose 
with less than 25% risk of the true DLT rate being equal or 
above 33% during the MTD evaluation period. 
∀
Number of patients with DLTs in the MTD evaluation period.
Phase Ib 
∀
Confirmed objective response (OR) as assessed by the 
investigator based on Response Evaluation Criteria in Solid
Tumors (RECIST 1.1) in patients with measurable disease, 
defined as the best overall response of complete response
(CR) or partial response (PR), from the first administration of 
trial medication until the earliest of progressive disease (PD), 
death or last evaluable tumor assessment before start of 
subsequent anti-cancer therapy.
∀
In PDAC cohort safety run-in part: number of patients with
DLTs during the MTD evaluation period assessed in the first 6 
patients.
Secondary endpoints:
Phase Ia
∀
The following PK parameters will be calculated after study 
treatment administration, as measured during the first cycle 
and after multiple cycles:
- Cmax: Maximum measured plasma concentration of 
BI 905711.
- AUC0-t2: Area under the concentration-time curve in plasma 


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of BI 905711
Phase Ib
∀
Progression-Free Survival (PFS) defined from date of start of 
treatment to the date of disease progression or death, 
whichever is earlier as assessed by the investigator according 
to RECIST 1.1.
∀
Radiological (CT Scan) tumor shrinkage, defined as the 
difference between the minimum post-baseline sum of longest 
diameters of target lesions and the baseline sum of longest 
diameters of the same set of target lesions according to 
RECIST 1.1.
∀
The duration of OR is measured from the time measurement 
criteria are first met for CR/PR (whichever is first recorded) 
until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest 
measurements recorded on study) according to RECIST 1.1.
∀
Disease control, defined as CR, PR, or stable disease (SD)
lasting at least 16 weeks according to RECIST 1.1 from the 
start of treatment until the earliest of PD, death or last 
evaluable tumor assessment and before start of subsequent 
anti-cancer therapy.
∀
The following PK parameters will be calculated after study 
treatment administration, as measured during the first cycle 
and after multiple cycles:
- Cmax: Maximum measured plasma concentration of 
BI 905711 in plasma.
- AUC0-t2: Area under the concentration-time curve for 
BI 905711 in plasma.
Trial design
Phase Ia is an open-label, non-randomized dose escalation study of BI 
905711 in combination with FOLFIRI and bevacizumab in patients 
with CRC. Dose escalation will be guided by a Bayesian logistic 
regression model (BLRM) with overdose control. Pharmacokinetics 
(PK) and efficacy will be evaluated to guide determination of the 
MTD/RDE.
Phase Ib is an open label study with the main objective to assess the 
safety and efficacy of BI 905711 in combination with chemotherapy
in 2 expansion cohorts. PK will be further characterised and the 
RP2D will be confirmed.
Phase Ib will consist of 2 cohorts of patients with 2 different tumor
types as described below. 
Randomized CRC expansion cohort:
CRC cohort is an open label, randomized cohort of CRC patients. 
Patients will be randomized in a 2:1 ratio into either


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•
Arm A = FOLFIRI plus bevacizumab plus BI 905711 at the 
RDE from Phase Ia 
  or
•
Arm B = FOLFIRI plus bevacizumab without BI 905711
Single Arm PDAC expansion cohort:
This is an open label single arm cohort of patients with advanced or 
metastatic PDAC. A safety run-in will be included in which the first 6 
patients will be treated with FOLFIRI (or Liposomal Irinotecan plus 
5-FU/Leucovorin) plus BI 905711 at the RDE determined in Phase Ia 
to confirm the RDE based on DLTs assessed during the first two 14-
day treatment cycles prior to enrolling further patients.
Total number of patients
treated
Up to approximately 100 patients
Number of patients per
treatment group
Phase Ia (dose escalation): approximately 20 evaluable CRC patients.
Phase Ib (dose expansion); approximately 60 evaluable CRC patients
and 20 evaluable PDAC patients.
Diagnosis
The patient with histologically or cytologically confirmed advanced 
unresectable or metastatic CRC (Phase Ia and Ib), and CDH17 
positive PDAC (Phase Ib only).
Main inclusion and 
exclusion criteria
Inclusion Criteria
Applicable to both Phase Ia and Phase Ib Cohorts:
1. Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.
2. Of legal adult age (according to local legislation) at screening.
3. Histologically or cytologically confirmed, advanced unresectable 
or metastatic colorectal adenocarcinoma
4. CRC Patients who have disease progression (PD) after prior 
oxaliplatin-based first line therapy or within 6 months after the 
end of oxaliplatin-based adjuvant therapy. 
5. Eastern Cooperative Oncology Group (ECOG) performance status 
≤ 1
6. Life expectancy ≥ 3 months in the opinion of the investigator
7. Availability and willingness to provide tumor tissue (fresh biopsy 
or archival) for biomarker analysis. Only non-significant risk 
procedures per the investigator’s judgment will be used to obtain 
any biopsies specified in this study. In case a fresh tumor biopsy 
cannot be obtained, the recruitment of the patient may proceed on 
a case-by-case basis after agreement between the investigator and 
BI. In such a case, an archived tumor tissue specimen must be 
submitted.
8. Adequate hepatic, pancreatic, renal and bone marrow functions as 
defined below:
o
Total bilirubin ≤1.5 x institutional upper level of 
normal (ULN)
o
Alanine transaminase (ALT) and Aspartate 


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transaminase (AST) ≤2.5 x institutional ULN or ≤5 x 
institutional ULN for patients with known liver 
metastases
o
Serum creatinine ≤1.5x institutional ULN. If creatinine 
is > 1.5 x ULN, patient is eligible if concurrent 
creatinine clearance ≥50 ml/min (≥ 0.05L/min) 
(measured or calculated by CKD-EPI formula or 
Japanese version of CKD-EPI formula for Japanese 
patients)
o
Absolute neutrophil count (ANC) ≥1.5 x 109/L, ≥ 1.5 x 
103/μL, or ≥ 1500/mm3
o
Platelets ≥ 100 x 109/ L, ≥ 100 x 103/μL, or ≥ 100 x 
103/mm3
o
Hemoglobin (Hb) ≥ 8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 
mmol/L (without transfusion within previous week)
o
Serum lipase ≤ 1.5 institutional ULN (Only for CRC 
cohort); >1.5 - 2.0 x ULN or asymptomatic >2.0 - 5.0 
x ULN if related to PDAC (Only for PDAC cohort)
9. Recovery, from any adverse events (AEs) of previous anti-cancer 
therapies, to Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 (CTCAE) grade 1 except for CTCAE grade 2 
alopecia or peripheral sensory neuropathy, or other CTCAE grade 
2 AEs considered not clinically significant in the investigator’s 
opinion.
10. Male or female patients. Women of childbearing potential 
(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 low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods 
meeting these criteria is provided in Section 4.2.3.3.
Additionally, criterion #11 is applicable to Phase Ia cohort only:
11. Patient with either measurable or non-measurable disease.
Additionally, criterion #12-14 is applicable to Phase Ib cohorts only:
12. At least one target lesion that can be accurately measured per 
RECIST 1.1
PDAC Patients must meet the following:
13. Histologically or cytologically confirmed, advanced unresectable 
or metastatic CDH17 positive pancreatic adenocarcinoma.
14. Patients who have PD after prior platin and/or gemcitabine-based 
first line therapy.
Exclusion criteria


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Applicable to both Phase Ia and Phase Ib cohorts
1. Any prior irinotecan-based therapy in the metastatic setting.
2. Previous systemic anti-cancer therapy within the specified 
timeframe from the last dose intake to the first dose of trial 
treatment as follows: 
o
Any non-investigational drug, including anti-
angiogenic agents (bevacizumab or ramucirumab or 
aflibercept) and anti-EGFR antibodies (cetuximab or 
panitumumab), within 14 days.
o
Any investigational drug or other antibodies including 
immune checkpoint inhibitors, within 28 days.
3. Currently enrolled in another investigational device or drug trial. 
Patients who are in follow-up/observation for another clinical trial 
are eligible.
4. Radiation therapy within 4 weeks prior to start of treatment. 
However, palliative radiotherapy for symptomatic metastasis is 
allowed if completed within 2 weeks prior to start of treatment.
5. Any serious concomitant disease or medical condition affecting 
compliance with trial requirements or which are considered 
relevant for the evaluation of the efficacy or safety of the trial 
drug, such as neurologic, psychiatric, infectious disease or 
active ulcers (gastro-intestinal tract, skin) or laboratory 
abnormality that may increase the risk associated with trial 
participation or trial drug administration, and in the judgment 
of the Investigator, would make the patient inappropriate for 
entry into the trial. 
6. Known pathological condition of GI tract, liver and pancreas, 
excluding the disease under study, that may interfere with 
assessment of drug safety or may increase the risk of toxicity:
a. inflammatory bowel disease
b. chronic pancreatitis
c. other serious GI pathological conditions by judgment of
the investigator e.g. autoimmune disease with GI involvement, 
unexplained active diarrhea CTCAE v5.0 grade ≥2. 
7. Known history of human immunodeficiency virus (HIV) 
infection. 
8. Any of the following laboratory evidence of hepatitis virus 
infection. Test results obtained in routine diagnostics are 
acceptable if done within 14 days before the informed consent 
date:
o
Positive results of hepatitis B surface (HBs) antigen
o
Presence of HBc antibody together with HBV-DNA
o
Presence of hepatitis C RNA
9. Previous or concomitant malignancies, other than the one treated 
in this trial within the last 2 years with the exception of the 
following:


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o
Effectively treated non-melanoma skin cancers
o
Effectively treated carcinoma in situ of the cervix
o
Effectively treated ductal carcinoma in situ
o
Other effectively treated malignancy that is considered 
cured by local treatment
10. Chronic alcohol or drug abuse or any condition that, in the 
investigator’s opinion, makes the patient an unreliable trial 
participant or unlikely to comply with the protocol requirements 
or not expected to complete the trial as scheduled.
11. Women who are pregnant, nursing, or who plan to become 
pregnant while in the trial; female patients who do not agree to the 
interruption of breast feeding from the start of study treatment 
through 6 month after the last study treatment. 
12. Presence of uncontrolled or symptomatic brain or subdural 
metastases. Inclusion of patients with brain metastases who 
have completed local therapy and are considered stable by 
the investigator, or with newly identified asymptomatic
brain metastases at screening will be allowed. Use of 
corticosteroids is allowed if the dose was stable for at least 
1 week before the baseline MRI.
13. Patients who are under judicial protection and patients who are
legally institutionalized.
14. Major surgery (major according to the investigator’s assessment) 
performed within 28 days prior to treatment start or planned 
within 3 months after screening, e.g. hip replacement.
15. Any of the following cardiac criteria:
a.
Resting corrected QT interval (QTc) >470 msec, 
based on local assessment
b. Any clinically important abnormalities (as assessed by the 
Investigator) in rhythm, conduction, or morphology of 
resting Electrocardiograms (ECGs), e.g., complete left 
bundle branch block, third degree heart block.
c.
Patients with an ejection fraction (EF) <50% or the lower 
limit of normal of the institutional standard will be 
excluded. Only in cases where the Investigator (or the 
treating physician or both) suspects cardiac disease with 
negative effect on the EF, will the EF be measured during 
screening using an appropriate method according to local 
standards to confirm eligibility (e.g., echocardiogram, 
multi-gated acquisition scan). A historic measurement of EF 
no older than 6 months prior to first administration of study 
drug can be accepted provided that there is clinical evidence 
that the EF value has not worsened since this measurement 
in the opinion of the Investigator or of the treating physician 
or both.
d. Patients with a history of stroke or myocardial infarction 
within 6 months prior to screening are not permitted.


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16. Known hypersensitivity to the trial medications or their 
excipients.
17. The patient has any known history or clinical evidence of 
Gilbert’s Syndrome, or is known to have any of the 
following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or 
UGT1A1*6/*28
18. Any contradictions to the proposed background therapy 
according to the current approved local labels. 
Test product(s)
BI 905711
dose
Phase Ia: starting dose of 0.6 mg/kg on Day 3 of each 14-day cycle
Phase Ib: RDE from phase Ia
Duration of treatment
BI 905711 will be administered until disease progression, 
unacceptable toxicity, or other reasons requiring
treatment discontinuation.
mode of 
administration
Intravenous
Combination
product(s)
Irinotecan 
Liposomal Irinotecan (PDAC cohort only)
Leucovorin (or Levoleucovorin)
Fluorouracil 
Bevacizumab (CRC cohort only)
Dose and Duration of 
background 
treatment
∀
Bevacizumab: 5 mg/kg IV over 30 minutes on Day 1 of each 
14-day cycle.
∀
Irinotecan: 180 mg/m2 IV over 1.5 hours on Day 1 of each 14-
day cycle.
∀
Liposomal Irinotecan: 70 mg/m2 IV over 1.5 hours on Day 1 
of each 14-day cycle.
∀
Leucovorin: 400 mg/m2 IV (in Japan, Levoleucovorin: 200 
mg/m2) over 2 hours on Day 1 of each 14-day cycle.
∀
Fluorouracil: 400 mg/m2 IV bolus on Day 1 of each 14-day 
cycle.
∀
Fluorouracil: 2400 mg/m2 IV 46 hours continuous infusion 
starting on Day 1 of each 14-day cycle. 
mode of
administration
All Intravenous
Statistical methods
Phase Ia: Dose escalation is guided by a BLRM with overdose control 
that will be fitted to binary toxicity outcomes (DLTs). The estimate of 
parameters will be updated as data are accumulated using the BLRM. 
Available safety data from BI Study 1412-0001 can be incorporated 
into the prior derivation meta-analytic predictive (MAP) approach.
Phase Ib: Primary and secondary endpoints will be analyzed
descriptively. If additional DLTs are observed during the safety run-
in phase, a separate BLRM with overdose control will be used to re-
estimate the recommended dose for PDAC cohort.


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FLOW CHARTS
FLOW CHART 1
PHASE IA -NO LONGER APPLICABLE PER CTP V4.0
Treatment Period
Post-Treatment
Visit
SCR
Cycle 1*
(14 days)
Cycle 2 *
(14 days)
Cycle 3 *
(14 days)
Cycle 4 *
(14 days)
Cycle 5 and 
beyond *
EoT**
EOR***
(FUP #1)
FUP for 
PD##
FUP for OS status ##
Day
(visit window)
-28 
- 1
1
3
4
5
10
(±2)
1
(+2)
3
4
1
(+2)
3
4
5
10
(±2)
1
(+2)
3
4
1 
(+2)
3
Day 0-
14 after 
disconti
nuation
30 (+5) 
days after 
last dose 
Informed Consent1
x
Demographics + Medical 
History
x
In- /Exclusion Criteria2
x16
x
Eligibility for re-treatment2
x
x
x
x
Physical Examination3,4
x
x
x
x
x
x
x
x
x
ECOG performance score5
x
x
x
x
x
x
x
x
x
Pregnancy test6
x
x
x
x
x
12-lead-ECG7
x
x
x
Infusion of BI 9057118
x
x
x
x
x
Infusion of FOLFIRI with 
bevacizumab8.1
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Safety lab testing9
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pharmacokinetics10
x
x
x
x
x
x
x
x
x
x
x
x
x10
x
x
ADA sampling10
x
x
x
x
x
Nab sampling10
x
x
x
x
x
Circulating free DNA10
x
x
x
x
x


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Flow Chart 1 
Phase Ia (cont.) -NO LONGER APPLICABLE PER CTP V4.0
Treatment Period
Post-Treatment
Visit
SCR
Cycle 1*
(14 days)
Cycle 2 *
(14 days)
Cycle 3 *
(14 days)
Cycle 4 *
(14 days)
Cycle 5 and 
beyond *
EoT**
EOR***
(FUP #1)
FUP for 
PD##
FUP for OS status ##
Day
(visit window)
-28 
- 1
1
3
4
5
10
(±2)
1
(+2)
3
4
1
(+2)
3
4
5
10
(±2)
1
(+2)
3
4
1 
(+2)
3
Day 0-
14 after 
disconti
nuation
30 (+5) 
days after 
last dose 
Plasma for cell death 
biomarkers10
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tumor tissue collection
x11
[18F]FDG-PET/CT 13
x
x
Adverse Events14
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant Therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tumor assessment by CT/MRI 
RECIST 1.115 and tumor 
marker measurement
x15
x15
Termination of all trial 
medication
x
Patient status
x


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BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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FLOW CHART 2
PHASE IB -NO LONGER APPLICABLE PER CTP V4.0
Treatment Period
Post-Treatment
Visit
SCR
Cycle 1*
(14 days)
Cycle 2 *
(14 days)
Cycle 3 *
(14 days)
Cycle 4 *
(14 days)
Cycle 5 and 
beyond *
EoT**
EOR***
(FUP #1)
FUP for 
PD##
FUP for OS status ##
Day
(visit window)
-28 
- 1
1
3
4
5
10
(±2)
1
(+2)
3
5
1
(+2)
3
4
5
10
(±2)
1
(+2)
3
4
1 
(+2)
3
Day 0-
14 after 
disconti
nuation
30 (+5) 
days after 
last dose 
Informed Consent1
x
Demographics + Medical 
History
x
In- /Exclusion Criteria2
x16
x
Eligibility for re-treatment2
x
x
x
x
Physical Examination3,4
x
x
x
x
x
x
x
x
x
ECOG performance score5
x
x
x
x
x
x
x
x
x
Pregnancy test6
x
x
x
x
x
12-lead-ECG7
x
x
x
Infusion of BI 9057118
x
x
x
x
x
Infusion of FOLFIRI (or 
Liposomal Irinotecan plus 5-
FU/Leucovorin (PDAC only)) 
with or without bevacizumab 8.1
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Safety lab testing9
x
x
x
x
x
x
x
x
x
x
x
x
x
Pharmacokinetics10
x
x
x
x
x
x
x
x
x
x
x
x
x10
x
x
ADA sampling10
x
x
x
x
x
Nab sampling10
x
x
x
x
x
Circulating free DNA10
x
x
x


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27 APR 2023
BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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Flow Chart 2 Phase Ib (cont.)
-NO LONGER APPLICABLE PER CTP V4.0
Treatment Period
Post-Treatment
Visit
SCR
Cycle 1*
(14 days)
Cycle 2 *
(14 days)
Cycle 3 *
(14 days)
Cycle 4 *
(14 days)
Cycle 5 and 
beyond *
EoT**
EOR***
(FUP #1)
FUP for 
PD##
FUP for OS status ##
Day
(visit window)
-28 
- 1
1
3
4
5
10
(±2)
1
(+2)
3
5
1
(+2)
3
4
5
10
(±2)
1
(+2)
3
4
1 
(+2)
3
Day 0-
14 after 
disconti
nuation
30 (+5) 
days after 
last dose 
Plasma for cell death 
biomarkers10
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tumor tissue collection
x11
x12
x12
[18F]FDG-PET/CT 13
x
x
Adverse Events14
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant Therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tumor assessment by CT/MRI 
RECIST 1.115 and tumor 
marker measurement
x15
x15
Termination of all trial 
medication
x
Patient status
x
PRO-CTCAE17
x
x
x
x
x
x
x17


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27 APR 2023
BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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Footnotes pertaining to both Flowchart 1 and 2 -NO LONGER APPLICABLE PER CTP V4.0
(*) Each treatment Cycle has a duration of 14 days. 
(**) Patients who discontinue trial treatment should undergo the End of Treatment (EoT) visit as soon as possible (Day 0-14 after treatment discontinuation). 
If assessments due at EoT are not completed, they may be performed at the End of Residual Effect Period (EoR) visit, which is also considered the first Follow-Up 
(FUP) Visit. 
(***) The End of Residual Effect Period (EoR) visit (FUP #1) should occur 30 (+5) days after the last dose of treatment (see Section 6.2.3.2).
(##) FUP visits For Progressive Disease (PD)
If a patient does not have documented progression prior to or at the EoR visit he/she will continue to have regular FUP visits for PD which will occur per the imaging 
schedule. Assessments will be performed as indicated in the Flow Chart.
The FUP visits for PD will end at the earliest once one of the following events is met:
∀
Confirmation of Disease progression
∀
Start of a new anti–cancer therapy 
∀
Death
∀
Lost to Follow-Up
∀
End of whole trial as specified in Section 8.6.
The following will be obtained and/or performed during the FUP visits for progression.
∀
Perform tumor assessment including physical examination and imaging. 
∀
ECOG performance score
∀
Treatment date with any subsequent anti-cancer drug / therapy including the name and type of the anti-cancer drug and/or best supportive care (if applicable).
∀
Outcome (date of and reason for death [if applicable], in case the patient had PD the actual date of PD shall be recorded)
(##) FUP for survival status
Once the FUP visits for progression end for patients with either a confirmation of disease progression or have started a new anti-cancer therapy, the FUP for survival 
status will start and be performed approximately every 12 weeks (+/-7 days) in person, by telephone or via written correspondence until death, lost to follow-up, 
withdrawal of consent, or end of the whole trial (see Section 6.2.3.3 and 8.6).
The following patient status information will be collected during the FUP timepoints for survival status:
∀
Date of contact
∀
Further anti-cancer treatment including surgery and radiotherapy: regimen and drug name, start and stop dates.
∀
For each reportable serious adverse event / AESI, the investigator should provide the information with regard to concomitant medication and the medication 
administered to treat the adverse events on the appropriate CRF pages and the SAE form including trade name, indication and dates of administration


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BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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∀
Outcome event (e.g. death: Record date of and reason for outcome event / death [if applicable])
1. Written informed consent must be obtained before any protocol specific screening assessments are performed. Re-consenting may become necessary when new 
relevant information becomes available and should be conducted according to the Sponsor’s instructions. Separate consent is to be obtained for optional biomarker 
sampling
2. Cycle 1, Day 1: Inclusion and exclusion criteria must be confirmed prior to first dose.
From Cycle 2 Day 1 onwards: Eligibility for further treatment should be confirmed prior to each dosing day (Day 1 of each cycle) by confirming the patient has not 
met any criteria for protocol discontinuation as described in section 3.3.4.1 and absence of any adverse event requiring treatment delay or discontinuation (section 
4.1.5.2 and 4.2.3). 
3. A full physical exam is inclusive of vitals, body weight and height. With the exception of height (performed only at Screening), a full physical is to be performed at 
Screening, at Day 1 of each cycle, at EoT, EoR and at further FUP visits for progression if applicable. Physical exam does not need to be repeated at Cycle 1 Day 1 if 
completed within the previous 24hours. See Section 4.1.5.1 for additional timepoints for assessing signs and symptoms of IRR and CRS on drug administration days. 
Patients should also be assessed for any new neurological signs and symptoms. See section 4.2.4.5.
4. For all cycles including cycle 1, weight can be collected up to 3 days prior to the visit. If the patient’s weight changes by ≤10% compared to the reference weight, the 
dose (in mg) may remain the same for subsequent cycles. If the weight changes by >10% the dose will be recalculated and the new weight will be used as the reference 
weight.
5. ECOG assessment to be performed at Screening, and Day 1 of each cycle, at EoT, EoR and at further FUP visits for progression if applicable. ECOG does not need to 
be repeated at Cycle 1 Day 1 if screening ECOG was completed within 72hours of Cycle 1 Day 1.
6. A urine pregnancy test is mandatory for female patients of childbearing potential and must be performed within 72 hours prior to start of study treatment (Day 1) at 
every 2 cycles and at EoT. If a urine pregnancy test is positive, a serum pregnancy test must be performed and resulted as negative prior to trial drug administration.
7. ECG to be performed at Screening, Day 1 of Cycles 3 and at EoR. An ECG can be added as well as repeated as clinically indicated per investigator’s discretion.
8. Dispensing of BI 905711 will be performed via the Interactive Response Technology (IRT). BI 905711 dose administrations must always be at least 14 days 
apart. Patients will remain under surveillance for at least 6 hours after the end of infusion during the first, second and third administrations of BI 905711. During the 
post-infusion observation period, body temperature, pulse rate and blood pressure will be measured at the end of the infusion and every 2 hours (± 15 minutes) 
thereafter.
See Section 4.1.5.1 for additional details of this observation period. 
8.1. The infusion of FOLFIRI (or Liposomal Irinotecan plus 5-FU/Leucovorin (PDAC only)) with or without bevacizumab will be done per local labels (See 
section 4 for more details of background administration)


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BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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9. Safety Lab testing will be performed locally and includes blood for Hematology, Biochemistry, Hepatitis and Coagulation, as well as Urinalysis. Refer to protocol 
Section 5.2.3 for specific laboratory requirements.
-
Safety lab tests performed during screening do not need to be repeated at Cycle 1 Day 1 if performed within 10 days prior to treatment start and there is no 
clinical reason to repeat lab tests.
-
During Cycle 1, safety labs should be performed on Day 3 (pre-dose), 4-6 hours post BI 905711 administration, on Day 4 (24 hr timepoint), and on Day 10.
-
During subsequent Cycles, safety labs on Day 1 should be performed within 48 hours prior to Day 1. During Cycle 2 and 3, safety lab should be performed on 
Day 1 and Day 3.  
-
All safety lab tests can be repeated at any other time points, if clinically indicated, at investigator’s discretion.
-
Safety labs are also performed at EoT and EoR visit and may be repeated if clinically indicated. 
-
At the Screening visit only, patients are to be tested for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection which includes hepatitis B surface 
   antigen (HbsAg), Hepatitis B core antibody (anti-HBc), HBV-DNA, as well as HCV RNA. Results for hepatitis virus infection obtained in routine diagnostics 
   are acceptable if done within 14 days before the informed consent date. Also refer to exclusion criteria for criteria for active infection.
10. For detailed information about pharmacokinetics (PK), Anti-drug antibodies (ADA), Neutralizing anti-drug antibodies (Nab), cell death biomarkers, and circulating 
tumor DNA (cfDNA) sampling timepoints and handling procedures, refer to Appendix 10.2. ADA sampling may be amended based on available data. If the 
patient will not continue treatment in the next cycle, pre-dose sampling scheduled for Day 3 of the next cycle (see Appendix 10.2) needs to be performed at the 
EoT visit. For cfDNA, first sample should be collected at baseline (Cycle 1, Day 1) before start of trial treatment. For subsequent cfDNA sample collection 
refer to Section 5.4.1 and Appendix 10.2 for more details on collection time points.
11. Tumor tissue collection during Screening:
For Phase Ia-
o
For all patients: Provision of an archived tumor tissue specimen is mandatory during screening. A fresh biopsy is only mandatory for patients who do not 
have archival tissue. 
For Phase Ib-
o
For all patients: Provision of archival tumor tissue or fresh biopsy is mandatory for all patients prior to treatment start on Day 1. Fresh biopsy sample 
should be provided if the archival tissue tested is greater than 6 months old from collection to start of treatment on this study. Even if fresh biopsy 
conducted, provision of an archived tumor tissue is recommended. For Non-CRC patients, CDH17 expression measurement by archival tumor tissue or 
fresh biopsy sample must be completed prior to treatment start on Day 1.
Only non-significant risk procedures per the investigator’s judgment will be used to obtain any biopsies specified in this study. For CRC patients only, in case a fresh 
tumor biopsy cannot be obtained, the recruitment of the patient may proceed on a case-by-case basis after agreement between the investigator and BI. In such a case, an 
archived tumor tissue specimen needs to be submitted.
12. For Phase Ib only: On-treatment tumor tissue collection at Cycle 2 Day 5, 48 h±4 after administration of BI 905711(optional) and/or at disease progression (EOT) 
(optional) for a patient in which a fresh biopsy has been successfully obtained before first study treatment.


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c35307392-04                                                                            Clinical Trial Protocol
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13. CRC patients only: [18F]FDG-PET/CT should be performed during screening and no later than 14 days (±7 days) prior to treatment start (Cycle 1 Day 1) after 
eligibility has been confirmed. A second [18F]FDG-PET/CT will be performed at the 8-week (±7 days) tumor assessment timepoint. It may be performed together with 
standard CT assessment if feasible. See section 5.4.2.6 for additional [18F]FDG-PET/CT details including patient fasting and voiding requirements.
14. After the patient’s end of trial, the investigator does not need to actively monitor the patient for new AEs but should report any occurrence of cancer and trial drug 
related SAEs and trial drug related AESIs of which the investigator may become aware of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form but not on the CRF, see Section 5.2.6.2.1.
15. Tumor assessment should include CT scans or MRI of the chest, abdomen, pelvis and, if clinically indicated, imaging of any other known or suspected sites of 
disease (e.g. brain, bone). The same radiographic procedure must be used throughout the study. Tumor assessment does not need to be performed at the Screening visit if 
there are valid results available from assessments which were performed as part of routine clinical practice within 28 days prior to start of treatment. Repeat tumor 
assessment will be performed every 8 weeks (± 7 days) until progression or start of further treatment for disease.
In the event of early discontinuation for reasons other than progressive disease or interruption/delay of treatment, the tumor assessment schedule should not be changed. 
If the patient finishes study treatment without having progressive disease, tumor assessment/imaging must be performed at the time of treatment discontinuation, unless 
it has been done within the past 4 weeks. 
CEA, CA19.9, etc., tumor marker levels should be obtained at baseline, every 2 cycles and at every protocol-specified tumor assessment timepoint in CRC and PDAC 
patients, respectively. 
16. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during 
screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of 
EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since 
this measurement in the opinion of the Investigator or of the treating physician or both.
17.  PRO-CTCAE should be conducted on Day 1 (allowance -1 day) of each cycle until Cycle 5, and Day 10 (allowance ±2 day) of cycle 1 and cycles 3. From Cycle 5, 
PRO-CTCAE should be conducted on Day 1 (allowance -1 day) of every 2 cycles (Cycle 7, 9, 11 and so on).


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BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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FLOW CHART 3
PHASE 1A/B – BIWEEKLY - REDUCED SCHEDULE PER CTP V4.0 – ONGOING PATIENTS
Treatment Cycle 
Post-Treatment
Visit
CxD1a
CxD3a
EOT**
EOR / EOS***
Day
(day range)
1 (+2)
3
Day 0-14 after discontinuation
30 (+5) days after last dose 
Physical Examination and Vital Signs
Per institutional practice
Safety lab parameters 
Per institutional practice
Tumor assessment by CT/MRI RECIST 1.11
Per institutional practice
Pregnancy test2
Per institutional practice
12-lead-ECG
Per institutional practice
Body weight
x
Infusion of FOLFIRI with
bevacizumab
x
Infusion of BI 9057113
x
Adverse Events4
x
x
x
x
Concomitant therapy5
x
x
x
x
Termination of study medication
x
After implementation of protocol version 04, the patient will have assessments as medically indicated to monitor the safety at the discretion of the investigator. These
assessments may include: physical examination, vital sign, safety lab and ECG at a frequency decided by the investigator. The study treatment is administered and the 
administration information will be documented in the eCRF. Tumour assessment will be performed according to standard of care based on medical opinion of the 
investigator. 
The results of any assessments will be documented in the source data, but will not be collected in the eCRF, except tumor assement (overall response and progression 
date).
Findings which qualify as an (S)AE will be reported in the eCRF and in case of an SAE, on the SAE form (timelines and distribution requirements for SAEs apply). 


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BI Trial No.: 1412-0003
c35307392-04                                                                            Clinical Trial Protocol
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The data collection is required only for the following items:
-
Adverse events
-
Concomitant medications that are used to treat adverse events
-
Drug admistration information 
-
Dose changes
-
Tumor assessment (overall response and progression date).
-
At EOT visit: visit date, end of treatment – BI 905711, and subject retention
-
At safety follow-up visit: visit date and end of study page
-
Death details (if applicable)
(*) Each treatment Cycle has a duration of 14 days
(**) Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EOT) visit as soon as possible. If assessments due at EOT are not 
completed, they may be performed at the 30-Day Safety FUP (i.e. EOR) Visit. 
(***) This combined visit is the End of Residual Effect Period visit (EOR) which must happen at the earliest 30 (+ 5) days after the last dose of treatment (see Section 
6.2.3.2). 
ax is the number of the treatment cycle
1Tumor assessment will be performed according to institutional practices. Images no longer need to be sent to imaging vendor. The overall response and progression 
date will be collected in the electronic CRF. 
2Serum and/or urine pregnancy testing to be performed for female patients of childbearing potential as per institutional practice within 72 hours prior to start of study 
treatment infusion, every odd number cycle starting at Cycle 3 and at EOT. 
3 Dispensing of BI 905711 will be performed via the IRT. Assessment for signs and symptoms of infusion-related reactions and Cytokine Release Syndrome (CRS) is 
described in Sections 4.2.4.1 and 4.2.4.2. 
4 After the individual patient’s end of trial: the investigator does not need to actively monitor for new AEs but should only report any occurrence of cancer of new 
histology, trial drug related SAEs and trial drug related AESIs of which the investigator may become aware of and only via the SAE form, see Section 5.2.6.2.1.
5Concomitant medications that are used to treat adverse events.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHARTS....................................................................................................................10
FLOW CHART 1
PHASE IA -NO LONGER APPLICABLE PER CTP V4.0 ............10
FLOW CHART 2
PHASE IB -NO LONGER APPLICABLE PER CTP V4.0 ............12
FLOW CHART 3
PHASE 1A/B – BIWEEKLY - REDUCED SCHEDULE PER CTP 
V4.0 – ONGOING PATIENTS..........................................................................18
TABLE OF CONTENTS ......................................................................................................20
ABBREVIATIONS AND DEFINITIONS...........................................................................25
1.
INTRODUCTION...............................................................................................29
1.1
MEDICAL BACKGROUND.............................................................................29
1.2
DRUG PROFILE................................................................................................29
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................33
1.4
BENEFIT - RISK ASSESSMENT.....................................................................36
1.4.1
Benefits.................................................................................................................36
1.4.2
Risks .....................................................................................................................36
1.4.3
Discussion.............................................................................................................40
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................42
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........42
2.1.1
Main objectives....................................................................................................42
2.1.2
Primary endpoint(s)............................................................................................42
2.1.3
Secondary endpoint(s) ........................................................................................42
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................45
3.1
OVERALL TRIAL DESIGN.............................................................................45
3.1.1
Dose escalation phase (Phase Ia)........................................................................46
3.1.2
Dose expansion phase (Phase Ib).......................................................................47
3.1.2.1
Randomized CRC expansion cohort.....................................................................47
3.1.2.2
Single Arm PDAC expansion cohort....................................................................47
3.1.3
Enrolment stopping rules...................................................................................47
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................48
3.3
SELECTION OF TRIAL POPULATION .......................................................48
3.3.1
Main diagnosis for trial entry ............................................................................49
3.3.2
Inclusion criteria .................................................................................................49
3.3.3
Exclusion criteria ................................................................................................51
3.3.4
Discontinuation of patients from treatment or assessments ...........................53


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3.3.4.1
Discontinuation of trial treatment .........................................................................53
3.3.4.1.1
Replacement of patients........................................................................................54
3.3.4.2
Withdrawal of consent to trial participation .........................................................55
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................55
4.
TREATMENTS...................................................................................................56
4.1
INVESTIGATIONAL TREATMENTS ...........................................................56
4.1.1
Identity of the Investigational Medicinal Product during Phase Ia...............56
4.1.2
Identity of the Investigational Medicinal Product during Phase Ib...............56
4.1.3
Selection of doses in the trial and dose modifications......................................56
4.1.3.1
Selection of BI 905711 dose for Phase Ib in combination with FOLFIRI with or 
without bevacizumab ............................................................................................57
4.1.3.2
Selection of FOLFIRI dose regimen and bevacizumab for Phase Ib....................57
4.1.4
Method of assigning patients to treatment groups...........................................58
4.1.5
Drug assignment and administration of doses for each patient......................58
4.1.5.1
Administration of FOLFIRI with or without bevacizumab ..................................59
4.1.5.2
Criteria for receiving further treatment.................................................................59
4.1.5.3
Dose modifications ...............................................................................................60
4.1.6
Blinding and procedures for unblinding...........................................................63
4.1.6.1
Blinding.................................................................................................................63
4.1.6.2
Unblinding and breaking the code ........................................................................63
4.1.7
Packaging, labelling, and re-supply...................................................................63
4.1.8
Storage conditions...............................................................................................63
4.1.9
Drug accountability.............................................................................................63
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................64
4.2.1
Background treatment for dose escalation (Phase Ia) and dose expansion 
(Phase Ib) .............................................................................................................64
4.2.1.1
FOLFIRI regimen and Liposomal Irinotecan plus 5-FU/Leucovorin (PDAC only)
...............................................................................................................................64
4.2.1.2
Bevacizumab.........................................................................................................65
4.2.2
Other treatments and emergency procedures..................................................65
4.2.2.1
Premedication........................................................................................................65
4.2.3
Restrictions ..........................................................................................................65
4.2.3.1
Restrictions regarding concomitant treatment ......................................................65
4.2.3.2
Restrictions on diet and lifestyle...........................................................................66
4.2.3.3
Contraception requirements..................................................................................67
4.2.4
Dose modification and management of adverse events ...................................67
4.2.4.1
Management of infusion-related reactions............................................................67
4.2.4.2
Management of CRS, other IRRs and events with similar signs/symptoms ........69
4.2.4.3
Management of diarrhea, nausea and vomiting ....................................................70
4.2.4.4
Tumor lysis syndrome...........................................................................................70
4.2.4.5
Neurological adverse events .................................................................................71
4.2.4.6
Renal adverse events.............................................................................................71
4.3
TREATMENT COMPLIANCE........................................................................71
5.
ASSESSMENTS..................................................................................................72


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5.1
ASSESSMENT OF EFFICACY........................................................................72
5.2
ASSESSMENT OF SAFETY.............................................................................72
5.2.1
Physical examination ..........................................................................................72
5.2.1.1
Body Weight .........................................................................................................72
5.2.2
Vital signs.............................................................................................................72
5.2.3
Safety laboratory parameters ............................................................................73
5.2.4
Electrocardiogram ..............................................................................................74
5.2.5
Other safety parameters.....................................................................................75
5.2.6
Assessment of adverse events.............................................................................75
5.2.6.1
Definitions of AEs ................................................................................................75
5.2.6.1.1
Adverse event........................................................................................................75
5.2.6.1.2
Serious adverse event............................................................................................75
5.2.6.1.3
AEs considered “Always Serious”........................................................................76
5.2.6.1.4
Adverse events of special interest.........................................................................76
5.2.6.1.5
Intensity (severity) of AEs....................................................................................78
5.2.6.1.6
Causal relationship of AEs....................................................................................78
5.2.6.2
Adverse event collection and reporting ................................................................79
5.2.6.2.1
AE Collection........................................................................................................79
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................79
5.2.6.2.3
Pregnancy..............................................................................................................80
5.2.6.2.4
Exemptions to AE reporting .................................................................................80
5.2.7
Dose limiting toxicities........................................................................................81
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................83
5.3.1
Assessment of pharmacokinetics .......................................................................83
5.3.2
Methods of sample collection .............................................................................83
5.3.4
Pharmacokinetic - pharmacodynamic relationship.........................................84
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................84
5.4.1
Drug interaction biomarkers .............................................................................85
5.4.2
Pharmacodynamics and patient selection biomarkers....................................85
5.4.2.1
Determination of CDH17 protein/mRNA expression...........................................85
5.4.2.2
Determination of activated cell death biomarker levels in plasma.......................86
5.4.2.3
Quantification of cell-free tumor DNA levels in plasma......................................86
5.4.2.4
Immunohistochemical analysis of apoptosis induction and tumor cell proliferation 
in tumor tissue.......................................................................................................86
5.4.2.5
Assessment of gene expression and cancer-related gene mutation in tumor 
biopsies..................................................................................................................86
5.4.2.6
[18F]FDG-PET/CT ................................................................................................86
5.4.3
Methods and timing of sample collection..........................................................87
5.4.3.1
Tumor Tissue collection........................................................................................87
5.4.3.2
Plasma samples .....................................................................................................88
5.5
BIOBANKING ....................................................................................................88
5.6
OTHER ASSESSMENTS...................................................................................89
5.6.1
Patient-reported outcomes .................................................................................89
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................89


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6.
INVESTIGATIONAL PLAN.............................................................................90
6.1
VISIT SCHEDULE.............................................................................................90
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................90
6.2.1
Screening period..................................................................................................90
6.2.2
Treatment period(s)............................................................................................91
6.2.3
Follow-up period and trial completion..............................................................92
6.2.3.1
End of treatment (EoT) visit .................................................................................92
6.2.3.2
End of Residual Effect Period (EoR)....................................................................92
6.2.3.3
Follow-up for progressive disease ........................................................................92
6.2.3.4
Follow-up for overall survival status ....................................................................92
6.2.3.5
Trial completion for an individual patient ............................................................93
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................94
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................94
7.2
PLANNED ANALYSES.....................................................................................94
7.2.1
General considerations .......................................................................................94
7.2.2
Handling of intercurrent events.........................................................................94
7.2.3
Primary objective analyses.................................................................................94
7.2.4
Secondary objective analyses.............................................................................98
7.2.5
Further objective analyses..................................................................................98
7.2.6
Safety analyses.....................................................................................................98
7.2.7
Other analyses .....................................................................................................99
7.2.8
Interim analyses ..................................................................................................99
7.3
HANDLING OF MISSING DATA ...................................................................99
7.4
RANDOMIZATION.........................................................................................100
7.5
DETERMINATION OF SAMPLE SIZE .......................................................100
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......102
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................102
8.2
DATA QUALITY ASSURANCE ....................................................................103
8.3
RECORDS.........................................................................................................103
8.3.1
Source documents .............................................................................................103
8.3.2
Direct access to source data and documents...................................................104
8.3.3
Storage period of records .................................................................................105
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................105
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......105
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................105
8.6
TRIAL MILESTONES.....................................................................................106
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................106
9.
REFERENCES..................................................................................................108
9.1
PUBLISHED REFERENCES..........................................................................108
9.2
UNPUBLISHED REFERENCES....................................................................112


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10.
APPENDICES...................................................................................................113
10.1
PHARMACOKINETIC ANALYSES.............................................................113
10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING NO LONGER APPLICABLE PER CTP V4.0........................115
10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS ...............................................................................121
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................126
11.1
GLOBAL AMENDMENT 1 ............................................................................126
11.2
GLOBAL AMENDMENT 2 ............................................................................128
11.3
GLOBAL AMENDMENT 3 ............................................................................132


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ABBREVIATIONS AND DEFINITIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ADA
Anti-drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline phosphatase
aPTT
Activated Partial Thromboplastin Time 
AxMP
Auxiliary Medicinal Products
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BLQ
Below the limit of quantification
BUN
Blood Urea Nitrogen
CDH17
Cadherin 17
cfDNA
Circulating free DNA
Cmax
Maximum Plasma Concentration
Cmin
Minimum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRC
Colorectal adenocarcinoma
CRS
Cytokine release syndrome
ctDNA
Circulating tumor DNA
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DRC
Data Review Committee
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram


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ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EF
Ejection Fraction
EOI
End of infusion
EoR
End of Residual Effect Period
EoT
End of Treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
EWOC
Escalation with Overdose Control
[18F]FDG-PET
[18F]Fluorodeoxyglucose-Positron Emission Tomography
FIH
First In Human
FUP
Follow-up
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRR
Infusion Related reactions
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLT
Last patient last treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
Nab
Neutralizing Anti-drug Antibodies
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
NOA
Not to the lag phase


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NOR
No valid result
NOS
No Sample
OR
Objective Response
OS
Overall Survival
OPU
Operative Unit
PDAC
Pancreatic Ductal Adenocarcinoma
p.o.
per os (oral)
PK
Pharmacokinetics
PD
Progressive disease
PFS
Progression Free Survival
PR
Partial Response
PRO
Patient Reported Outcome
PT
Prothrombin Time
RBC
Red Blood Cell
RDE
Recommended Dose for Expansion
RECIST
Response Evaluation Criteria in Solid Tumors
REP
Residual effect period
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SCR
Screening
SD
Stable Disease
SOI
Start of infusion
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TLS
Tumor Lysis Syndrome
tmax
Timepoint of maximum plasma concentration
TRAIL
TNF Related Apoptosis-Inducing Ligand
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
WBC
White Blood Cell
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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5-FU
Fluorouracil


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Tumor cell death and apoptosis can be induced by activation of the extrinsic apoptosis 
pathway via targeting TRAIL (TNF Related Apoptosis-Inducing Ligand) receptors (R16-
1878). TRAILR2 represents a valid target for anti-cancer treatment, but conventional 
TRAILR2 antibodies have not been successful in the clinic so far due to insufficient agonistic 
properties or liver toxicity (P16-04691) (R17-2985). 
Published data suggest that activation of TRAIL receptor depends not only on binding of the 
ligand to the receptor but requires also a hyperclustering of the receptor that is critical for 
apoptosis induction (R17-2986). Agonistic properties of TRAILR2 antibodies can be highly 
enhanced by antibody immobilisation via binding of their Fc part on the solid surface in-vitro
or FcR cross-linking on membrane of the tumor infiltrating immune cells in-vivo (R17-2987). 
1.2
DRUG PROFILE
Mode of action
BI 905711 is a tetravalent bispecific molecule targeting both TRAILR2 and Cadherin 17 
(CDH17), and it is designed to selectively induce apoptosis in CDH17 expressing tumor cells 
via the CDH17-dependent clustering of TRAILR2 (R17-4112). CDH17 is a cell surface 
molecule expressed in gastrointestinal (GI) adenocarcinomas (R18-1615) (R17-4114).
In humans, CDH17 is also present on normal cells of the stomach, intestine, pancreas and gall 
bladder, but it is not expressed in normal liver tissue. Normal GI tissues were shown to be 
resistant to TRAILR2-induced apoptosis (R16-4563) while liver tissue may be sensitive to 
TRAILR2 activation (R16-1795). 
The L234A/L235A mutations were incorporated into the BI 905711 molecule to specifically 
avoid CDH17-independent cross-linking by ablating binding to Fc#R and complements. BI 
905711 has the potential to avoid hepatotoxicity associated with clustering of TRAILR2 and 
apoptosis induction in the liver (R16-1795) due to the lack of detectable CDH17 protein in 
normal liver tissue (R17-2598). Moreover, the non-neoplastic tissues with CDH17 expression 
as listed above, should be spared from apoptosis and tissue damage due to their low 
sensitivity to TRAILR2 activation (R17-4113, R16-4563). For a more detailed description of 
the BI 905711 pharmacologic profile, refer to the current Investigator’s Brochure (IB) 
(c16856466).
Key pharmacokinetic (PK) characteristics
Preliminary PK results from the Phase I FIH study 1412-0001, using planned PK sampling 
timepoints, were available for patients treated in at dose levels 1-8 (0.02 mg/kg-4..8 mg/kg, 


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total N=42 patients in 1412-0001 clinical trial. Following intravenous administration of BI 
905711, peak plasma concentrations occurred around the end of the infusion at 0.5 h. 
Terminal Half life was about 3 days at 1.2 mg/kg dose and above. Inter-patient variability 
was evident. The maximum plasma concentrations (Cmax) were comparable between cycle 1 
and cycle 3.
The systemic exposure (AUC0-336) values of BI 905711 were comparable between cycle 1 and 
cycle 3. Thus, no accumulation was seen between cycle 1 and cycle 3 at the analyzed dose 
levels between cycle 1 and cycle 3.
Distribution
No dedicated distribution studies have been performed. 
Metabolism
BI 905711 is a protein and is expected to undergo protein catabolism in humans to peptides 
and amino acids. Dedicated metabolism studies were not conducted for BI 905711.
Excretion
The molecular weight of BI 905711 is approximately 201 kDa, which is above the renal
filtration cut-off threshold (approximately 60 kDa). Dedicated excretion studies were not
conducted.
Pharmacokinetic drug-drug interactions
BI 905711 is a protein, and its clearance is through protein catabolism. BI 905711
is not an immune modulator and is not expected to impact expression and production of
cytochrome P450 enzyme or certain drug transporters that may affect indirectly the exposure
of co-administered small molecules. Therefore, pharmacokinetic drug-drug interaction
between BI 905711 and co-administered small molecules is not expected. 
Residual Effect Period (REP)
The expected REP of BI 905711 is 30 days (+ 5 days). This is the period after the last dose 
with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from non-clinical studies
BI 905711 demonstrated high preclinical anti-tumor activity in-vitro and in-vivo in CDH17 
positive tumor cell lines. A short summary is given below. For more details, refer to the 
current IB (c16856466).
The sensitivity to BI 905711 of a panel of 24 CDH17-positive CRC cell lines was evaluated
and is shown in Figure 1.2: 1. A V-shaped dose-response is predicted for this bi-specific 
antibody where concentrations above the optimum will favour individual target recruitment, 
thus preventing TRAILR2 cross-linking and therefore reducing efficacy. Within the range of 
concentrations tested, different cell lines showed a reduced efficacy when using higher than 
optimal doses. Importantly, despite differences in CDH17 and TRAILR2 protein expression 
levels and the intrinsic sensitivity to TRAILR2 agonists among these cells, there was a 
common concentration range inducing the maximal effect in all tested cells (Figure 1.2: 1)


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Figure 1.2:1
Sensitivity to BI 905711 of a panel of 24 CDH17-positive CRC cell lines
BI 905711 was also tested in CDH17 negative liver-derived cells, and Hep G2 was used as a 
surrogate for TRAIL sensitive hepatocytes. In Hep G2 cells, no significant effect of BI 
905711 decreasing cell viability was observed. The potent tetrameric nanobody agonist 
targeting TRAILR2 (EX 77749) was used as a reference for sensitivity to TRAILR2 agonists. 
As expected for a CDH17-independent molecule, a significant effect of EX 77749 decreasing 
cell viability was observed independently of the absence of CDH17 membrane expression 
(Figure 1.2: 2).


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Figure 1.2: 2
Representative graph of concentration response curves as determined in the 
72h Hep G2 Cell Titer-Glo assay (c16856466).
BI 905711 in vivo efficacy was demonstrated in the COLO 205 xenograft tumor model, 
where a single dose administration (0.3, 1, 5 and 15 mg/Kg) led to significant growth 
inhibition for all treatment groups. The GP2d cell line was selected as a second CRC 
xenograft tumor model for in vivo profiling of BI 905711. Compared to COLO 205 derived 
tumor samples, CDH17 distribution in GP2d derived tumor samples was more similar to 
those of metastatic CRC patients. BI 905711 was initially administered at doses of 1.67, 5 
and 15 mg/kg. After a single dose, BI 905711 administered at 1.67 mg/kg led to sustained 
tumor regressions for most of the tumors from day 6 until day 36 (end of the experiment). In 
a follow up study, BI 905711 was administered at lower doses (0.05, 0.2, 0.8, and 1.67
mg/kg). Similar to the 1.67mg/kg group, BI 905711 administered at 0.8 mg/kg as a single
dose led to sustained tumor regressions for most of the tumors from day 3 until day 29. The
minimal efficacious dose was defined as 0.2 mg/kg with only a few regressions as compared 
to the 1.67 and 0.8 mg/kg groups but still demonstrated statistically significant tumor growth
inhibition at the end of the experiment.
To evaluate the combination potential of BI 905711 with chemotherapeutics, in vivo efficacy 
experiments in several CRC and gastric-esophageal xenograft tumor models were performed
(P19-11314, P20-10420). Combination of BI 905711 with irinotecan or paclitaxel or 
oxaliplatin, resulted in a statistically significant tumor growth control, as compared with 
vehicle and either compound as monotherapy.


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Preclinical toxicology
Preclinical toxicology is fully described in the IB (c16856466). BI 905711 intravenously 
administered once per week to cynomolgus monkeys for 6 weeks up to dose levels of 100 
mg/kg produced no overt adverse effects. No changes in clinical pathology (hematology, 
clinical chemistry, urinalysis), ophthalmology, or immunophenotyping were observed, nor 
were any alterations to body weight or food consumption apparent. The majority of treated 
monkeys displayed ADAs to BI 905711 at the end of the 6-week drug phase, which slightly 
reduced total exposure (AUC0-168) when compared to the first administration.
BI 905711-related effects in the 6-week monkey study were limited to microscopic findings
in the brain (choroid plexus, meninges of the cerebrum, and/or cerebral cortex) at ≥ 30 
mg/kg, and in the spinal cord (meninges, gray matter) and kidney (glomerulus) at 100 mg/kg. 
Changes in the brain and spinal cord were characterized by minimal to mild perivascular 
mononuclear cell infiltrates that contained admixed eosinophils. In animals allowed a 4-week 
recovery phase, changes in the choroid plexus and meninges of the brain remained apparent, 
but no findings were noted in the spinal cord. The perivascular accumulation of mononuclear 
cell infiltrates may represent immune responses originating within the Virchow-Robin space, 
continuous with the subarachnoid space and outside of the blood-brain barrier. In the kidney, 
glomerulopathy was observed in monkeys at the end of treatment and recovery phases and 
was considered related to BI 905711 administration, although no alterations to serum blood 
urea nitrogen and creatinine or urinary protein were observed. Immunohistochemical (IHC)
staining of affected tissues revealed granular deposits containing human IgG (BI 905711) 
and/or monkey IgG in the kidneys of animals displaying glomerulopathy. These deposits are 
consistent with immune complex formation, deposition, and clearance in monkeys that have 
generated ADA in response to administration of a heterologous protein. An immune 
complex-mediated basis for the perivascular mononuclear cell infiltrates with admixed 
eosinophils in the brain and/or spinal cord could not be confirmed by IHC staining.
No hemolytic or local effects due to BI 905711 intravenous injection were noted. BI 905711 
did not cause in vitro cytokine release (c16856466).
Data from clinical studies
The first-in-human trial 1412-0001 assessing BI 905711 as monotherapy in patients with 
treatment-refractory GI cancers has been initiated in several countries and is currently 
ongoing.
For a more detailed description of the BI 905711 profile (limited clinical data are available so 
far), refer to the current IB (c16856466).  
1.3
RATIONALE FOR PERFORMING THE TRIAL
Efficacy of current standard of care therapies for GI cancers at advanced or metastatic stage 
is limited. The majority of these patients die due to resistance to therapy, thus there is a need 
to develop new treatment approaches.
BI 905711 is a tetravalent bispecific antibody targeting both TRAILR2 and CDH17, and is 
designed to selectively induce apoptosis in CDH17 expressing tumour cells via CDH17-
dependent clustering of TRAILR2. CDH17 is a membrane protein that is expressed only in 


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GI tissues including GI cancers but not in normal hepatic cells. Thus, BI 905711 has the 
potential to avoid liver toxicity.
The potential indications for BI 905711 include GI adenocarcinomas expressing CDH17 
including but not limited to: CRC, gastric, oesophageal, pancreatic and biliary tract cancers as 
indicated in Table 1.3: 1. CRC consistently expresses CDH17 at a high or intermediate level 
by immunohistochemistry (IHC) in both primary tumors and metastatic sites (R17-2598, 
R18-1615). High CDH17 expression in metastatic CRC samples was confirmed in a BI 
prevalence study and showed CDH17 expression in 100 % of the samples analyzed (n=39), 
and 97% of the samples showed CDH17 expression on over 50% of the tumor cells (77% of 
samples with >90% positive cells). Expression of CDH17 in gastric, oesophageal, and 
pancreatic adenocarcinomas and biliary tract cancers is more variable.
Table 1.3: 1
Gastrointestinal cancers expressing CDH17. The percentage indicates
the relative number of positive tumors for CDH17 by IHC/IF* 
according to tumor origin and histology type
Altree-Tacha et al, 
2017
(R18-2263) 
Panarelli et al, 
2012
(R18-1615)
BI’s Prevalence 
study
(data on file)
Colon adenocarcinoma
97%
100%
100%#
Esophageal 
adenocarcinoma
39%
82%
48%
Gastric adenocarcinoma
64%
90%
84%
Pancreatic ductal 
adenocarcinoma
39%
50%
70%
Cholangiocarcinoma
33%
53%
* Method and threshold for CDH17-positivity by IHC vary between reports.
# Only metastatic samples
BI 905711 can potentially activate TRAILR2 on both CDH17 positive tumor cells and 
adjacent tumor cells (cis- and trans-activation). BI 905711 can therefore induce TRAILR2 
activation in the CDH17 negative cells if surrounded by CDH17 positive cells.
BI 905711 showed efficacy in relevant GI cancer preclinical models as single agent and in 
combination with chemotherapy agents like capecitabine, irinotecan, paclitaxel and 
oxaliplatin.
Chemotherapy combinations commonly used in first- and second-line treatment of CRC 
include leucovorin calcium, fluorouracil (5-FU) and irinotecan (FOLFIRI regimen), or 
leucovorin, 5-FU and oxaliplatin (FOLFOX regimen) with or without an anti- angiogenic 
agents such as bevacizumab, or, if RAS wild type, an EGFR antibody. 
Second-line treatment options in metastatic pancreatic cancer depend on the therapies 
previously given in the first-line setting and the patient’s performance status, and include:


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FOLFIRI or FOLFIRINOX/mFOLFIRINOX (preferred option for patients who progressed 
on prior gemcitabine-based treatment), gemcitabine plus nab-paclitaxel, FOLFOX, or single 
agent gemcitabine or 5-FU, (R20-3885).
Chemotherapy induces apoptosis via activation of the intrinsic pathway while 
TRAILR2/CDH17 antibody induces apoptosis via the activation of the extrinsic pathway.
Thus, the combination of BI 905711 with FOLFIRI (+/- bevacizumab) should increase the 
apoptosis signal by the activation of both intrinsic and extrinsic apoptosis pathways in cancer 
cells. An increased efficacy of BI 905711 in combination with chemotherapy has been 
observed in CRC GP2d xenograft models (c16856466). BI 905711 plus irinotecan or 
oxaliplatin showed increased efficacy in the CRC GP2d xenograft models as compared to 
single agents. The combination with irinotecan showed the deepest and longest tumor growth 
control. Moreover, the efficacy of the sequential administration of irinotecan and BI 905711 
was analysed in preclinical models by measuring the induction of caspase cleavage in tumor 
tissue at baseline and at several timepoints on treatment. The results showed that pro-
apoptotic priming with irinotecan followed, 24 hours later, by the administration of BI 
905711 led to the highest synergistic effect (cCasp3 activation) as compared to co-
administration on the same day (data on file). These data are consistent with published data 
demonstrating that pre-treatment with chemotherapy eg. cisplatin or irinotecan, sensitizes 
cancer cells to TRAILR2 agonistic antibodies and the sequential administration might 
overcome resistance (R21-2020, R21-2040, R21-2041).
The first-in-human trial 1412-0001 is assessing BI 905711 as monotherapy in patients with
advanced or metastatic GI cancers. In Phase Ia, 45 patients (26 with CRC, 19 with non-CRC 
GI cancers) have received BI 905711 (dose range 0.02–4.8 mg/kg). No safety concerns or 
dose-limiting toxicities have been observed to date (c16856466) and the MTD was not 
reached. Based on safety, pharmacokinetic, and pharmacodynamic profiles, as well as 
preliminary antitumor activity of BI 905711, three dose levels (0.6 mg/kg, 1.2 mg/kg and 2.4 
mg/kg) given biweekly or one dose level (0.6 mg/kg) given weekly were selected for 
assessment of BI 905711 monotherapy in 1412-0001 expansion phase 1b.
As of Apr 2022, 37 out of 45 (82.2%) patients treated with BI 905711 monotherapy (dose 
range 0.02 mg/kg-4.8 mg/kg) experienced at least 1 adverse event (AE). Most of the reported 
AEs were consistent with known signs and symptoms of advanced colorectal, biliary and 
pancreatic cancers. 15 out of 45 patients experienced grade 1-3 drug-related AEs consisting 
of general disorders and administration site conditions, and gastrointestinal disorders. A total 
of 11 patients experienced SAEs, and 2 events were considered drug-related by the 
investigators.
There were no dose-limiting toxicities identified and there was no pattern of any anticipated 
adverse effects (see section 7 of the current BI 905711 investigator’s brochure). There were 4
AEs leading to dose reduction and/or discontinuations of study medication. In addition, there 
was no evidence of any dose/(adverse) effect relationship regarding both frequency as well as 
severity.


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There were 2 cases of hepatic laboratory abnormalities suspicious for drug induced liver 
injury (DILI) which meeting to Hy’s law criteria, and there was no evidence indicative for 
(laboratory) tumor lysis syndrome or cytokine release syndrome (CRS). 3 patients
experienced Grade 1-2 infusion related reaction (IRR).
In order to address future scientific questions, patients will be asked to voluntarily donate 
biospecimens for banking (please see Section 5.5). If the patient agrees, banked samples may 
be used for future biomarker research and drug development projects, e.g. to identify patients 
that are more likely to benefit from a treatment or to experience an adverse event (AE), or to 
gain a mechanistic or genetic understanding of drug effects and thereby better match patients 
with therapies.
Based on available preliminary data from phase I clinical studies (1412.1 and 1412.3), the 
decision was made to terminate BI 905711 (TRAILR2/CDH17) development program. This 
decision is not related to any safety concerns or unfavorable benefit/risk balance, but to the 
lack of predictive biomarkers and the limited efficacy particularly in the context of the 
evolving treatment landscape for advanced CRC and other GI cancers.
The purpose of CTP v4.0 is to reduce the study related activities to the minimum required to 
monitor patient safety and to avoid undue burden on patients.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Most patients with advanced or metastatic GI cancers have limited effective treatment 
options, develop resistance to currently available therapies, and succumb to their disease. BI 
905711 in combination with chemotherapy (+/- bevacizumab) can potentially provide a new 
therapeutic option for these patients as suggested by its efficacy in relevant preclinical GI 
cancer models and further supported by extensive pharmacology and toxicology preclinical 
data.
1.4.2
Risks
TRAILR2 agonistic antibodies, both as single agents and in combination with chemotherapy, 
have been extensively tested in the clinic and showed a good safety profile with the exception 
of TAS266 (R16-1795). The majority of these compounds did not induce dose limiting 
toxicities (DLTs) in phase I trials with no established maximum tolerated dose (MTD). 
Treatment-related adverse events (AEs) reported with these compounds mostly included GI
AEs (nausea, vomiting, diarrhea, stomatitis, decreased appetite) and elevation of aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) and pancreatic amylase (R16-1793, 
R16-1794, R17-2590, R17-2600, R17-2601, R16-4524, R17-2606, R18-2222). There is 
limited clinical experience with the second generation of compounds inducing TRAILR2 
clustering independently of FcR interactions. Phase I data of the TRAILR2 binding tetramer 
(TAS 266) reported reversible liver toxicity at the first administered dose level leading to 
TAS 266 discontinuation from further development (R16-1795). Published pre-clinical and 


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clinical data suggest that a relatively high exposure at the starting dose in the phase I trial 
may have contributed to the observed liver toxicity (R16-1800, R18-2222). Another 
TRAILR2 agonist (ABBV-621) currently under clinical investigation reported mainly liver 
and GI AEs with no defined MTD, and 1 partial response out of 24 patients each in CRC and 
pancreatic cancer patients (R18-2222). A bi-specific compound targeting TRAILR2 and FAP 
(RG 7386) has completed phase I with no reported DLTs and MTD (R18-1695).
So far AEs reported were consistent with known signs and symptoms of an end-stage CRC 
population. A total of11 patients experienced SAEs, and 2 events were considered drug-
related by the investigator. There were no dose-limiting toxicities identified and there was no 
pattern of any anticipated safety topics (acc section 7 of the current BI 905711 investigator’s 
brochure). In addition, there was no evidence of any dose/(adverse) effect relationship 
regarding both frequency as well as severity.
In addition, there were 2 cases of hepatic laboratory abnormalities suspicious for drug-
induced liver injury (DILI) which met Hy’s law criteria; and there was no evidence
indicative of (laboratory) tumor lysis syndrome or cytokine release syndrome (CRS). 3 
patients experienced Grade 1-2 infusion-related reaction (IRR).
The safety data will be closely monitored throughout this trial, and a Data Review Committee 
(DRC) will be implemented for this purpose.
Table 1.4.2: 1 
Overview of trial related risks
Possible or 
known risks of 
clinical relevance
for this trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product: BI 905711
The anticipated AEs based on the BI 905711 mode of action, pharmacological data and results of preclinical 
toxicology studies are described below; For more details, refer to the IB (c16856466).
Injury of GI 
tissues expressing 
CDH17
BI 905711 may potentially cross-link 
TRAILR2 to CDH17 in GI tissues and 
induce apoptosis and injury. No signs of GI 
injury were observed in preclinical 
toxicology studies in cynomolgus monkeys 
up to the highest administered dose. In-vitro 
data suggest that normal human colon 
epithelial cells are insensitive to TRAILR2 
induced apoptosis, but their sensitivity can 
be increased during inflammation or viral 
infection (R16-4563, R17-2592). Based on 
above considerations, possible anticipated 
AEs of BI 905711 may include nausea, 
anorexia, diarrhea, vomiting, pancreatitis, 
increase in pancreatic amylase, abdominal 
pain and/or other GI tract related 
signs/symptoms.
Patients with inflammatory bowel 
disease or bowel infection, or history of 
chronic pancreatitis should not 
participate in clinical trials with BI 
905711. Guidelines for management of 
nausea, diarrhea and vomiting is 
provided in Section 4.2.4.3.


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Table 1.4.2: 1
Overview of trial related risks (cont)
Possible or 
known risks of 
clinical 
relevance for 
this trial
Summary of data, rationale for the risk
Mitigation strategy
Drug-induced 
liver injury
Liver tissue is reported as the most sensitive 
non-cancerous tissue to TRAILR2 mediated 
apoptosis (R16-1795, R16-1793). Human 
hepatocytes do not express CDH17 and in 
Hep G2 cells used as a surrogate for TRAIL 
sensitive hepatocytes, no significant effect 
of BI 905711 on cell viability was observed. 
However, liver damage cannot be excluded 
particularly in patients with liver metastases. 
Timely detection, evaluation, and 
follow-up of alterations in selected 
liver laboratory parameters to ensure 
patients´safety will be implemented.
Renal Injury
A 6-week GLP toxicology study in monkeys 
showed glomerulopathy at the highest tested 
dose of 100 mg/kg. These finding were not 
accompanied by clinical or biochemical 
changes in renal function. There was no 
proteinuria and no increase in serum 
creatinine or blood urea nitrogen (BUN). 
The relevance of these renal findings 
for humans is unknown. Patients will 
be monitored for changes in renal 
functions by routine measurement of 
creatinine and urea in blood and 
protein in urine. See section 4.2.4.6
Infusion-related 
reaction (IRR)
As with any mAb, hypersensitivity reactions 
with BI 905711 are possible. BI 905711 is a 
humanized bi-specific antibody with atypical 
format which may induce IRR via multiple 
mechanisms. Recent data with a bi-specific 
antibody targeting TRAILR2 and FAP, and a 
TRAILR1/R2 agonist (ABBV-261) reported 
an incidence of 9% and 8% of grade 1-2 
infusion reactions respectively but no grade 
≥3 (R18-1695, R20-0970).
Patients with a known hypersensitivity 
to the trial medications or their 
excipients are excluded.
Management guidelines for IRR are 
provided in Section 4.2.4.1
Cytokine release 
syndrome (CRS) 
and immune-
mediated 
reactions
CRS is a supra-physiologic response 
resulting in the activation or engagement of 
T cells and / or other immune effector cells, 
which can be serious or life-threatening. The 
TRAIL pathway has been implicated in 
inflammation, in some preclinical 
experiments, but the clinical relevance of 
these findings is unknown (R18-2770). BI 
905711 did not induce any cytokine release 
using a standard in vitro assay (c16856466). 
There was no CRS reported in historical 
studies with conventional TRAILR2 
agonists (R16-1793, R16-1794, R17-2590, 
R17-2600, R17-2601, R16-4524, R17-
2606).
The risk of CRS cannot be excluded, 
and patients should be followed for 
possible occurrence of CRS. 
Guidelines are provided in Section 
4.2.4.2


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Table 1.4.2: 1
Overview of trial related risks (cont)
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale for the risk
Mitigation strategy
Tumor Lysis 
Syndrome (TLS)
BI 905711 induces apoptosis within a short 
time frame in-vitro and leads to tumor 
regression in-vivo in preclinical models. 
Theoretically, TLS can occur.
Patients should be monitored for 
occurrence of TLS particularly after 
the first administration of BI 905711. 
Guidelines are provided in Section 
4.2.4.4
Neurological 
adverse events
A six-week GLP toxicology study in 
monkeys showed minimal to mild 
perivascular eosinophilic/monocyte cell 
infiltrations in brain and spine at doses of 
30mg/kg and 100mg/kg with no apparent 
clinical neurological finding in affected 
animals. More details are described in 
section 1.2 and the IB (c16856466)
Relevance of these findings for 
humans is unknown. Human exposure 
to the highest planned dose of 4.8 
mg/kg is estimated to be 3 to 4-fold 
below exposure in monkeys at the 30 
mg/kg (NOAEL). CDH17 is an 
epithelial protein and it is not 
expressed in brain tissue. No 
neurological AE related to BI 905711 
have been observed in preclinical 
studies and in ongoing FIH phase I 
trial. Thus, BI905711 is not expected 
to induce neurological adverse events.
Patients who develop new 
neurological symptoms or deficits 
need to undergo neurological 
investigations including a brain MRI, 
and treatment with BI 905711 must be 
interrupted or discontinued. Guidelines 
for management of potential 
neurological toxicities are provided in 
Section 4.2.4.5 and their relationship 
to ADA will be assessed in this trial.
ADA (anti-drug 
antibodies) related 
adverse reactions
ADA to BI 905711 were observed in 
monkeys and were considered an immune 
response to a humanized monoclonal 
antibody. The presence of ADA in monkeys 
is not indicative of a similar response in 
humans (c16856466). BI 905711 may lead 
to development of ADA in humans, and its 
occurrence will be explored in this study 
(see Section 5.3.2). The consequence of 
ADA on safety is currently unknown, 
however there is a single preclinical report 
indicating the possibility of ADA-mediated 
clustering of TRAILR2 and its potential 
contribution to liver injury (R17-2603).
Patients will be followed for 
development of liver injury, and 
possible contribution of ADA to liver 
injury will be assessed.


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Table 1.4.2: 1
Overview of trial related risks (cont)
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale for the 
risk
Mitigation strategy
SARS CoV-2 
infection
Due to the underlying disease, exposure 
to intensive anti-cancer treatments 
and/or immunosuppressive therapies, 
patients in this trial may be immuno-
compromised and at higher risk for 
infection and/or severe illness from 
COVID-19.
A Benefit-Risk assessment in the context 
of the COVID-19 pandemic for patients 
treated with BI 905711 has been 
performed. Based on its mode of action, 
BI 905711 is not expected to have a 
relevant impact on the susceptibility to or 
the course of a COVID-19 infection. In 
case of a confirmed infection, continued 
use of trial treatment will be left to the 
investigator’s benefit-risk assessment on a 
case-by-case basis. Withdrawing 
treatment in a cancer patient who may 
have few or no alternative treatment 
options requires a careful, individual 
evaluation.
Trial procedures
Tumor Biopsy
There is an added risk for pain, swelling, 
bleeding for those patients who will 
undergo tumor biopsies. As the results 
from the biopsy will provide more 
information which will assist clinical 
decisions for future patients, the benefit 
is assumed to outweigh the risks.
Biopsies will only be performed when 
deemed safe by the investigator and if the 
platelet count is sufficient to allow for 
haemostasis.
Background therapy
Irinotecan, 
Leucovorin, 
Fluorouracil, 
Bevacizumab
Refer to the most recent approved local 
labels.
The investigator must review the label for 
each background therapy and implement 
any additional required safety monitoring 
to reduce the risk to the patient.
1.4.3
Discussion
There may be a potential benefit, eg. improved disease control and survival while 
maintaining quality of life, to patients from the addition of BI 905711 to FOLFIRI (or 
Liposomal Irinotecan plus 5-FU/Leucovorin) in pancreatic cancer, or to FOLFIRI plus 
bevacizumab in CRC.
The first in human (FIH) Phase I study of BI 905711 (1412-0001) currently being conducted 
in Asia, Europe and USA, is investigating the recommended phase 2 dose, safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 905711 as 
monotherapy in patients with advanced or metastatic GI cancers. At the initiation of trial 
1412-0003, the FIH monotherapy study 1412-0001 will be still ongoing, and the available 
preliminary safety data in monotherapy will serve as a reference for the starting and 


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subsequent dose levels of BI 905711 in combination with background treatment for the dose 
escalation phase.
So far AEs reported were consistent with known signs and symptoms of an end-stage CRC 
population. A total of 11 patients experienced SAEs, and 2 events were considered drug-
related by the investigator. There were no dose-limiting toxicities identified and there was no 
pattern of any anticipated safety topics (acc section 7 of the current BI 905711 investigator’s 
brochure). In addition, there was no evidence of any dose/(adverse) effect relationship 
regarding both frequency as well as severity.
The DRC will assess trial data to ensure the overall safety of enrolled patients. The DRC will 
also provide the investigators and the Sponsor with advice about the overall conduct of the 
trial (refer to Section 8.7).
The Sponsor will continuously assess the risks and benefits based on accumulating data from 
all clinical trials with BI 905711. Any significant change in risk-benefit ratio will be 
communicated to investigators and patients. 
In summary, this trial will implement multiple safety measures to mitigate possible risks for 
participating patients. It is assumed that participation in this study and treatment with BI 
905711 in combination with the background treatment may potentially provide patients with 
clinical benefit at an acceptable risk.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
Phase Ia:
∀
To determine the maximum tolerated dose (MTD) and the recommended dose for 
expansion (RDE) of BI 905711 in combination with FOLFIRI regimen plus 
bevacizumab in CRC patients based on the frequency of patients experiencing dose 
limiting toxicities (DLT) during the MTD evaluation period (as defined in section
3.1.1).
∀
To explore pharmacokinetics/pharmacodynamics, and efficacy to guide the 
determination of a MTD or a potentially effective dose in the absence of MTD, of BI 
905711 in combination with FOLFIRI plus bevacizumab.
Phase Ib
∀
To evaluate the efficacy and safety of BI 905711 in combination with FOLFIRI plus 
bevacizumab in the CRC cohort, and define RP2D (Recommended phase II dose).
∀
To evaluate the efficacy and safety of BI 905711 in combination with FOLFIRI (or 
Liposomal Irinotecan plus 5-FU/Leucovorin) in PDAC cohort, and define RP2D.
2.1.2
Primary endpoint(s)
Phase Ia
∀
Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk 
of the true DLT rate being equal or above 33% during the MTD evaluation period. 
∀
Number of patients with DLTs in the MTD evaluation period.
Phase Ib 
∀
Confirmed objective response (OR) as assessed by the investigator based on Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) (R09-0262) in patients with 
measurable disease, defined as the best overall response of complete response (CR) or 
partial response (PR), from the first administration of trial treament until the earliest 
of progressive disease (PD), death or last evaluable tumor assessment before start of 
subsequent anti-cancer therapy.
∀
In safety run-in part of PDAC cohort: number of patients with DLTs during the MTD 
evaluation period assessed in the first 6 patients.
2.1.3
Secondary endpoint(s)
Phase Ia


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∀
The following PK parameters will be calculated after study treatment administration, 
as measured during the first cycle and after multiple cycles:
- Cmax: Maximum measured plasma concentration of BI 905711.
- AUC0-t2: Area under the concentration-time curve in plasma of BI 905711
Phase Ib
∀
Progression-Free Survival (PFS) defined from date of start of treatment to the date of 
disease progression or death, whichever is earlier as assessed by the investigator
according to RECIST 1.1.
∀
Radiological (CT Scan) tumor shrinkage, defined as the difference between the 
minimum post-baseline sum of longest diameters of target lesions and the baseline
sum of longest diameters of the same set of target lesions according to RECIST 1.1.
∀
The duration of OR is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements 
recorded on study) according to RECIST 1.1.
∀
Disease control, defined as CR, PR, or stable disease (SD) lasting at least 16 weeks 
according to RECIST 1.1 from the start of treatment until the earliest of PD, death or 
last evaluable tumor assessment and before start of subsequent anti-cancer therapy.
∀
The following PK parameters will be calculated after study treatment administration, 
as measured during the first cycle and after multiple cycles:
- Cmax: Maximum measured plasma concentration of BI 905711 in plasma.
- AUC0-t2: Area under the concentration-time curve for BI 905711 in plasma.


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3.1.1
Dose escalation phase (Phase Ia)
Phase Ia is an open-label, non-randomized dose escalation study of BI 905711 in combination 
with FOLFIRI and bevacizumab in patients with CRC. Refer to Figure 3.1: 1. The objective 
of the phase Ia is to determine the MTD/RDE.
A Bayesian logistic regression model (BLRM) with overdose control (R13-4803) will be 
used to determine the MTD. The BLRM estimates the MTD by updating the probability of 
observing a DLT for each dose level in each dose escalation cohort. At any time during the 
trial, it will not be permitted to escalate to a dose which does not fulfil the escalation with 
overdose control (EWOC) criterion.
The MTD evaluation period is defined as a two 14-day treatment cycle (from cycle 1 
Day 1 until the day before cycle 3 Day 1, or end of the REP in case of discontinuation 
before start of cycle 3).
Patients will receive increasing doses of BI 905711 in combination with FOLFIRI plus 
bevacizumab until either the MTD or the RDE in the absence of MTD, is reached. 
Incremental dose increases of BI 905711 in successive patient cohorts will be no more than 
100% of the previous dose level. 
At each dose level, all patient cohorts will include at least 3 patients. In the case that only 2 
out of 3 patients in a cohort are evaluable and neither has experienced a DLT within the MTD 
evaluation period, dose-escalation can occur based on the data from these 2 patients. 
As soon as all patients at a dose level have either experienced a DLT or have completed the 
MTD evaluation period without experiencing a DLT, a BLRM with overdose control will be 
re-run with the newly accumulated data. Based on the estimates from the model and on 
additional information (i.e. PK and PD as available), the DRC will reach a joint 
recommendation of the next dose level to be investigated, the size of the next cohort, as well 
as the potential recommendation to expand the size of the recruiting cohort.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to this dose cohort will be stopped. The BLRM will be re-run to 
confirm whether the dose level still fulfils the EWOC criterion. Based on this information, 
the DRC will evaluate whether the next patients will be enrolled at the same dose level or at a 
lower dose level including intermediate dose levels.
No further dose escalation will take place after the criterion for MTD is fulfilled. Further 
patients may be included to confirm this MTD estimate, i.e. to confirm that the EWOC 
criterion is still fulfilled. The DRC can declare any dose fulfilling the EWOC criterion as the 
RDE, independent of the MTD estimate. The RDE will not exceed the MTD. Any DLTs 
occurring after the MTD evaluation period will be considered for the evaluation of the RDE.
If no DLT is observed, the DRC may decide to declare the RDE based on PK/PD and 
efficacy endpoints, and overall safety profile.


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3.1.2
Dose expansion phase (Phase Ib)
Phase Ib is an open label study with the main objective to assess the safety and efficacy of BI 
905711 in combination with chemotherapy (with or without bevacizumab) in 2 expansion 
cohorts. PK will be further characterised and the RP2D will be determined.
Phase Ib will consist of 2 cohorts of patients with 2 different tumor types as described below. 
Refer to Figure 3.1: 1 for the planned randomized CRC cohort and single arm PDAC cohort.
3.1.2.1
Randomized CRC expansion cohort
This is an open label, randomized cohort of approximately 60 CRC patients. Patients will be 
randomized in a 2:1 ratio into either:
•
Arm A = BI 905711 (at the RDE from Phase Ia) plus FOLFIRI and bevacizumab 
or
•
Arm B = FOLFIRI plus bevacizumab 
3.1.2.2
Single Arm PDAC expansion cohort
This is an open label single arm cohort of approximately 20 patients with CDH17-positive 
PDAC. 
A safety run-in will be included in which the first 6 patients will be treated with BI 905711 
(at the RDE from Phase Ia) plus FOLFIRI (or Liposomal Irinotecan plus 5-FU/Leucovorin), 
to confirm the RDE based on DLTs assessed during the MTD evaluation period as defined 
for the Phase Ia, prior to enrolling further patients.
3.1.3
Enrolment stopping rules
All safety information will be carefully analysed by the sponsor. Enrolment will be 
temporarily stopped if a clinically relevant AE occurs which meets both of the following 
criteria: 
∀
associated with evidence suggesting a reasonable possibility that the investigational 
drug caused the AE
∀
occurs at a frequency or with severity that suggest that the risk-benefit profile of the 
investigational drug should be reassessed 
If the DRC determine that the above criteria are met, the enrolment to the trial will be 
temporarily stopped to allow for in-depth analysis of the safety profile of BI 905711 plus the 
applicable background treatment. The benefit-risk profile will be re-assessed by the DRC to 
determine if the trial should be continued as planned, or permanently discontinued or will 
continue with modification to the trial protocol. The purpose of any modifications to the 
protocol will be to mitigate patient-risk and ensure that the benefit-risk assessment for 
continued investigation of BI 905711 plus applicable background treatment remains positive. 
The DRC will also consider and provide guidance for the management of patients who are 
already receiving study treatment. The outcome of the analysis and the recommendations will 


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be shared with all involved Health Authorities prior to a planned re-start of enrolment. In case 
the benefit-risk assessment is no longer considered positive, the trial will be discontinued.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
FOLFIRI in combination with Bevacizumab is indicated for first- and second-line treatment 
of CRC, including those who have progressed on a first-line bevacizumab-containing 
regimen. FOLFIRI (or Liposomal Irinotecan plus 5-FU/Leucovorin) is a second-line 
treatment option for patients with PDAC.
In Phase Ia, the selection of dose levels and patient cohort size will be guided by a BLRM 
with overdose control. An EWOC design will increase the chance of treating patients at 
efficacious doses while reducing the risk of overdosing. This design is based on practical 
experience and is an efficient method due to its ability to identify the dose with a desired 
toxicity rate and its allocation of a greater proportion of patients to doses at, or close to, that 
desired dose (R13-4802, R13-4804, R13-4805). The use of BLRM for Phase I trials has also
been advocated by the EMA guideline on small populations (R07-4856) and by the FDA 
(R13-4881).
3.3
SELECTION OF TRIAL POPULATION
This is an international multi-center trial.
For phase Ia (dose escalation) approximately 20 patients are planned to be entered at 
approximately 4-5 sites. The total number of patients will depend on the number of dose 
levels to be tested and the size of the dose escalation cohorts. 
For phase Ib, approximately 80 patients are planned to be entered at sites that participate in 
the dose escalation part of the study as well as additional sites that will be initiated as needed 
to fulfill the planned enrolment. If participating sites are unable to recruit patients, additional 
sites may be opened, and under-performing sites may be closed.
Screening of patients for this trial is competitive, however in Phase Ia, recruitment slots will 
be assigned by the Sponsor. Screening for the trial will stop at all sites at the same time once 
a sufficient number of patients has been screened. Investigators will be notified about 
screening completion and will then not be allowed to screen additional patients for this trial.
Any patients already in screening at the time of screening completion, will be allowed to 
continue to receive treatment if eligible.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
or not.
If retrospectively it is found that a patient has been entered in error (=did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment a decision will be 
made whether continued trial participation is possible or not.


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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. 
A patient who has been declared as a “screening failure” may be re-screened once.
In this situation, patients will be handled as new patients i.e. sign a new informed consent, 
allocate a new patient number, and undergo full screening assessments to assess eligibility.
3.3.1
Main diagnosis for trial entry
The patient population for this trial includes patients with histologically or cytologically 
confirmed advanced unresectable or metastatic colorectal adenocarcinoma (CRC), and
CDH17 positive pancreatic ductal adenocarcinoma (PDAC) (Phase Ib only).
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
Applicable to both Phase Ia and Phase Ib Cohorts:
1. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
2. Of legal adult age (according to local legislation) at screening.
3. Histologically or cytologically confirmed, advanced unresectable or metastatic colorectal 
adenocarcinoma
4. CRC : Patients who have PD after prior oxaliplatin-based first line therapy or within 6 
months after the end of oxaliplatin-based adjuvant therapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
6. Life expectancy ≥ 3 months in the opinion of the investigator
7. Availability and willingness to provide tumor tissue (fresh biopsy or archival) for 
biomarker analysis as described in the Flow Chart Footnotes and in Section 5.4.3.1
Only non-significant risk procedures per the investigator’s judgment will be used to 
obtain any biopsies specified in this study. In case a fresh tumor biopsy cannot be 
obtained, the recruitment of the patient may proceed on a case-by-case basis after 
agreement between the investigator and BI. In such a case, an archived tumor tissue 
specimen must be submitted.


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8. Adequate hepatic, pancreatic, renal and bone marrow functions as defined by all of the 
below:
o
Total bilirubin ≤1.5 x institutional upper level of normal (ULN).
o
Alanine transaminase (ALT) and Aspartate transaminase (AST) ≤2.5 x
institutional ULN or ≤5 x institutional ULN for patients with known liver 
metastases. 
o
Serum creatinine ≤1.5x institutional ULN. If creatinine is > 1.5 x ULN, patient 
is eligible if concurrent creatinine clearance ≥50 ml/min (≥ 0.05L/min)
(measured or calculated by CKD-EPI formula or Japanese version of CKD-EPI 
formula for Japanese patients).
o
Absolute neutrophil count (ANC) ≥1.5 x 109/L, ≥ 1.5 x 103/μL, or ≥ 1500/mm3
o
Platelets ≥ 100 x 109/L, ≥ 100 x 103/μL, or ≥ 100 x 103/mm3
o
Hemoglobin (Hb) ≥ 8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 mmol/L (without transfusion
within previous week)
o
Serum lipase ≤ 1.5 institutional ULN (Only for CRC cohort); >1.5 - 2.0 x 
ULN or asymptomatic >2.0 - 5.0 x ULN if related to PDAC (Only for PDAC 
cohort)
9. Recovery, from any adverse events (AEs) of previous anti-cancer therapies, to Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grade 1 except for CTCAE 
grade 2 alopecia or peripheral sensory neuropathy, or other CTCAE grade 2 AEs 
considered not clinically significant in the investigator’s opinion.
10. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods meeting these criteria is 
provided in Section 4.2.3.3.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Additionally, criterion 11 is applicable to Phase Ia cohort only
11. Patient with either measurable or non-measurable disease.
Additionally, criterion 12-14 is applicable to Phase Ib cohorts only
12. At least one target lesion that can be accurately measured per RECIST 1.1
PDAC Patients must also meet the followings:


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13. Histologically or cytologically confirmed, advanced unresectable or metastatic CDH17 
positive pancreatic adenocarcinoma
14. Patients who have PD after prior platin and/or gemcitabine-based first line therapy.
3.3.3
Exclusion criteria
Applicable to both Phase Ia and Phase Ib cohorts
1. Any prior irinotecan-based therapy in the metastatic setting.
2. Previous systemic anti-cancer therapy within the specified timeframe from the last 
dose intake to the first dose of trial treatment as follows: 
∀
Any non-investigational drug, including anti-angiogenic agents (bevacizumab 
or ramucirumab or aflibercept) and anti-EGFR antibodies (cetuximab or 
panitumumab), within 14 days.
∀
Any investigational drug or other antibodies including immune checkpoint 
inhibitors, within 28 days.
3. Currently enrolled in another investigational device or drug trial. Patients who are in 
follow-up/observation for another clinical trial are eligible.
4. Radiation therapy within 4 weeks prior to start of treatment. However, palliative 
radiotherapy for symptomatic metastasis is allowed if completed within 2 weeks prior 
to start of treatment.
5. Any serious concomitant disease or medical condition affecting compliance with trial 
requirements or which are considered relevant for the evaluation of the efficacy or 
safety of the trial drug, such as neurologic, psychiatric, infectious disease or active 
ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug administration, and in the judgment of 
the Investigator, would make the patient inappropriate for entry into the trial.
6. Known pathological condition of GI tract, liver and pancreas, excluding the disease
under study, that may interfere with assessment of drug safety or may increase the risk 
of toxicity:
a. inflammatory bowel disease
b. chronic pancreatitis
c. other serious GI pathological conditions by judgment of the investigator e.g. 
autoimmune disease with GI involvement, unexplained active diarrhea CTCAE v5.0
grade ≥2. 
7. Known history of human immunodeficiency virus (HIV) infection. 


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8. Any of the following laboratory evidence of hepatitis virus infection. Test results 
obtained in routine diagnostics are acceptable if done within 14 days before the informed 
consent date:
o
Positive results of hepatitis B surface (HBs) antigen
o
Presence of HBc antibody together with HBV-DNA
o
Presence of hepatitis C RNA
9. Previous or concomitant malignancies, other than the one treated in this trial within the 
last 2 years with the exception of the following:
o
Effectively treated non-melanoma skin cancers
o
Effectively treated carcinoma in situ of the cervix
o
Effectively treated ductal carcinoma in situ
o
Other effectively treated malignancy that is considered cured by local 
treatment
10. Chronic alcohol or drug abuse or any condition that, in the investigator’s 
opinion, makes the patient an unreliable trial participant or unlikely to 
comply with the protocol requirements or not expected to complete the trial 
as scheduled.
11. Women who are pregnant, nursing, or who plan to become pregnant while in the trial; 
female patients who do not agree to the interruption of breast feeding from the start of 
study treatment through 6 months after the last study treatment. 
12. Presence of uncontrolled or symptomatic brain or subdural metastases. Inclusion of 
patients with brain metastases who have completed local therapy and are considered 
stable by the investigator, or with newly identified asymptomatic brain metastases 
at screening will be allowed. Use of corticosteroids is allowed if the dose was stable 
for at least 1 week before the baseline MRI.
13. Patients who are under judicial protection and patients who are legally institutionalized.
14. Major surgery (major according to the investigator’s assessment) performed within 28 
days prior to treatment start or planned within 3 months after screening, e.g. hip 
replacement.
15. Any of the following cardiac criteria:
a.
resting corrected QT interval (QTc) >470 msec based on local assessment
b. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, 
conduction, or morphology of resting Electrocardiograms (ECGs), e.g., complete 
left bundle branch block, third degree heart block.
c.
Patients with an ejection fraction (EF) <50% or the lower limit of normal of the 
institutional standard will be excluded. Only in cases where the Investigator (or the 
treating physician or both) suspects cardiac disease with negative effect on the EF, 
will the EF be measured during screening using an appropriate method according to 
local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition 
scan). A historic measurement of EF no older than 6 months prior to first 


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administration of study drug can be accepted provided that there is clinical evidence 
that the EF value has not worsened since this measurement in the opinion of the 
Investigator or of the treating physician or both.
d. Patients with a history of stroke or myocardial infarction within 6 months prior to 
screening are not permitted.
16. Known hypersensitivity to the trial medications or their excipients
17. The patient has any known history or clinical evidence of Gilbert’s Syndrome, or is 
known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, 
or UGT1A1*6/*28
18. Any contradictions to the proposed background therapy according to the current 
approved local label. 
3.3.4
Discontinuation of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(“withdrawal of consent”) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2).
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see section 5.2.6)
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product.
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, pregnancy, or nursing). 
∀
Has radiological (or clinical) documentation of progressive disease on the current 
treatment (see section 5.1) unless the investigator documents that the patient will 
continue treatment beyond progression due to clinical benefit.
The patient may continue treatment beyond initial RECIST progression if:


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∀
The patient is clinically benefiting, 
∀
The criteria described below are met, 
∀
It is agreed between the Investigator and the Sponsor, 
∀
The patient has signed an informed consent describing this circumstance.
Criteria required to continue treatment beyond RECIST-defined radiological progression of 
disease: 
∀
Absence of clinical symptoms or signs indicating clinically significant disease 
progression
∀
No decline in performance status
∀
Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites [e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression] requiring urgent alternative medical intervention
∀
No significant, unacceptable or irreversible toxicities related to study treatment
If a patient becomes pregnant during the trial, trial treatment must be stopped immediately. 
The patient will be followed up until delivery or termination of pregnancy.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their 
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and section 6.2.3.
3.3.4.1.1
Replacement of patients 
Patients will be considered non-evaluable for MTD determination in the following 
circumstances;
∀
Patients who withdraw consent or who are lost from follow-up or for any other reason 
other than DLT before completing the first two cycles of study treatment.
∀
Patients who have received less than 70% of the planned BI 905711 doses during first 
two cycles of study treatment and does not experience a DLT
∀
Patients who miss 2 or more partial or complete visits during the first two cycles of 
study treatment, with missing PK and safety parameters needed to accurately assess 
DLT and MTD determination. 
∀
Patients found to be non eligible after starting study treatment based on a case by case
basis


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Non-evaluable patients will be replaced and not included in the primary analysis model 
whenever additional patients are required in order to ensure there are a sufficient number of 
evaluable patients in a cohort. 
Of note, the dose escalation will be determined based on all the safety information of all 
treated patients including those who will not be included in the BLRM analysis.
Patients who experience a DLT during the MTD evaluation period as well as patients who 
withdraw after the MTD evaluation period will not be replaced. 
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further treatment and follow up of patients affected will occur as described in Section 
3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Product during Phase Ia
Table 4.1.1: 1
BI 905711 
Substance:
BI 905711
Pharmaceutical formulation:
Powder for Solution for Infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
100 mg/vial (10 mg/mL)
Posology:
Single administration every 2 weeks (Day 3 of each 
14-day cycle)
Method and route of administration:
Intravenous
See Section 4.2 for AxMP (background therapy) required in Phase Ia.
4.1.2
Identity of the Investigational Medicinal Product during Phase Ib
Table 4.1.2: 1
BI 905711
Substance:
BI 905711
Pharmaceutical formulation:
Powder for Solution for Infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
100 mg/vial (10 mg/mL)
Posology:
Single administration every 2 weeks (Day 3 of each 14-
day cycle)
Method and route of administration:
Intravenous
See Section 4.2 for AxMP (background therapy) required in Phase Ib.
4.1.3
Selection of doses in the trial and dose modifications
A dose of 0.6 mg/kg of BI 905711 was selected as a starting dose for this combination trial 
because this dose level as well as the next dose level (i.e. 1.2 mg/kg) were considered safe 
and well tolerated (i.e. no observed DLTs or AEs of CTCAE grade >1) as assessed in the 
monotherapy dose escalation trial 1412-0001 in 4 patients each with CRC (data on file).
The dose of BI 905711 will be escalated in patient cohorts at the provisional dose levels (as 
shown in Table 4.1.3: 1) until the MTD or the monotherapy recommended dose (as 
established in trial 1412-0001) is reached. The dose level tested will never exceed the highest 
dose level deemed safe by the DRC in the monotherapy trial 1412-0001.
BI 905711 dose levels may be escalated up to 4.8 mg/kg which is based upon the 
pharmacodynamic modeling. Based on the available safety data and statistical model 
evaluation, exploration of doses higher than 4.8 mg/kg and up to 9 mg/kg, may be 
considered. The selection of the dose levels higher than 4.8 mg/kg that may be tested will be 


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defined by the DRC. Intermediate dose levels may be investigated as long as they fulfill the 
EWOC criterion.
At the end of the MTD evaluation period, BI will convene a meeting with the DRC. At these
meetings, the clinical course including all safety information, PK and pharmacodynamics 
biomarker data as available, for each patient in the current dose cohort, will be described. 
Updated safety data on other ongoing patients, including data beyond the MTD evaluation 
period, will be discussed as well. Based on the data, a decision on the next dose level of BI 
905711 is made. Incremental dose increases in successive cohorts will be no more than 100%
of the previous dose level.
Dose escalation will continue until identification of the MTD or recommended dose for 
expansion (RDE) in case no MTD is established, or safety concerns arise, or the trial is 
terminated for other reasons.
Table 4.1.3: 1
Provisional dose levels of BI 905711 and possible cohort size within 
each escalation group in phase Ia 
Dose 
level
Dose
mg/kg
Increment from 
previous dose
Minimum 
number of 
patients
1
0.6 
Starting dose
3
2
1.2 
100%
3
3
2.4 
100%
3
4
3.6 
50%
3
5
4.8 
33%
3
4.1.3.1
Selection of BI 905711 dose for Phase Ib in combination with FOLFIRI with or 
without bevacizumab
The BI 905711 dose for phase Ib will be selected by the DRC with the aim to select a safe 
and potentially effective dose of BI 905711 based on all data collected in phase Ia (including
safety, PK, biomarker, efficacy).
4.1.3.2
Selection of FOLFIRI dose regimen and bevacizumab for Phase Ib
The dose of FOLFIRI (or Liposomal Irinotecan plus 5-FU/Leucovorin) regimen in PDAC 
and FOLFIRI regimen in combination with bevacizumab in CRC will be in accordance to 
respective NCCN Guidelines (R21-2007, R21-2008).


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4.1.4
Method of assigning patients to treatment groups
Recruitment into the trial will be conducted in a controlled manner. Patient numbers will be 
assigned via Interactive Response Technology (IRT) upon registration of screening. 
In both phase Ia and Phase Ib, each eligible patient will be assigned and receive the 
appropriate dose for their assigned cohort.
In both phases, BI 905711 will be assigned via IRT. Each medication vial will have a unique 
medication number. The medication number assigned will be documented in the CRF. Note 
that the medication number is different from the patient number (the latter is generated during 
screening via the IRT System).
For phase Ib, patients in the CRC expansion cohort, will be randomized via IRT into one of 2 
arms; (BI 905711 + FOLFIRI +Bevacizumab arm) or (FOLFIRI +Bevacizumab arm) with 
2:1 randomization ratio. The dose level of BI 905711 is determined at phase 1a. 
4.1.5
Drug assignment and administration of doses for each patient
BI 905711 will be prepared and handled according to the 1412-0003 ‘Preparation and 
Handling Instructions” which will be filed in the ISF. Each patient will receive the 
appropriate trial medication and dose for their assigned dose cohort.
IMP (BI 905711 and background therapy for Phase Ib CRC cohort, if considered as IMP per 
local regulations) will be assigned via IRT for each treatment cycle. Upon notification that a 
patient will be treated in the study, the pharmacy will prepare the trial medication at the 
assigned dosage for administration to the patient.
The Cycle 1 Day 3 dose of BI 905711 will be calculated using the Cycle 1 Day 1 weight or 
up to 3 days prior as the reference weight. If the patient’s weight changes by ≤10% compared 
to the reference weight, the dose (in mg) may remain the same for subsequent cycles. If the 
weight changes by >10% the dose will be recalculated and the new weight will be used as the 
reference weight.
All IMP as well as background treatment will be given as an intra-venous infusion by 
authorised site staff in a specialised unit where emergency care can be provided. 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 905711 i.v. infusions. (refer to Section 
4.2.2.1). Refer to section 4.2.2.1 for premedication for background therapy.
The BI 905711 i.v. infusion should take place over 30 minutes (+/-10 minutes), unless there 
is a necessity of administration rate reduction according to the protocol (e.g., in case of 
infusion-related reaction). If a patient’s weight is ≤50 kg, the infusion duration may be less 
than 30 minutes depending upon the infusion rate and the patient’s condition. 


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Priming and flushing should not be included in the administration duration. Total storage 
time for ready-to-use solution at room temperature should not exceed 150 minutes between 
preparation and end of infusion time. 
Observation period for CRS/IRR
∀
Patients will remain under surveillance for at least 6 hours after the end of infusion after 
the first, second and third administrations of BI 905711. During the post-infusion 
observation period, body temperature, pulse rate and blood pressure will be measured at 
the end of the infusion and every 2 hours (± 15 minutes) thereafter.
∀
If no adverse signs or symptoms, e.g. infusion-related reactions, are observed during the 
first 3 administrations, the duration of the post-infusion observation period may be 
reduced to 4 hours for subsequent administrations. Body temperature, pulse rate and 
blood pressure will be measured at the end of the infusion, then after 2 and 4 hours (± 15 
minutes).
∀
After 6 administrations in the absence of infusion-related reactions, the post-infusion 
observation period can be reduced to 2 hours at investigator’s discretion. Body 
temperature, pulse rate and blood pressure will be measured at the end of the infusion, 
then after 2 hours (± 15 minutes). 
4.1.5.1
Administration of FOLFIRI with or without bevacizumab
Background therapy FOLFIRI (or Liposomal Irinotecan plus 5-FU/Leucovorin) in patients 
with PDAC and FOLFIRI in combination with bevacizumab in patients with CRC will be 
administered in accordance to respective NCCN Guidelines (R21-2007, R21-2008).
See Section 4.2 for background treatment for dose escalation (Phase Ia) and dose expansion 
(Phase Ib).
4.1.5.2
Criteria for receiving further treatment
Eligibility for further treatment should be confirmed prior to dosing on Day 1 of each cycle
(and on Day 3 prior to administration of BI 905711 for clinical criteria only) by confirming 
the patient has not met any criteria for protocol discontinuation as described in section 3.3.4.1
and absence of any adverse event requiring treatment discontinuation (section 4.2.3).
To continue treatment the following criteria must be met:
∀
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, ≥ 1.5 x 103/μL, or ≥ 1500/mm3
∀
Platelets ≥ 75 x 109/L, ≥ 75 x 103/μL, or ≥ 75000/mm3
∀
Adequate renal function: for bevacizumab, proteinuria should be monitored per local 
site practice.


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∀
Absence of worsening (any CTCAE grade) or new neurological signs/symptoms 
CTCAE grade > 1.
∀
Absence of progressive disease unless the investigator documents that the patient will 
continue treatment beyond progression due to clinical benefit and after agreement
with Sponsor).
If the criteria are not met but the patient is recovering, the patient should continue to be 
assessed regularly and the next dose of treatment may be delayed for up to 28 days until the 
criteria are met. Dose modification may be appropriate (see Section 4.1.5.3).
4.1.5.3
Dose modifications
Individual patients must not receive a higher dose than assigned to them at the start of the 
trial. Dose escalation is allowed in cases where the dose has been reduced in error. At the 
time the recommended doses for expansion are determined by DRC, patients that are on any 
other dose levels may be adapted to the recommended dose at investigator's discretion. The 
dose cannot be escalated if the dose has been previously reduced for toxicity reason.
Dose modification of BI 905711 and FOLFIRI (or Liposomal Irinotecan plus 5-
FU/Leucovorin (PDAC only)) regimen should be based on the worst preceding toxicity. Dose 
adjustment should not be considered for bevacizumab and leucovorin.
Subsequent doses should be adjusted as suggested in Table 4.1.5.3:1.
Table 4.1.5.3:1
Dose modifications of BI 905711 and background therapy
Agents
Starting dose
Dose level -1
Dose level -2
Irinotecan
180
150
120
Liposomal Irinotecan 
70
50
43
5-FU (bolus)
400
200
0
5-FU (infusion)
2400
1920
1440
BI 905711
Current DL
DL-1 per protocol
DL-2 per protocol
Bevacizumab and 
Leucovorin
No dose adjustment. 
Recommendations on dose modification of irinotecan (refer latest local package insert), 
liposomal irinotecan (refer latest local package insert) and 5-FU (refer latest local package 
insert), and BI 905711 are summarized in Table 4.1.5.3:2. 


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Table 4.1.5.3:2
Dose modification for FOLFIRI (or Liposomal Irinotecan plus 5-
FU/Leucovorin) regimen and BI 905711 
CTC Grade (Value) 
Action on FOLFIRI (or Liposomal 
Irinotecan plus 5-FU/Leucovorin) at the 
Start of Subsequent Cycles
BI 905711
Neutropenia 
Each drug should be delayed until ANC 
>1500/μl and platelet count >100 000/μl.
Delay as for FOLFIRI (or 
Liposomal Irinotecan plus 5-
FU/Leucovorin)
Resume at same dose
1 (1500 to 1999/mm3) 
Maintain dose level of both Irinotecan and 5-
FU
2 (1000 to 1499/mm3) 
Maintain dose level of both Irinotecan and 5-
FU
3 (500 to 999/mm3) 
↓ 1 dose level of both Irinotecan and 5-FU
4 (<500/mm3) 
↓ 2 dose levels of both Irinotecan and 5-FU
Neutropenic fever 
Omit irinotecan or Liposomal Irinotecan dose 
until resolved, then ↓ 2 dose levels 
Other hematologic 
toxicities 
Dose modifications for leukopenia or 
thrombocytopenia during a cycle of therapy 
and at the start of subsequent cycles of therapy 
are also based on NCI toxicity criteria and are 
the same as recommended for neutropenia 
above. 
Diarrhea 
1 (2-3 stools/day > pretx) 
2 (4-6 stools/day > pretx) 
3 (7-9 stools/day > pretx) 
4 (≥10 stools/day > pretx) 
Withhold treatment until resolution of 
diarrhea for at least 24 hours off all 
antidiarrheal medications.
Maintain dose level of irinotecan
Maintain dose level of irinotecan
1 lower dose level of irinotecan
2 lower dose levels of irinotecan
Withhold 5-FU for diarrhea ≥grade 2 and 
restart at reduced dose by 20% after 
resolution.
Withhold treatment until 
resolution of diarrhea for at 
least 24 hours off all 
antidiarrheal medications. 
For diarrhea grade ≥ 3 restart 
at one lower dose level.
Other nonhematologic 
toxicities (except alopecia, 
anorexia or asthenia)
1 
2 
3 
4 
If grade 3 or 4, hold treatment until ≤grade 1 
or baseline value. Decrease the dose of 5FU 
by 20%.
Maintain dose level of irinotecan
Maintain dose level or irinotecan
1 lower dose level of irinotecan
2 lower dose levels of irinotecan
Hold treatment if FOLFIRI 
(or Liposomal Irinotecan plus 
5-FU/Leucovorin) is on hold.
If the AE is grade 3 or 4 and 
deemed related to 
BI 905711 in the 
investigator’s judgement, 
restart at 1 lower dose level.
Skin/mucosal toxicities
Withhold 5-FU for ≥grade 2 PPE*, ≥grade3 
mucositis/stomatitis and resume 5-FU at a 
20% reduced dose after improvement to ≤
grade 1 or baseline value.
No change
Interstitial lung disease
Permanently discontinue liposomal irinotecan
Discontinue treatment if 
FOLFIRI (or Liposomal 
Irinotecan plus 5-
FU/Leucovorin) is on hold.
Anaphylactic
Reaction
Permanently discontinue liposomal irinotecan
Discontinue treatment if 
FOLFIRI (or Liposomal 
Irinotecan plus 5-
FU/Leucovorin) is on hold.
*PPE - Palmar-Plantar Erythrodysesthesia (hand-foot syndrome)


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Recommendations on dosage modification of bevacizumab (refer local package insert) are 
summarized in Table 4.1.5.3:3.
Table 4.1.5.3:3
Dose adjustment for bevacizumab (refer to local package insert)
Dosage Modifications 
for Adverse Reactions 
Severity 
Dosage Modification 
Gastrointestinal 
Perforations and Fistulae 
• Gastrointestinal perforation, any 
grade
• Tracheoesophageal fistula, any 
grade 
• Fistula, grade 4 
• Fistula formation involving any 
internal organ 
Discontinue Bevacizumab 
Wound Healing 
Complications 
• Wound healing complications 
requiring medical intervention 
• Necrotizing fasciitis 
Discontinue Bevacizumab 
Hemorrhage 
• Grade 3 or 4 
Discontinue Bevacizumab 
• Recent history of hemoptysis of 1/2 
teaspoon (2.5 mL) or more 
Withhold Bevacizumab 
Thromboembolic Events 
• Arterial thromboembolism, severe 
Discontinue Bevacizumab 
• Venous thromboembolism, grade 4 
Discontinue Bevacizumab 
Hypertension 
• Hypertensive crisis 
• Hypertensive encephalopathy 
Discontinue Bevacizumab 
• Hypertension, severe 
Withhold Bevacizumab if 
not controlled with medical 
management; resume once 
controlled 
Posterior Reversible 
Encephalopathy Syndrome 
• Any 
Discontinue Bevacizumab 
Renal Injury and 
Proteinuria 
• Nephrotic syndrome 
Discontinue Bevacizumab 
• Proteinuria ≥2 grams per 24 hours 
in absence of nephrotic syndrome 
Withhold Bevacizumab
until proteinuria less than 2 
grams per 24 hours 
Infusion-Related Reactions 
• Severe 
Discontinue Bevacizumab 
• Clinically significant 
Interrupt infusion; resume 
at a decreased rate of 
infusion after symptoms 
resolve 
• Mild, clinically insignificant 
Decrease infusion rate 
Congestive Heart Failure 
Any 
Discontinue Bevacizumab 
∀
No more than two dose reductions are allowed for each study drug. 
∀
Trial treatment, or individual drugs of background therapy or BI 905711 may be 
discontinued or withheld depending on the type and severity of related adverse 
effects. 
∀
Any trial drug should be discontinued permanently in case the related adverse events 
(as detailed in the table above) do not recover to grade ≤1 or baseline after 28 days.


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4.1.6
Blinding and procedures for unblinding
4.1.6.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The
CRF will contain information on randomized treatment.
4.1.6.2
Unblinding and breaking the code
Not applicable.
4.1.7
Packaging, labelling, and re-supply
All IMP will be provided by BI or a designated CRO. They will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice (GMP). Re-supply to the
sites will be managed via an IRT system, which will also monitor expiry dates of supplies 
available at the sites.
For details of packaging and the description of the label, refer to the ISF.
For details of background treatment see section 4.2.1.
4.1.8
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Trial 
Manager (as provided in the list of contacts) must be contacted immediately.
4.1.9
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / Ethics Committee
∀
Availability of a signed and dated clinical trial contract between the sponsor or delegate
and the investigational site,
∀
Approval / notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
Availability of the proof of a medical license for the Principal Investigator,
∀
Availability of FDA Form 1572 (for USA).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 


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drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, or destruction on site according to local site procedure, the 
investigator or designee 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
Background treatment for dose escalation (Phase Ia) and dose expansion 
(Phase Ib) 
The following required background treatment, considered as AxMP are commercially 
available and locally supplied by sites according to local regulations. Documentation of 
administered background treatment must be noted in the patient’s source and the CRF.
4.2.1.1
FOLFIRI regimen and Liposomal Irinotecan plus 5-FU/Leucovorin (PDAC only)
FOLFIRI in combination with bevacizumab will be administered to the CRC patients in 
Phase Ia and Phase Ib, FOLFIRI (or Liposomal Irinotecan plus 5-FU/Leucovorin) to PDAC 
patients in the expansion phase (Phase Ib), in accordance with NCCN Guidelines as described 
below (R21-2007, R21-2008):
FOLFIRI regimen to be administered on Day 1 of each 14-day treatment cycle:
∀
Irinotecan:180 mg/m2 IV over 1.5 hours on Day 1 of each 14-day cycle.
∀
Leucovorin: 400 mg/m2 IV (in Japan, Levoleucovorin: 200 mg/m2) over 2 hours on 
Day 1 of each 14-day cycle.
∀
Fluorouracil: 400 mg/m2 IV bolus on Day 1 of each 14-day cycle.
∀
Fluorouracil: 2400 mg/m2 IV 46 hours continuous infusion starting on Day 1 of each 
14-day cycle. 
Liposomal Irinotecan plus 5-FU/Leucovorin (PDAC only) regimen to be administered on 
Day 1 of each 14-day treatment cycle:
∀
Liposomal Irinotecan: 70 mg/m2 IV over 1.5 hours on Day 1 of each 14-day cycle.
∀
Leucovorin: 400 mg/m2 IV (in Japan, Levoleucovorin: 200 mg/m2) over 2 hours on 
Day 1 of each 14-day cycle.
∀
Fluorouracil: 2400 mg/m2 IV 46 hours continuous infusion starting on Day 1 of each 
14-day cycle. 


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4.2.1.2
Bevacizumab
Bevacizumab will be administered to CRC patients in Phase Ia and Phase Ib at 5 mg/kg IV 
over 30 minutes on day 1 before start of chemotherapy and repeated every 14 days, in 
combination with FOLFIRI regimen, in accordance with NCCN guidelines (R21-2007).
4.2.2
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Rescue medications to reverse the actions of BI 905711 or FOLFIRI (or Liposomal 
Irinotecan plus 5-FU/Leucovorin) and bevacizumab are not available. Potential adverse 
events should be treated symptomatically with concomitant medications to provide adequate 
supportive care as clinically necessary. Section 4.2.4 provides guidance for management of 
adverse events.
Radiotherapy for local symptom control of non-target lesions may be allowed if agreed 
between the investigator and Sponsor.
4.2.2.1
Premedication
No routine premedication will be required for BI 905711 i.v. infusions. 
See Section 4.2.4.1 for pre-medication requirements for all subsequent treatment infusions of 
BI 905711 after symptoms of an IRR ≥ grade 2 occur.
Pre-medication for background therapy must be given in accordance with the local approved 
label, which includes but not limited to;
∀
Anti-emetics prior to irinotecan infusion
4.2.3
Restrictions
4.2.3.1
Restrictions regarding concomitant treatment
Anti-cancer treatment
No experimental or approved anti-cancer treatment including chemotherapy, targeted 
therapy, immunotherapy, hormone therapy (except as stated below), or radiotherapy is 
allowed throughout the study treatment period. Radiotherapy for local symptom control of 
non-target lesions may be allowed if agreed between the investigator and Sponsor.
Gonadotropin-releasing hormone or luteinizing hormone releasing hormone analogs for 
patients with prostate cancer or breast cancer can be continued but should not be initiated 
during trial.
Anticoagulants


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Therapy with factor Xa inhibitors, direct thrombin inhibitors, and warfarin is allowed. 
Patients receiving warfarin must have their INR values closely monitored according to 
institutional guidelines.
The use of heparin (including flushing and locking of intravenous catheters) or LMWH is 
permitted during study treatment. However, the following restrictions must be applied: 
∀
BI 905711 and heparin should not be mixed or infused through the same IV line
∀
If the same IV line has to be used, flush thoroughly with 0.9% saline prior to and 
following BI 905711 infusion.
If a catheter will be locked with heparin, this must be flushed thoroughly with 0.9% saline 
prior to and following BI 905711 infusion.
Hematopoietic growth factors
Hematopoietic growth factor agents are not allowed for use as primary prevention during the 
first two 14-day cycles. Thereafter hematopoietic growth factor agents may be used 
according to institutional standard.
Erythropoietic therapy is allowed when used in accordance with the American Society of 
Clinical Oncology/American Society of Hematology or the National Comprehensive Cancer 
Network (NCCN) guidelines. In Japan, erythropoietic therapy is not approved for anemia 
caused by cancer chemotherapies.
COVID-19 Vaccination and other preventive measures
The decision on COVID-19 vaccination of a BI study patient must be taken based on an 
individual Benefit-Risk Assessment by the investigator after thorough discussion with the 
patient. This assessment should consider the approved labels of the respective vaccines as 
well as the provisions given in the protocol, including the time point when the vaccination 
should be given or a potential delay of the vaccination or of the study treatment.
The package insert for approved COVID-19 vaccinations should be carefully reviewed for 
local guidance considering acute moderate/severe febrile illness, and the risk of an 
anaphylactic reaction to the vaccine. Furthermore, the diminished response to the vaccine 
needs to be considered for immunocompromised conditions which may be observed in BI 
905711 treated patients.
It is important to encourage to continue taking precautions such as wearing a mask, 
maintaining social distancing and washing hands frequently, even after a patient receives a 
COVID-19 vaccine. These precautions will be necessary until public health experts advise 
otherwise.
4.2.3.2
Restrictions on diet and lifestyle
There are no restrictions regarding diet and lifestyle.


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4.2.3.3
Contraception requirements
WOCBP (for the definition please refer to section 3.3.3) and men able to father a child must 
use two medically approved methods of birth control throughout the trial, and for a period of 
at least 6 months after last trial drug intake, one barrier method, and one highly effective non-
barrier method.
Men (trial participant or partner of a trial participant) must be vasectomised with documented 
absence of sperm or use a condom if their sexual partner is a WOCBP.
WOCBP (trial participant or partner of a trial participant) must use a highly effective method 
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly if their sexual partner is a man able to father a child.
∀
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral [approved in Japan], intravaginal [unapproved in Japan], transdermal 
[unapproved in Japan]).
∀
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable) [unapproved in Japan].
∀
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
∀
Bilateral tubal occlusion
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
Breast feeding should be interrupted from the start of study treatment through 6 month after 
the last study treatment
4.2.4
Dose modification and management of adverse events
4.2.4.1
Management of infusion-related reactions
Infusion-related reactions (IRR) involve the immune system; however, they can have 
different mechanisms. Some are allergic in nature and are usually mediated by 
immunoglobulin E while others are not classical allergic reactions (so-called anaphylactoid 
reactions e.g. caused by cytokine release). Although infusional reactions can be allergic or 
nonallergic, clinical symptoms are difficult to distinguish and require rapid assessment and 
immediate management to avoid severe adverse events, including fatality.
If an infusion-related reaction of ≥ CTCAE Grade 3 occurs, trial treatment must be 
permanently discontinued.


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If symptoms of an infusion-related reaction of CTCAE Grade 2 occur, which do not qualify 
as DLT according to Section 5.2.7 the infusion should be temporarily stopped. Institute 
medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for 
infusion reactions as needed. Upon recovery, the following guidance must be followed.
∀
If at least 50% of the planned dose of BI 905711 was administered, no further BI 
905711 will be administered until the next scheduled dose.
∀
If less than 50% of the planned dose of BI 905711 was administered due to an 
infusion-related reaction, 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. Administration may occur within up to 2 days after the original planned 
dose (Subsequent treatments, FOLFIRI+bevacizumab + BI905711 or FOLFIRI (or 
Liposomal Irinotecan plus 5-FU/Leucovorin) + BI 905711 should be also delayed 
so that the interval between BI 905711 is 14 days). Refer to Appendix 10.2 for 
details regarding PK collection. Remaining solution from the original dose must 
be discarded, and a new kit must be dispensed to prepare the dose of 50% of the 
intended total dose. 
∀
During the first re-exposure, patients must remain under observation for at least 6
hours post start of infusion. If required, patients may be hospitalised for a longer 
observation period at the investigator’s discretion.
∀
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. Total storage time for ready-to-use solution at room temperature should 
not exceed 150 minutes between preparation and end of infusion time. See section 
4.1.5
If infusion reactions and/or hypersensitivity reactions occur in a substantial proportion of
treated patients without premedication, the DRC may decide that all future patients treated in 
the trial must receive premedication (as described above) prior to BI 905711 infusion; the 
dosage and schedule of premedication will be aligned and will take into account any local 
clinical standards. Such a decision will be communicated to all investigators in writing.
Premedications should be recorded in the eCRF.
For bevacizumab refer to table 4.1.5.3.3 for guidance in case of infusion reactions and/or 
hypersensitivity reactions.
For irinotecan, liposomal irinotecan and 5-FU refer to local approved label for guidance in 
case of infusion reactions and/or hypersensitivity reactions.


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4.2.4.2
Management of CRS, other IRRs and events with similar signs/symptoms
CRS is a supra-physiologic response following any therapy that results in the activation or 
engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms 
can be progressive, include fever at the onset, and may include hypotension, hypoxia, 
capillary leak syndrome and end organ dysfunction. Other signs/symptoms of CRS can be 
e.g. tachypnea, headache, tachycardia, rash, nausea, vomiting, increased transaminases, and 
increased bilirubin. CRS can be serious or life threatening.
CRS signs/symptoms may occur quickly during or after administration, or after several hours 
or days. Occurrence of such signs/symptoms temporally related to administration of trial 
medication, requires immediate management and rapid diagnosis to avoid severe 
complications.
The manifestations of CRS overlap with those of other types of IRRs, infection, capillary leak 
syndrome and haemophagocytic lymphohistiocytosis/macrophage activation syndrome 
(HLH/MAS). IRRs can be allergic or non-allergic (due to release of histamine or cytokines, 
respectively). Mixed type reactions may occur. CRS, other IRRs and events with similar 
signs/symptoms are difficult to distinguish.
Patients must remain under observation for potential signs and symptoms of CRS (e.g. 
hypotension, rash, tachypnea, hypoxia, tachycardia, fever, nausea, fatigue, headache, 
myalgias and malaise) for at least 6 hours following the end of infusion of BI 905711. If no 
signs or symptoms of CRS are observed during the first 3 administrations, the duration of 
observation may be reduced to 4 hours for subsequent administrations. After 6 
administrations, in the absence of potential signs and symptoms of CRS, the observation 
period can be reduced to 2 hours at investigator’s discretion. During all post infusion 
observation periods, body temperature, pulse rate and blood pressure must be monitored as 
described in section 4.1.5.
In case of CRS, other IRRs or events with similar signs/symptoms, appropriate measures 
depending on the type and severity of the reaction should be taken by the investigator 
according to international standards (R19-0311, R20-2020), best medical judgement, and 
local guidelines. Supportive therapy including antipyretics, intravenous fluids, and low dose 
vasopressors may be used. In patients who do not respond to these treatments, 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 4.2.4.1).
Appropriate drugs and medical equipment to treat CRS, other IRRs and events with similar 
signs/symptoms must be immediately available, and trial personnel must be trained to 
recognise and treat such events. The trial site must have immediate access to emergency 
resuscitation teams and equipment in addition to the ability to admit patients to an intensive 
care unit, if necessary. 


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4.2.4.3
Management of diarrhea, nausea and vomiting
The occurrence, severity and duration of diarrhea, vomiting and nausea, and the outcomes of 
these events will be documented in detail in the eCRF. Further tests and examinations e.g. 
colonoscopy, gastroscopy should be performed according to the severity of the symptoms in 
order to document and obtain more information about the extent of possible injury due to BI 
905711. If severe injury to GI tissues is excluded, these events could be managed 
symptomatically according to Tables 4.2.4.3: 1 and 4.2.4.3: 2.
Table 4.2.4.3: 1
Management of diarrhea
CTCAE Grade
Action for anti-diarrheal treatment
Grade 1
Anti-diarrheal treatment according to the local standard e.g. 
loperamide p.r.n. and hydration
Grade 2 > 7 days despite 
optimal medical management
Anti-diarrheal treatment according to the local standard e.g. 
loperamide p.r.n, and hydration
Grade ≥3
Anti-diarrheal treatment according to the local standard e.g. 
loperamide p.r.n, and hydration
Table 4.2.4.3: 2
Management of nausea and vomiting
CTCAE Grade
Anti-emetic treatment
Nausea Grade 1
Anti-emetic treatment may be considered according to the local 
standard e.g. metoclopramide p.r.n.
Nausea Grade 2 and/or 
vomiting Grade 1
Start anti-emetic treatment according to local standard of care e.g. 
metoclopramide or 5-HT3 receptor antagonist.
If ineffective, patients should be treated according to treatment of 
vomiting >2 or nausea CTCAE Grade ≥ 3 as shown below.
Vomiting Grade ≥2 and/or 
nausea Grade ≥ 3
Anti-emetic treatment according to local standard of care e.g.: 
with 5-HT3 receptor antagonist and/or corticosteroid
4.2.4.4
Tumor lysis syndrome
All patients have to be assessed for clinical or laboratory suspicion of tumor lysis syndrome. 
To prevent tumor lysis syndrome, patients should remain appropriately hydrated throughout 
the administration period. For details of laboratory assessment, refer to Section 5.2.3. In case 
tumor lysis syndrome (TLS) is observed, patients should be managed according to local or 
available guidelines (R10-4517).


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4.2.4.5
Neurological adverse events
Toxicology studies in cynomolgus monkeys showed that BI 905711 at high doses induced 
minimal to mild monocytic/eosinophilic cells infiltrates in CNS (c16856466). Clinical 
significance of these findings for humans is currently unknown. Human exposure to the 
highest planned dose of 4.8 mg/kg is estimated to be 3 to 4-fold below exposure in monkeys 
at the 30 mg/kg. As CDH17 is not expressed in brain tissue, BI905711 is not expected to 
induce neurological adverse events. No neurological AE related to BI905711 or background 
therapy have been observed so far. Patients shall be monitored for possible neurological 
toxicity. Patients who develop worsening or new neurological signs/symptoms CTCAE 
grade ≥ 2 should undergo full neurological investigation including a brain MRI. Treatment 
with BI 905711 must be interrupted or permanently discontinued unless alternative etiology 
is documented e.g. new metastases in the CNS, metabolic disturbances, sepsis, infection, 
hypoxia, tumor lysis syndrome, trauma, adverse effect of concomitant medications. 
Additional workup may be performed if clinically indicated e.g. lumbar puncture.
4.2.4.6
Renal adverse events
Toxicology studies in cynomolgus monkeys showed that BI 905711 at high doses induced 
minimal to mild glomerulopathy with no proteinuria or increase of serum creatinine and urea 
(c16856466). Clinical significance of these findings for humans is currently unknown. 
Patients will be followed periodically for kidney function by measurement of serum 
creatinine and a qualitative urine protein. 
Patients with a 2+ or greater protein reading on a urine dipstick should be followed by a 24 
hour urine collection for a quantitative protein.
Patients with proteinuria ≥ CTCAE grade 3 (>3.5 g/24 hours) should interrupt BI 905711. 
Continuation of treatment with BI 905711 at a reduced dose may be considered if proteinuria 
recovers to ≤ grade 1 within 3 weeks.
Patients receiving bevacizumab should suspend administration for urine protein levels ≥2
g/24 hours and resume when proteinuria is <2 gm/24 hours. Bevacizumab must be 
permanently discontinued in patients with nephrotic syndrome.
4.3
TREATMENT COMPLIANCE
BI 905711 and background therapy will be administered as an intravenous infusion at the 
clinical site under the supervision of trained site personnel. Therefore, actual dosing is 
expected to follow the protocol. The doses administered will be recorded in the eCRF and 
any irregularities in dosing will also be documented in the eCRF by the investigator or 
designee.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Tumor response and progression will be evaluated by investigator review in this study 
according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline (Version 1.1) 
(R09-0262).
Tumor assessment will be performed per institutional practice. Only the overall response and 
disease progression will be collected in the eCRF. 
Tumor assessments should include computed tomography (CT) scans or MRI of chest, 
abdomen, and pelvis. If clinically indicated, imaging of any other known or suspected sites of 
disease (e.g. brain, bone) should be performed. 
5.2
ASSESSMENT OF SAFETY
Safety will mainly be evaluated by severity and incidence of AEs, graded according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 (R18-1357). Criteria for DLT are described in Section 5.2.7.
5.2.1
Physical examination
A complete physical examination will be performed as per institutional practice. It includes at 
a minimum general appearance, neck, lungs, cardiovascular system, abdomen, extremities, 
and skin.
Measurement of height (cm) and body weight (kg) and the evaluation of ECOG performance 
score will be performed at the time points specified in the flowchart.
The results must be included in the source documents available at the site. 
5.2.1.1
Body Weight
Body weight measurements should be done on the same scale for each patient. In order to get 
comparable body weight values, body weight measurements should be performed per the 
following:
•
shoes and coat/jackets should be taken off
•
pockets should be emptied of heavy objects (i.e. keys, coins etc)
5.2.2
Vital signs
Vital signs will be evaluated as per institutional practice, prior to blood sampling.
This includes systolic and diastolic blood pressure, body temperature and pulse rate 
(electronically or by palpation count for 1 minute) in a seated position after 2 minutes of rest. 
The results must be included in the source documents available at the site.


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5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1 and will be performed 
by a local laboratory as per institutional practice
The site will file the respective reference ranges in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
It is the responsibility of the investigator to evaluate the laboratory reports. Clinically relevant 
abnormal findings as judged by the investigator will be reported as adverse events (please 
refer to section 5.2.6).
In case a treatment course is delayed due to an adverse event, the patient should visit the site 
at least once a week for assessment of safety laboratory and adverse events. More frequent 
visits may be appropriate as assessed by the investigator.
Additional parameters may be measured if they are part of the standard panel of the 
institution laboratory. The sponsor and investigator may discuss and agree that individual 
parameters will not be measured if they are not part of the standard panel of the institution 
laboratory. The investigator should complete additional evaluations of laboratory tests as 
clinically indicated. Any abnormal and clinically relevant finding from these investigations 
will be reported as an Adverse Event.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the eDC system
and ISF. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
Table 5.2.3: 1 
Safety laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit, Haemoglobin, Red blood cell (RBC) count, White blood cell
(WBC) count including differential (absolute)
RBC indices, Reticulocytes, Platelet count
Coagulation
Activated partial thromboplastin time (aPTT),
Prothrombin Time (PT) or if applicable, International Normalises Ratio (INR)
Biochemistry
Glucose, Blood urea nitrogen (BUN), Creatinine, Inorganic Phosphate,
Sodium, Potassium, Calcium, Total Protein, Albumin, Uric Acid, Lipase, 
Amylase, Total Bilirubin (indirect and direct in case of elevated total or if 
required per local guidelines)
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline 
phosphatase (AP), Lactate dehydrogenase (LDH)
Note: Creatinine can be assessed by any of these methods: 
∀
CREE (enzymatic serum creatinine assay), 
∀
CREJIDMS (IDMS standardized Jaffe), or 
∀
CREJ (non-IDMS standardized Jaffe).


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Table 5.2.3: 1
Safety laboratory tests (cont)
Functional lab group
Test name 
Pregnancy testing
A Human Chorionic Gonadotropin urine pregnancy test needs to be obtained 
at the time points indicated in the Flowchart in patients of childbearing 
potential. A serum pregnancy test should be performed at screening if urine 
test is positive.
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be analyzed by 
routine analysis and reported as semiquantitative measurements. In case of 
pathological findings, further evaluation should be performed and results 
documented.2
Infectious disease1
Hepatitis B: Hepatitis B surface (HBs) antigen (qualitative), HBcAb
(qualitative), HBV-DNA (quantitative)
Hepatitis C: HCV-RNA. (qualitative) 
Results for hepatitis virus infection obtained in routine diagnostics are 
acceptable if done within 14 days before the informed consent date.
1.
At Screening visit, patients are to be tested for hepatitis B and C virus infection. See Section 3.3.3 for hepatitis 
exclusion criteria. 
2.
In case of a 2+ or greater urine protein by urine dipstick is found, a 24-hours urine should be collected for a 
quantitative protein
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name
Infectious disease
∀
Positive Hepatitis B surface (HBs) antigen
∀
Positive HBc antibody together (qualitative) with HBV-DNA (quantitative)
∀
Positive Hepatitis C (HCV-RNA)- qualitative
Hepatic, renal and bone 
marrow functions
∀
Total bilirubin >1.5 x ULN. 
∀
Alanine transaminase (ALT) and Aspartate transaminase (AST) > 2.5 x 
ULN or > 5 x ULN for patients with known liver metastases. 
∀
Serum 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).
∀
Absolute neutrophil count (ANC) < 1.5 x 109/L, < 1.5 x 103/μL, or <
1500/mm3
∀
Platelets < 100 x 109/ L, < 100 x 103/μL, or < 100 x 103/mm3
∀
Hemoglobin (Hb) < 8.5 g/dl, < 85 g/L, or < 5.3 mmol/L (without 
transfusion within previous week)
∀
Serum lipase > 1.5 ULN
5.2.4
Electrocardiogram
The 12-lead ECGs will be performed per institutional pracctice. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and assess clinical relevance. 
ECGs may be repeated for quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.


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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
Not Applicable
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀
Worsening of the underlying disease if certain conditions are met – refer to section 
5.2.6.2.4
∀
Worsening of pre-existing conditions other than the underlying disease.
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 


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above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: An event that possibly leads to disability will be handled as ‘deemed serious 
for any other reason’ and, therefore, reported as an SAE.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
Every occurrence of cancer of new histology must be classified as a serious event regardless 
of the time since the discontinuation of the trial medication and must be reported as described 
in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Potential Severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the 
following alterations of hepatic laboratory parameters: 
For patients with normal ALT and AST levels at baseline:
∀
An elevation of AST (Aspartate Aminotransferase) and / or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood sample, or in samples drawn within 30 days of each 
other, or
∀
ALT and / or AST elevations ≥10-fold ULN.
For patients with abnormal aminotransaminase levels between >1 and <3 x ULN at 
baseline:
∀
An elevation of AST and / or ALT ≥3-fold the baseline value combined with an 
elevation of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is 


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elevated at baseline), measured in the same blood sample, or in samples drawn within 
30 days of each other; or;
∀
Aminotransferase elevations ≥5-fold the baseline value.
For patients with abnormal aminotransaminase levels between ≥3 x ULN and <5 x ULN 
at baseline:
∀
An elevation of AST and / or ALT ≥2-fold the baseline value combined with an 
elevation of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is 
elevated at baseline); measured in the same blood sample or in samples drawn within 
30 days of each other; or;
∀
Aminotransferase elevations ≥3-fold the baseline value.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary, in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
For further details see figure 5.2.6.1.4: 1 below.
Figure 5.2.6.1.4: 1
Potential severe DILI reporting


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Dose Limiting Toxicity
Any medical event fulfilling the criteria of DLT (see Section 5.2.7) should be reported as an 
AESI.
Infusion-related reactions
The following AEs, when occurring with a temporal relationship to the infusion, are 
considered as potential infusion-related reactions and should be reported as AESIs, regardless 
of their CTCAE grade:
•
Infusion-related reaction (synonyms: infusion reactions, infusion-like reactions)
•
Allergic reaction
•
Anaphylaxis
•
Cytokine-release syndrome
•
Any other event which the investigator considers as a potential infusion-related 
reaction.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of AEs should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
(R18-1357).
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the trial drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 


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of drug administration; an allergic reaction weeks after discontinuation of the trial 
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.
∀
There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned.
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s EoR visit (FUP 
#1)): all AEs (non-serious and serious) and all AESIs.
•
After the individual patient’s EoR visit until the individual patient’s end of trial:
cancers of new histology and exacerbations of existing cancer, all trial drug related SAEs 
and all trial drug related AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only
report any occurrence of cancer of new histology and trial drug related SAEs and trial 
drug related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
Section 5.2.6.2.2), but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see Section 5.2.6.2.4.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 
hours of becoming aware of the event, the country specific process will be specified in the 
ISF. The same timeline applies if follow-up information becomes available. In specific 
occasions, the investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 


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be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires 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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and / or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE 
form is to be completed. If there is an SAE and / or AESI associated with the pregnancy an 
SAE form must be completed in addition.
5.2.6.2.4
Exemptions to AE reporting
Collection and reporting of PD
The outcome progressive disease (PD) is used to assess trial endpoints for the analysis of 
efficacy. It will be recorded on the appropriate page of the eCRF. 
If the disease progression does not meet standard seriousness criteria (see section 5.2.6.1.2), 
then it is exempt from AE reporting, and will only be recorded on the appropriate page of the 
eCRF. 
For example, asymptomatic disease progression detected on a routine scan would be exempt 
from AE reporting, even if disease progression is on the “always serious” list. 
However if there is evidence suggesting a causal relationship between the investigational 
drug(s) and the progression of the underlying malignancy, the event must be recorded as an 
SAE on the AE page in the eCRF and reported as an SAE on the SAE Form.
If disease progression meets the standard seriousness criteria (see section 5.2.6.1.2) it will be 
recorded on the AE page in the eCRF and on the SAE form and SAE reporting process will 
be followed.
Lab values meeting the potential severe DILI definition in section 5.2.6.1.4 must always be 
reported as AESI, even if the most likely cause is disease progression. No exemption to AE 
reporting applies.


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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 
seriousness criteria, they will additionally be reported as SAEs on the SAE form and SAE 
reporting procedures will be followed. If signs and symptoms are attributable to a diagnosis, 
reporting the diagnostic term is preferable e.g. pulmonary embolism rather than dyspnoea, 
intestinal obstruction rather than abdominal pain.
Exempted events are reviewed at appropriate intervals by the Sponsor and the DRC.
5.2.7
Dose limiting toxicities
Any of the following AEs will be classified as DLTs, unless unequivocally due to underlying 
malignancy or an extraneous cause:
Table 5.2.7: 1
Dose limiting toxicities
Category
Criteria and CTC AE Grade defining a DLT
Treatment delay*
∀
Any toxicity that result in a treatment delay >14 days
Hematologic 
laboratory*
∀
Grade 4 neutropenia lasting ˃7 days.
∀
Grade ≥ 3 neutropenia with documented infection.
∀
Grade ≥ 3 febrile neutropenia defined as ANC <1000/mm3 (< 1.0 x109//L, < 
1.0 x103 /μL) and a single temperature of ≥ 38.3 degrees C (101 degrees F) or a 
sustained temperature of ≥ 38 degrees C (100.4 degrees F) for more than one 
hour; or where there are life-threatening consequences or urgent intervention 
indicated.
∀
Grade 3 thrombocytopenia <50,000/m3 ( < 50 x10 9 /L, < 50 x103/ μL) 
associated with bleeding excluding grade 1 epistaxis.
∀
Grade 4 thrombocytopenia (platelet count <25,000/m3 ( < 25 x 109 /L, < 25 x 
103 / μL) .
∀
Thrombocytopenia or anemia requiring transfusion per local or international 
guidelines.
∀
Neutropenia that requires administration of hematopoietic growth factor agents 
per local or international guidelines.
Non-hematologic 
laboratory*
∀
Any Grade 3 or Grade 4 non-hematologic laboratory value if:
-
Medical intervention is required to treat the patient, or
-
The abnormality is a serious adverse event, or
-
The abnormality persists >1 week, and considered significant enough to 
be qualified as DLT in the investigator’s opinion, and confirmed by the 
DRC.
∀
An elevated AST or ALT value ≥ 3 x the upper limit of normal (ULN) and an 
elevated total bilirubin value ≥ 2 x ULN measured in the same blood draw 
sample and, at the same time, an alkaline phosphatase value < 2 x ULN, as 
determined by way of protocol-specified lab testing or unscheduled lab testing.
∀
An elevated AST or ALT value ≥ 5 x ULN and an elevated total bilirubin value 
≥ 2 x ULN measured in the same blood draw sample, with the exclusion of 
causes due to underlying diseases (for patients with elevated liver enzymes at 
baseline).
*Except if the event is considered due to background therapy only.


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Table 5.2.7: 1 Dose limiting toxicities (cont)
Category
Criteria and CTC AE Grade defining a DLT
∀
Any Grade 4 non laboratory toxicity possibly related to study therapy, 
irrespective of whether patient received maximal supportive therapy.
∀
Any Grade 3 non laboratory toxicities despite the use of adequate/maximal 
medical interventions and/or prophylaxis as dictated by local institutional 
clinical practices or the judgment of the investigator, except for:
-
Fatigue/ asthenia present at baseline that worsens on study and lasts 
less than 7 days. 
-
New onset of Grade 3 nausea or Grade 3 vomiting lasting ≤ 48 hours, 
and which resolved to ≤Grade 1 either spontaneously or with 
conventional medical intervention. 
-
Nausea or vomiting present at baseline that worsens on-study, and 
resolves with treatment within 24 hours.
-
Grade 3 diarrhea not requiring hospitalization, lasting ≤ 48 hours, and 
which resolved to ≤ Grade 1 either spontaneously or with conventional 
medical intervention.
∀
Any other toxicity considered significant enough to be qualified as DLT in the 
opinion of the investigator, and confirmed by the DRC, will be reported as a 
DLT.
∀
Any toxicity Grade ≥ 2 leading to dose reduction will be considered as a DLT.
∀
Any death not clearly due to the underlying disease or extraneous causes.
Dose-limiting toxicities (DLTs) will be recorded throughout the trial. Any DLT must be 
reported to the Sponsor’s Pharmacovigilance Department by the Investigator or designee 
within 24 hours of first knowledge regardless of the relationship to the study drug. All DLTs 
will be agreed upon by the DRC after review of the data from each cohort. Only DLTs 
occurring in the first two cycles are necessary for dose-escalation decisions made by the 
DRC. DLTs observed during the MTD evaluation period will be considered for MTD 
determination. However, all AEs and SAEs meeting criteria of DLT observed in all treatment 
cycles will be considered for determining a RP2D.
Replacement of patients for DLT evaluation during MTD evaluation period
For the definition of DLT, it is essential that patients are sufficiently treated according to
supportive care standards described in Section 4.1.5.1. Patients with treatable AEs (eg. 
nausea, vomiting, and diarrhea) that are not sufficiently treated do not qualify for DLT and 
need to be replaced, if this occurs in the first two Cycles. Dose escalation will be determined 
based on all safety information of all treated patients including those who do not complete the 
first two cycles for reasons other than a DLT. Criteria for replacement of patients during the 
MTD evaluation period is described in Section 3.3.4.1.1.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
The evaluation of BI 905711 concentrations will be performed according to BI standards and 
processes.
Pharmacokinetic (PK) profiles of BI 905711 will be investigated after the first and after
repeated doses. Standard PK parameters as listed in Appendix 10.1 will be calculated, if data 
allows and if scientifically reasonable. Noncompartmental PK parameters will be calculated 
based on actual sampling times using a validated PK software (Phoenix® WinNonlin® 6.3). 
Individual concentration data and the PK parameters calculated thereof will be tabulated and 
graphically displayed. Statistical analyses will be performed as described in Section 7.3. A 
patient’s PK data will be flagged and excluded from the statistical analyses in case of 
protocol deviations relevant to the evaluation of PK (to be decided no later than in the 
Blinded Report Planning Meeting) or in case of PK non-evaluability (as revealed during data 
analysis, based on internal procedures). Reasons for exclusion of a patient’s data will be 
documented in the Clinical Trial Report (CTR). PK data may be additionally analyzed using 
a population PK approach. If required, modelling activities will be planned and documented 
separately according to internal and external guidelines and SOPs.
Preliminary PK and Immunogenicity analyses can be performed as necessary e.g. as 
additional information for the DRC. In contrast to the final PK and Immunogenicity analysis, 
the preliminary analyses will be based on planned sampling times rather than on actual times; 
no supplementary patient information, e.g. on AEs or concomitant medication, will be used in 
these analyses, and the outputs will not be validated. Minor numerical discrepancies between 
preliminary and final results may therefore occur.
The presence of ADA to BI 905711 will be assessed at pre-dose and regularly during 
treatment according to the sampling scheme in Appendix 10.2
5.3.2
Methods of sample collection
Effective from CTP v4.0, PK and ADA/Nab samples are no longer collected for ongoing 
patients.
Details of the sample collection, preparation, storage and shipment are described in the 
ISF/laboratory manual.
The timepoints for collection of PK and ADA/Nab samples are given in Appendix 10.2.
Date and clock time of drug administration(s) and PK sampling will be recorded in the CRFs.
Exact time points of plasma sampling will be documented in the CRFs or sent as electronic 
files to the Trial Data Manager.
The samples may be used for further methodological investigations, (e.g. stability testing for 
PK, or to further characterise ADA/Nabs response or to address Health authority questions 


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regarding the results/methodology) however, only data related to the analyte and ADAs/Nabs
will be generated by these additional investigations. 
After analysis of PK samples, leftover samples may be used to explore the effect of high 
mannose glycoforms on the PK of BI 905711. It is not intended to include the results from 
such analysis in the clinical trial report. The results may be provided in a stand-alone report.
The study samples will be discarded after completion of additional investigations including 
high mannose assessment but not later than 5 years after the final study report has been 
signed.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No formal analysis of a pharmacokinetic/pharmacodynamic relationship is planned.
Exploratory PK/PD relationship may be investigated depending on the suitability of the data.
In addition, exploratory correlation may also be made between drug concentration
and AEs. If required, modeling activities will be planned and documented separately
according to internal and external guidelines and SOP.
5.4
ASSESSMENT OF BIOMARKER(S)
Effective from CTP v4.0, biomarker samples, tumor biopsies samples and [18F]FDG-PET are 
no longer collected for ongoing patients.
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in Sections 5.1 and 5.2.
The study of biomarkers will be mostly exploratory hypothesis-generating and will be used to 
expand our understanding of the disease and trial drug. The following biomarkers are planned 
to be examined in this trial (for detailed sampling times, refer to Appendix 10.2 and
Flowchart):
∀
Determination of CDH17 expression (see Section 5.4.2.1).
∀
Determination of cell death biomarkers in plasma and tumor tissue, including but not
limited to: activated caspase 3/7, at screening, baseline and on treatment as an indicator 
for apoptosis induction in the body (see Section 5.4.2.2).
∀
Quantification of cell-free tumor DNA levels in patients plasma at baseline and after
treatment as an indicator for apoptotic tumor cells and tumor burden (see Section 5.4.2.3).
∀
Measurement of gene expression in tumor biopsies taken at baseline and on treatment
addressing a potential correlation with treatment response (see Section 5.4.2.5).


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∀
Determination of correlation of cancer-related mutations/biomarkers with clinical signals 
and/or PD biomarker modulation and/or mRNA gene expression via Next Generation 
Sequencing (NGS). (see Section 5.4.2.5)
∀
Determination of change in tumor cell glucose uptake by [18F]FDG-PET as surrogate to 
assess tumor cell apoptosis induced by the study drug (see Section 5.4.2.6)
As medical knowledge in this field is constantly evolving, other tissue/blood biomarkers that
may become relevant e.g. as predictive markers of treatment response may also be explored
via available tissues/blood. The list of biomarkers planned to be studied during the trial may
change based on assay validity, new information in the literature or insights from early
analyses.
The biomarker analyses will be performed by Boehringer Ingelheim or laboratories 
authorized by Boehringer Ingelheim.
Data obtained from the biomarker analysis will not be disclosed to patients because the
analysis is exploratory. If consent is withdrawn, all data that had already been collected up to 
the time of withdrawal of consent will still be used.
5.4.1
Drug interaction biomarkers
Please refer to Section 1.2
5.4.2
Pharmacodynamics and patient selection biomarkers
5.4.2.1
Determination of CDH17 protein/mRNA expression
CDH17 protein expression will be measured in an IHC assay using FFPE tumor material.
Where feasible samples will also be evaluated for CDH17 mRNA expression using 
appropriate technologies.
After eligibility has been confirmed, all CRC patients will be enrolled in the trial irrespective 
of CDH17 expression. Where feasible, the CDH17 expression data from all patients will be 
used for retrospective correlation with treatment response or clinical outcome in phase Ia and 
phase Ib and will help to determine a threshold for possible patients´ selection based on 
CDH17 expression.
For Non-CRC patients CDH17 expression will be used as part of the enrolment criteria in 
phase Ib. Only non CRC patients showing positive CDH17 expression will be entered in the 
trial. Where feasible, the CDH17 expression data will be used for retrospective correlation 
with treatment response or clinical outcome in order to refine the threshold of expression that 
could be used for patient selection. 
Due to science continually evolving, it may be necessary to perform additional biomarker 
assessments using tumor tissue material remaining after completion of assessments described 
in Section 5.4.2. Such assessments may include but are not limited to the measurement of 
proteins relevant to TRAILR2 engagement in the tumors.


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5.4.2.2
Determination of activated cell death biomarker levels in plasma
Caspase 3/7 activity in plasma will be measured at screening, baseline and on treatment. 
Possible other cell death biomarkers in plasma, including but not limited to e.g. caspase-
cleaved CK18 (M30) and/or total CK18 (M65) may also be measured.
5.4.2.3
Quantification of cell-free tumor DNA levels in plasma
Analysis of cell-free DNA (cfDNA), including ctDNA (circulating tumor DNA) provides a
non-invasive technique that may help early detection of tumor response. Quantification and
mutation analysis will be performed in cfDNA extracted from pre-treatment, on treatment 
and post-treatment plasma samples prepared from whole blood.
5.4.2.4
Immunohistochemical analysis of apoptosis induction and tumor cell 
proliferation in tumor tissue
Protein expression in tumor tissue collected pre and on treatment will be assessed by 
Immunohistochemistry in Phase Ib to indicate potential treatment effects on tumor cell 
apoptosis and proliferation. Protein markers to be analyzed include, but are not limited to, 
cleaved caspase 3 and Ki67. 
5.4.2.5
Assessment of gene expression and cancer-related gene mutation in tumor 
biopsies
Gene-expression analysis and assessment of cancer-related gene mutation will be performed 
in tumor biopsies. The purpose of this analysisis to study the biology of the tumors at 
baseline (prior to first treatment). If feasible data will be used for retrospective correlation 
with treatment response or clinical outcome in phase Ia and phase Ib. Furthermore, should on 
treatment samples be attained changes induced by the treatment intervention will be 
investigated via gene expression analysis.
Details on biopsy sample collection and shipment will be provided in the Laboratory Manual
and the ISF.
5.4.2.6
[18F]FDG-PET/CT
To evaluate tumor cell death and apoptosis induced by BI 905711, [18F]FDG-PET/CT is
intended to be used as a sensitive non-invasive PD marker measuring drug-induced changes 
in metabolic activity of the tumor. [18F]FDG-PET/CT will be performed in CRC patients in 
both phase Ia and phase Ib.
Two scans will be performed during the study; one during screening (baseline) and one on 
treatment (at the 8 week (± 7 days) tumor assessment timepoint). The PET scan may be 
performed together with CT scan if feasible. The PET scan at screening should preferably be 
performed no later than 14 days (±7 days) prior to first treatment.
[18F]FDG-PET/CT examination procedure


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To undergo a [18F]FDG-PET/CT examination, patients should fast before i.v. injection of
[18F]FDG. At the time point of [18F]FDG injection, plasma glucose level of the patient will be 
assessed. Immediately after [18F]FDG injection, patients must be advised to remain seated or 
to lie down and relax for approximately one hour before start of PET/CT scanning. Patients 
should be asked to void immediately prior to the PET/CT scan to reduce bladder activity.
Radiation dosimetry
The effective dose of [18F]FDG is 0.019 mSv/MBq (approximately 6-8 mSv per scan) (R18-
3386). The organ receiving the largest radiation dose is the bladder (0.13 mGy/MBq) (R18-
3386). National regulations must be complied with in regard to the administration of 
radioactive substances and the CT exposure for the purpose of this study.
Image analysis
Visual, semi-quantitative and quantitative image interpretation will be performed (SUV
parameters). Treatment response will be scored according to standard guidelines e.g. EORTC 
response criteria (R14-1470).
Further details regarding [18F]FDG-PET/CT imaging will be outlined in the Imaging Manual.
5.4.3
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Appendix 10.2 and Flow Chart.
5.4.3.1
Tumor Tissue collection
For fresh biopsies always use the equivalent of at least two core needle biopsies (18 gauge or 
greater). Tissue needs to be provided as formalin-fixed and paraffin-embedded tissue block.
Potential prioritization of the biomarker analyses might be made according to the available 
tissue amount. In case a tissue block cannot be collected as indicated, the site needs to contact 
the Sponsor for agreement regarding fresh biopsy collection.
Archival tumor tissue samples should be provided as FFPE. For samples collected during 
screening mounted tissue sections (at least 19 sections of 4-5 μm thickness), where feasible
under RNase free conditions, should be prepared and shipped. For all samples to be provided 
post-confirmation of eligibility an embedded FFPE block is preferable. Please refer to the 
Flow Chart for sampling timepoints.
Tumor tissue collection in Phase Ia
∀
Provision of an archived tumor tissue specimen is mandatory during screening for all 
patients. A fresh biopsy is only mandatory for those patients who do not have archival 
tissue.
Tumor Tissue collection in Phase Ib
∀
For all patients: Provision of archival tumor tissue or fresh biopsy is mandatory for 
all patients prior to treatment start on Day 1. Fresh biopsy sample should be provided 
if the archival tissue tested is greater than 6 months old from collection to start of 


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treatment on this study. Even if fresh biopsy conducted, provision of an archived 
tumor tissue is recommended. For Non-CRC patients, CDH17 expression 
measurement by archival tumor tissue or fresh biopsy sample must be completed prior 
to treatment start on Day 1.
∀
On-treatment biopsies should be taken on Cycle 2 Day 5, 48h after administration of 
BI 905711 (optional) and/or at disease progression (optional) for a patient in which a 
fresh biopsy has been successfully obtained before first study treatment.
Only non-significant risk procedures per the investigator’s judgment will be used to obtain 
any biopsies specified in this study.
In case a fresh pre-treatment tumor biopsy cannot be obtained, an archived tumor tissue 
specimen must be submitted (mandatory).
Timepoints for fresh tumor biopsy collection are detailed in the Flowchart.
Left over tumor samples will be biobanked (Section 5.5). For patients who do not consent to 
biobanking, remaining samples will be disposed of at the latest 5 years after the final trial 
report has been signed. Until then, samples will be stored at Boehringer Ingelheim or a 
designated CRO.
5.4.3.2
Plasma samples
Plasma for cell death biomarkers
Cell death biomarkers will be measured. (see Flowcharts and Appendix 10.2).
Collection of plasma for analysis of cell death biomarkers is mandatory.
cfDNA (including ctDNA)
Additional blood/plasma samples will be collected from all patients (see Flowchart and
Appendix 10.2). 
Collection of one blood sample (baseline only) and up to four plasma samples for analysis of 
cfDNA is mandatory.
All samples must be adequately labelled by the trial site personnel. Further details about
tumor tissue and blood sample collection, plasma preparation, required tubes, labelling of
tubes, storage and shipment (frequency and addresses) will be provided in the laboratory
manual and the ISF.
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements. China will not participate to this 
biobanking.


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The following biomarker samples specified in section 5.4, Assessment of Biomarkers, will be 
banked: pre-treatment and post-treatment biopsies, fixed in formalin and embedded in 
paraffin (From Phase Ia/Ib, and both archival/fresh).
5.6
OTHER ASSESSMENTS
5.6.1
Patient-reported outcomes
Patient-reported outcomes (PRO) are considered important to prescribers,
patients and health care decision-makers when evaluating the clinical utility of medical
intervention. The information collected using PRO instruments can lend supportive
arguments to the clinical activity or tolerability of a therapy and describe the extent to which 
patients’ physical, emotional and social well-being are affected by treatment. 
Patient-reported symptom data will be measured with the Patient Reported Outcomes version 
of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) (R18-2068)
Questionnaires will be completed at the time points specified in the Flow Chart. Paper
questionnaires should be completed at the site by patients prior to seeing the clinician,
prior to clinical assessment, prior to any treatment at the clinic, and before provision of
any new information about their disease status so that the responses are not influenced
(biased). The responses recorded on the questionnaires will not be recorded as adverse
events. Adverse events are collected during protocol specified study visits with the clinician.
The questionnaire generally takes about 10 minutes to complete. Patients will receive
the questionnaire in their native language in countries where validated translations
exist. The answered questionnaires will be entered into the CRF by the site personnel.
PRO-CTCAE
PRO-CTCAE is a patient-reported outcome measure developed to evaluate symptomatic
toxicity in patients in cancer clinical trials. It was designed to be used as a companion to
the CTCAE criteria, the standard lexicon for adverse event reporting in cancer trials. 
5.7
APPROPRIATENESS OF MEASUREMENTS
All methods used are standard. Determination of MTD is based on toxicities graded 
according to CTCAE version 5.0 (R18-1357). The CTCAE criteria are commonly used in the 
assessment of AEs in cancer patients. RECIST 1.1 (R09-0262) is used for evaluation of 
response. These criteria are well-established and scientifically accepted.
PRO-CTCAE has been developed and validated in accordance with FDA and EMA guidance 
for patient-reported outcome measures.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients must satisfy all inclusion and exclusion criteria prior to treatment administration (see
Section 3.3). Details of any patient who is screened for the study but is found ineligible must 
be entered in an enrolment log (see ISF) and documented in the eCRF. All patients are to 
adhere to the visit schedule as specified in the Flowchart. 
If a patient misses a visit during which there is no treatment administration planned, the visit 
should be rescheduled as soon as possible and the delayed visit documented with the actual 
date and the reason for the delay. The scheduling of subsequent visits must not be altered, so 
if it is not possible to reschedule prior to the next planned visit, the missed visit should be 
skipped.
If a patient is hospitalised for administrative reasons to allow treatment and PK sampling this 
will not be considered an SAE, unless any other criteria for an SAE are fulfilled.
In addition to the scheduled assessments, unscheduled visits and unscheduled assessments for 
safety reasons may be performed at any time according to clinical need.
In the event of force majeure or other disruptive circumstances (e.g. pandemic), sites should 
adhere to the required protocol procedures as close as possible, however the investigational 
plan as per this clinical trial protocol may not be feasible at a site. The patient may also be 
unable or unwilling to attend a clinic visit. The investigator must assess the risk-benefit for 
the individual patient and in agreement with the Sponsor may decide to implement alternative 
solutions (i.e. virtual patient visits and assessments) if this is in the best interest of the patient. 
Patient safety must be ensured when determining if a visit may be remote. The 
implementation of any alternative solutions will depend on patient’s consent, operational 
feasibility, local law and regulations. If alternative methodology is implemented, the 
deviations from the original plan will be precisely documented.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Refer to the Flow Charts and Section 5 for details on the procedures performed at each visit.
6.2.1
Screening period
Following informed consent, the patient will undergo screening assessments as indicated in 
the Flowchart.The assessments required during the screening period do not need to be 
conducted on the same day but must be conducted within a time interval of 28 days prior to 
the Cycle 1 Day1. 
Screening assessments may be repeated as long as they fall within the 28 day screening visit 
window. If more than one screening assessment is available, the latest assessment prior to the 
start of treatment must be used to assess eligibility. 


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Rescreening for non CRC patients will be allowed if CDH17 positivity is confirmed.
A patient who has been declared as a “screening failure” may be re-screened once.
In this situation patients will be handled as new patients i.e. sign a new informed consent, 
allocate a new patient number, and undergo full screening assessments to assess eligibility.
Tumor assessments performed prior to informed consent as part of routine clinical practice 
can be accepted if they meet the requirements of the protocol. For example, during the 
screening period, a tumor assessment does not need to be performed if there are valid results 
available from assessments which were performed within 28 days prior to start of treatment.
Demographics to be collected during the screening period
∀
During the screening visit, demographics information will be collected. This includes: 
age on the day of informed consent (in years).
∀
Sex (male, female in order to describe the subject`s sex at birth), 
∀
Gender identity (male, female, other in order to describe how the subject self-
identifies regardless of their genotypic or phenotypic sex)
∀
For women: of childbearing potential yes / no in order to characterize the patient 
population and as a basis for contraception requirements.
∀
Ethnicity and race in order to sufficiently characterize the patient population and to 
support possible subgroup analyses unless not acceptable according to local 
regulations.
Baseline Conditions
Baseline conditions and concomitant therapies present during screening will be recorded in
the eCRF.
Medical History:
A general medical history and a detailed oncological disease history will be collected.
The oncological history to be reported on the eCRF will include:
∀
Date of first histological diagnosis
∀
The primary tumor site
∀
Staging and grading information
∀
The number and location of metastatic sites
∀
Previous treatment for the tumor, including any surgery, radiotherapy, and/or 
systemic therapy including start and stop dates and outcome.
∀
Any known genomic alterations such as but not limited to BRAF, KRAS, HER2,
BRCA, and the immune markers status (i.e. microsatellite instability and/or DNA 
mismatch repair deficiency).
∀
The date of tumor progression after previous lines of treatment will be recorded if 
known, including start and end dates and outcome.
6.2.2
Treatment period(s)
If a patient is eligible for trial participation, the cycle 1 day 1 assessments will be performed 
as noted in the Flow Charts.


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Treatment cycles are 14 days in duration.
Subsequent visits and assessments during the treatment period are performed as described in 
the Flowchart. 
See Section 4.1.5.2 for criteria for receiving further treatment.
Patients may continue on treatment for unlimited cycles until criteria for stopping treatment 
are met (See Section 3.3.4.1).
PK, biomarkers, other speciality samples collected for reasons other than safety may be 
discontinued if the sponsor decides that sufficient information has been collected. 
6.2.3
Follow-up period and trial completion
The post treatment period will consist of an End of Treatment (EoT) visit, a 30-day safety 
follow-up visit (EoR) as well as follow-up visits for disease progression (PD) and overall 
survival (OS).
6.2.3.1
End of treatment (EoT) visit
The EoT visit will be performed as soon as possible but not later than 14 days after 
permanent discontinuation of trial medication for any reason or e.g. when the investigator 
decided with the patient to permanently discontinue the trial medication or became aware that 
the trial medication had been terminated. The EoT assessments will be performed instead of 
the next planned visit as noted in the Flow Charts.
6.2.3.2
End of Residual Effect Period (EoR)
The End of Residual Effect Period (EoR) visit (FUP #1) should occur no earlier than 30 days 
(+ ≤ 5 days) after the last dose of treatment in order to evaluate safety. Assessments will be 
performed as noted in the Flow Charts
6.2.3.3
Follow-up for progressive disease
The end of study is defined as EOR. No further follow-up visits after EOR are required, 
unless follow-up is for S(AE) that occurred before EOR period. 
If death date is known, this should be reported in the CRF.  
6.2.3.4
Follow-up for overall survival status
Effective from CTP v4.0, this section is not applicable.
All patients will be followed-up for survival status at approximately 12 week (+/-7 days) 
intervals until;
•    Death
•    Withdrawal of consent


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•    Lost to follow-up or
•    Completion of the whole trial
The follow-up visits for survival status will be performed in person, by telephone or via 
written correspondence. If a patient cannot be contacted for survival status, information may 
also be obtained by other means in accordance with informed consent language and local 
regulations (e.g. contact with patients’ health care providers, public sources, e.g. death 
registry, obituary listing, etc.) when it is available and verifiable. The last follow-up visit will 
be considered the “end-of-trial” visit.
The following patient status information will be collected during the FUP timepoints for 
survival status:
∀
Date of contact
∀
Further anti-cancer treatment including surgery and radiotherapy: regimen and drug 
name, start and stop dates.
∀
For each reportable serious adverse event / AESI, the investigator should provide the 
information with regard to concomitant medication and the medication administered 
to treat the adverse events on the appropriate CRF pages and the SAE form including 
trade name, indication and dates of administration
∀
Outcome event (e.g. death: Record date of and reason for outcome event / death [if 
applicable])
6.2.3.5
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:
• Completion of planned follow-up period
• Lost to follow-up
• Refusal to be followed-up
• Death


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The statistical analyses in this trial are descriptive and exploratory. No formal statistical test 
will be performed.
7.2
PLANNED ANALYSES
7.2.1
General considerations
No per protocol set will be used in the analysis. However, important protocol deviations
(iPDs) will be summarised. Adherence to the protocol will be assessed by the trial team. iPDs
categories will be specified in the iPD specification document. IPDs will be identified at trial 
oversight meetings and documented in the iPD log. The iPD categories will be updated as 
needed.
For determination of the MTD, only MTD evaluable patients with be considered. For 
analyses of secondary and further endpoints, all patients in the treated set (i.e., patients 
treated with at least one dose of trial medication) will be used if not specified differently. Any 
other analysis set will be defined in the TSAP.
7.2.2
Handling of intercurrent events
The expected intercurrent events of interest are:
- treatment discontinuation during the MTD evaluation period
- progressive disease during the MTD evaluation period
- death during the MTD evaluation period
- dose reduction during the MTD evaluation period
- any events that cause missed visits during the MTD evaluation period
The strategy for handling intercurrent events in this trial is as follows: 
If the intercurrent event follows criteria defined in section 3.3.4.1.1 then the patient will be 
considered not evaluable for MTD and will not be considered in the primary analysis, 
otherwise the patient should still be considered in the primary analysis. This corresponds to a 
principal stratum strategy. 
7.2.3
Primary objective analyses
Phase Ia dose escalation:
This trial will be performed as an open label. 
The primary objective in phase Ia is to determine the MTD and the recommended dose for 
expansion (RDE) of BI 905711 in combination with FOLFIRI plus bevacizumab. MTD is 
defined as the highest dose with less than 25% risk of the true DLT rate being equal or above 
0.33 (EWOC criterion). Dose-escalation for each group will be guided by a two-parameter 
Bayesian Logistic Regression Model (BLRM), escalating with overdose control (EWOC) 


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(R13-4803; R13-4806). 
The Bayesian logistic regression model (BLRM) is formulated as follows:
Xd ~ Binomial (nd, πd),
logit(πd) = log(α) + β*log(d/d*), 
where logit(π) = log(π/(1-π)).
Xd denotes the random variable describing the observed number of DLTs in nd patients at the 
dose d.
πd represents the probability of having a DLT in the the MTD evaluation period at dose d, d* 
= 3.6 mg/kg is the reference dose, allowing for the interpretation of α as the odds of a DLT at 
dose d*, and θ = (log(α), log(β)) with α, β > 0 is the parameter vector of the model.
The estimated probability of a DLT at each dose level from the model will be summarized 
using the following intervals:
Under toxicity: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM-recommended dose for the next dose cohort is the dose level with the highest 
posterior probability of the DLT rate falling in the target interval of [0.16, 0.33) among the 
doses fulfilling the EWOC principle. With the EWOC criterion, it should be unlikely (i.e. 
posterior probability <25%) that the DLT rate at the recommended dose will exceed 0.33. 
The maximum allowable dose increment for each escalation step shall not be more than 
100%. 
The MTD will be considered reached if one of the following criteria is fulfilled: 
∀
the posterior probability of the true DLT rate in the target interval [0.16, 0.33) of the 
MTD is above 0.5
∀
OR at least 12 patients have been treated in phase Ia, of which at least 6 at the MTD. 
The DRC may recommend stopping the dose escalation phase after the criterion for MTD is 
fulfilled. 
Prior derivation:
By the time BLRM is analyzed, safety data for BI 905711 are expected to be available from
BI Study 1412-0001. The information can be incorporated into the prior derivation meta-
analytic predictive (MAP) approach. The safety data for BI 905711 in 1412-0001 dated April 
15th 2021 can be found in Table 7.2.3:1, and is used in prior derivation.




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distributions inform. A detailed evaluation of the model using hypothetical data scenarios is 
provided in the statistical Appendix 10.3.
Table 7.2.3: 2
Mixture of prior distributions for CRC group
Prior Component
Mixture Weight
Mean 
θ = (log(α), 
log(β))
SD 
θ = (log(α), 
log(β))
Correlation
1: Weakly inf.
0.9
-1.62, 0.39
1.75, 0.97
0.35
2: High Tox
0.1
0.045, 0.22
2, 1
0
Table 7.2.3: 3
Prior probabilities of DLT at selected doses – CRC group
Dose
Probability of true DLT rate in
Quantiles
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
SD
2.5%
50%
97.5%
0.6
0.895
0.058
0.047
0.06
0.133
0
0.01
0.496
1.2
0.823
0.094
0.084
0.095
0.164
0
0.027
0.639
2.4
0.652
0.168
0.18
0.175
0.214
0.002
0.084
0.803
3.6
0.456
0.2
0.344
0.283
0.266
0.007
0.19
0.909
4.8
0.354
0.174
0.471
0.38
0.313
0.009
0.298
0.979
The prior may be updated once the data in trial 1412-0001 has been updated. The prior used 
for each BLRM analysis for the DRC meetings will be documented in the DRC minutes, the 
prior used for the final analysis will be documented in the TSAP.
Phase Ib Dose Expansion:
A safety run-in will be performed for the first 6 patients in the PDAC expansion cohort. After 
the first 6 patients have been treated for at least two cycles, the DRC will assess the overall 
safety profile and confirm the RDE of BI 905711 plus FOLFIRI (or Liposomal Irinotecan 
plus 5-FU/Leucovorin) in PDAC cohort. If additional DLTs are observed during the safety 
run-in phase, a separate BLRM with overdose control will be used to re-estimate the 
recommended dose for PDAC expansion cohort. The available data from CRC cohorts can be 
incorporated into the model by a meta-analytic predictive (MAP) approach.
The primary endpoint in the dose-expansion part is objective response (OR) derived from the 
data of all cycles. Descriptive analyses will be conducted for this endpoint.
Details will be specified in the TSAP.


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7.2.4
Secondary objective analyses
Secondary time-to-event endpoints will be analyzed by Kaplan-Meier estimates. Other
secondary endpoints will be analyzed descriptively. Details of the secondary endpoint 
analyses will be specified in the trial statistical analysis plan (TSAP).
7.2.5
Further objective analyses
PK analyses are specified in Section 5.3.1 and will be calculated by means of 
noncompartmental analysis. Descriptive statistics will be used to evaluate plasma 
concentration data and PK parameters. Further details on analysis will be described in the 
TSAP.
Biomarker analysis are specified in Section 5.4. Exploratory analysis will be used to evaluate 
potential patient selection biomarkers and pharmacodynamic changes triggered by treatment 
intervention between baseline and on-treatment samples. All analysis will be further 
described in the TSAP.
The precise level of tumor markers could be expressed as median, mean, and range values 
including changes over time. Pearson correlation analysis could be used as acorrelation 
analysis of CEA and CA19-9. Further details and decisions on the analysis will be described 
in the TSAP.
PRO data collected using the PRO-CTCAE questionnaire will be analysed descriptively,
including changes over time. Further details on analysis will be described in the TSAP.
7.2.6
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP will be assigned to the on-
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.


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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.
7.2.7
Other analyses
Not applicable
7.2.8
Interim analyses
In the Phase Ia, interim safety evaluations will be performed as considered necessary. In 
particular safety evaluations, after each dose cohort, will be performed by the DRC. Based on 
this, the DRC will recommend the next dose level as well as the corresponding cohort size.
In the phase Ib, if any DLTs observed in patients enrolled in phase Ib, the BLRM will be run 
to confirm if the dose level still fulfills the overdose risk control.
No formal interim analysis of efficacy data is foreseen, although efficacy data, PK and 
biomarker data when available may be considered as part of the regular evaluation of trial 
data.
No formal interim analysis is planned for PK and immunogenicity.
Preliminary, exploratory analysis of PK and if applicable of immunogenicity may be 
performed prior to database lock during study conduct based on all evaluable data at the time 
of analysis. In contrast to the final calculations, the preliminary, exploratory analysis will be 
based on planned sampling times rather than on actual times, regardless of whether actual 
times were within the time windows or not. Therefore, minor deviations in preliminary and 
final results may occur. No formal preliminary PK and immunogenicity report will be 
written.
7.3
HANDLING OF MISSING DATA
Plasma concentration - time profiles 
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not to the 
lag phase) will be ignored and not replaced by zero at any time point (including the lag 
phase). Descriptive statistics of concentrations at specific time points will be calculated only 
when at least 2/3 of the individuals have concentrations within the validated concentration 
range. The overall sample size to decide whether the “2/3 rule” is fulfilled will be based on 


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the total number of samples intended to be drawn for that time point (i.e., BLQ (below the 
limit of quantification), NOR, NOS, NOA are included).
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ values in the lag phase will be set to zero. The lag phase is 
defined as the period between time zero and the first time point with a concentration above 
the quantification limit. All other BLQ values of the profile will be ignored.
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. If the actual sampling time is not recorded or is missing for a certain time 
point, the planned time will generally be used for this time point instead. Pharmacokinetic 
parameters which cannot be determined will be identified by "not calculated" (NC).
In general, no imputation will be performed on missing efficacy data. Missing baseline 
laboratory values will be imputed by the respective values from the screening visit. No other 
imputations will be performed on missing data although every effort will be made to obtain 
complete information on all AEs, with emphasis on potential DLTs.
7.4
RANDOMIZATION
Randomization will be performed in the CRC cohort of phase Ib part of this trial only. 
The randomization list will be generated using a validated system. Randomization ratio is 2:1 
for BI 905711 with FOLFIRI plus bevacizumab and FOLFIRI plus bevacizumab arms. 
The randomization list will be generated using a validated system. Access to the 
randomization codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for this 
trial. The sample size for dose escalation relies on the assumption of dose-toxicity correlation 
model. Up to 20 patients in dose escalation group are planned to be enrolled into the dose 
escalation phase based on the expected dose levels that are going to be investigated. However, 
the actual number of patients will depend on the number of dose cohorts tested. 
In phase Ib 2nd line CRC cohort, 60 patients will be enrolled. Specifically, 40 patients will be 
treated with BI 905711 in combination with FOLFIRI + bevacizumab as treatment arm, and 


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20 patients will be treated with FOLFIRI + bevacizumab as control arm. The sample size is 
considered sufficient to limit the error probability of observing more than 15% difference in 
response rate to no more than around 6% if the true response rates are constant 30% in both 
arms. With this number of patients, the probability of observing a 15% increase in ORR from 
treatment arm to control arm will be at least around 75% under the scenario where ORR was 
assumed to be 20% higher in treatment arm than control arm.
In phase Ib 2nd line PDAC cohort, 20 patients will be enrolled. Historical control response
rate for 2L PDAC is around 15% (chemotherapy only). The probability of observing 5 or 
more responders from 20 patients is no more than 17% assuming no additional benefit from 
investigational combination. 


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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 Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations. Investigators and
site staff must adhere to these principles. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
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 according to national and international regulations. The same 
applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 


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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit / inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.9.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least 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.


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Copies of source documents may be collected for safety review (i.e. CT/MRI, ECG). Before
sending or uploading those copies, the investigator must ensure that all patient identifiers (e.g. 
patient’s name, initials, address, phone number, social security number) have properly been 
removed or redacted from any copy of the patients’ source documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient
was informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if 
available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion / exclusion criteria does not 
make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator / institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents / data, including progress notes, copies of laboratory and medical test results, 
which must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor or delegate will also monitor compliance with the protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see section 6). Site access may be restricted thus limiting the ability to perform standard site
monitoring activities on site such as on-site source data review and source data verification.


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Therefore, some of these activities may be performed remotely or replaced by centralized 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
Exemptions from expedited reporting are described in section 5.2.6.2.4.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. The code is only available at the site and must not be forwarded to the sponsor. In case 
patient’s records will be forwarded e.g. for SAE processing or adjudication committees, 
personal data that can identify the patient will be redacted by the site prior to forwarding.
Access to the patient files and clinical data is strictly limited: personalised treatment data may 
be given to the patient’s personal physician or to other appropriate medical personnel 
responsible for the patient’s welfare. Data generated at the site as a result of the trial need to 
be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular
∀
Sample and data usage has to be in accordance with the separate biobanking informed 
consent


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∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
∀
A fit for purpose approach will be used for assay / equipment validation depending on 
the intended use of the biomarker data
∀
Samples and / or data may be transferred to third parties and other countries as
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial (start of 
Phase Ia signs informed consent.
The end of the trial is defined as the date of last patient in the whole trial (end of Phase Ib) 
(“Last Patient Completed”), or when all patients have been discontinued from study treatment 
and have been followed up for overall survival for at least 12 weeks after treatment 
discontinuation.
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).


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A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A DRC composed of participating investigators and members of the BI trial team will be 
established to review individual and aggregated safety data at regular intervals to determine 
the safety profile and risk/benefit ratio and make decisions on next dose level, dose 
escalation, dose de-escalation, dose modification and next cohort size. Further details are 
contained in the DRC charter.
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 web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers, Clinical 
Research Associates (CRAs), and investigators of participating countries.
In the participating countries the trial will be performed by the respective local or regional 
BI-organisation (Operating Unit, OPU) in accordance with applicable regulations and BI
SOPs, or by a Contract Research Organisation (CRO) based on a contract outlining the 
responsibilities.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central imaging service and an IRT vendor will be used in this 
trial. Details will be provided in the IRT Manual and Central Laboratory Manual, available in 
the ISF.


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Wakelee HA, Patnaik A, Sikic BI, Mita M, Fox NL, Miceli R, et al. Phase I 
and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 
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(2010)
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Papadopoulos KP, Isaacs R, Bilic S, Kentsch K, Huet HA, Hofmann M, et 
al. Unexpected hepatotoxicity in a phase I study of TAS266, a novel 
tetravalent agonistic Nanobody targeting the DR5 receptor. Cancer 
Chemother Pharmacol 75 (5), 887 - 895 (2015)
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Huet HA, et al. Multivalent nanobodies targeting death receptor 5 elicit 
superior tumor cell killing through efficient caspase induction. MAbs 6 (6), 
1560 - 1570 (2014)
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Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. 
Nat Rev Drug Discov 7 (12), 1001 - 1012 (2008)
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Herbst RS, Kurzrock R, Hong DS, Valdivieso M, Hsu CP, Goyal L, et al. A 
first-in-human study of conatumumab in adult patients with advanced solid 
tumors. Clin Cancer Res 16 (23), 5883 - 5891 (2010)
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Straeter J, Walczak H, Pukrop T, Mueller L von, Hasel C, Kornmann M, et 
al. TRAILand its receptors in the colonic epithelium: a putative role in the
defense of viral infections. Gastroenterology 122 (3), 659 - 666 (2002)
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Camidge DR, Herbst RS, Gordon MS, Eckhardt SG, Kurzrock R, Durbin B. 
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Cancer Res 16 (4), 1256 - 1263 (2010)
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Begue B, Wajant H, Bambou JC, Dubuquoy L, Siegmund D, Beaulieu JF, 
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Su MC, Yuan RH, Lin CY, Jeng YM. Cadherin-17 is a useful diagnostic 
marker for adenocarcinomas of the digestive system. Mod Pathol 21, 1379 -
1386 (2008)
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Forero-Torres A, Infante JR, Waterhouse D, Wong L, Vickers S, 
Arrowsmith E, et al. Phase 2, multicenter, open-label study of tigatuzumab 
(CS-1008), a humanized monoclonal antibody targeting death receptor 5, in 
combination with gemcitabine in chemotherapy-naive patients with 
unresectable or metastatic pancreatic cancer. Cancer Med 2 (6), 925 - 932 
(2013)
R17-2601
Forero-Torres A, Shah J, Wood T, Posey J, Carlisle R, Copigneaux C, et al. 
Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal 
antibody targeting death receptor 5 (DR5). Cancer Biother Radiopharm 25 
(1), 13 - 19 (2010)
R17-2603
Zuch de Zafra CL, Ashkenazi A, Darbonne WC, Cheu M, Totpal K, Ortega 
S, et al. Antitherapeutic antibody-mediated hepatotoxicity of recombinant 
human Apo2L/TRAIL in the cynomolgus monkey. Cell Death Dis 7, e2338 
(2016)
R17-2606
Sharma S, Vries EG de, Infante JR, Oldenhuis CN, Gietema JA, Yang L, et 
al. Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody 
LBY135 alone and in combination with capecitabine in patients with 
advanced solid tumors. Invest New Drugs 32, 135 - 144 (2014)
R17-2985
Wajant H. Principles of antibody-mediated TNF receptor activation. Cell 
Death Differ 22, 1727 - 1741 (2015)
R17-2986
Valley CC, Lewis AK, Mudaliar DJ, Perlmutter JD, Braun AR, Karim CB, 
et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 
induces death receptor 5 networks that are highly organized. J Biol Chem 
287 (25), 21265 - 21278 (2012)
R17-2987
Li F, Ravetch JV. Apoptotic and antitumor activity of death receptor 
antibodies require inhibitory Fcgamma receptor engagement. Proc Natl 
Acad Sci USA 109 (27), 10966 - 10971 (2012)
R17-4112
Kaplan-Lefko PJ, Graves JD, Zoog SJ, Pan Y, Wall J, Branstetter DG, et al.
Conatumumab, a fully human agonist antibody to death receptor 5, induces 
apoptosis via caspase activation in multiple tumor types. Cancer Biol Ther 
9 (8), 618 - 631 (2010)
R17-4113
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al.
Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin 
Invest 104 (2), 155 - 162 (1999)
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Ordonez NG. Cadherin 17 is a novel diagnostic marker for 
adenocarcinomas of the digestive system. Adv Anat Pathol 21 (2), 131 -
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R18-1357
U.S. Department of Health and Human Services Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017).
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
CTCAE_v 5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 
(access date: 9 April 2017); U.S. Department of Health and Human 
Services, National Institutes of Health, National Cancer Institute (2017)
R18-1615
Panarelli NC, Yantiss RK, Yeh MM, Liu Y, Chen YT. Tissue-specific 
cadherin CDH17 is a useful marker of gastrointestinal adenocarcinomas 
with higher sensitivity than CDX2. Am J Clin Pathol 138 (2), 211 - 222 
(2012)
R18-1685
Frey N. Cytokine release syndrome: who is at risk and how to treat. 
Baillieres Best Pract Res Clin Haematol 30, 336-340 (2017)
R18-1686 
Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for 
acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ 
Program 2016 (1), 567-572 (2016)
R18-1695
Bendell J, Blay JY, Cassier P, Bauer T, Terret C, Mueller C, et al.
Phase 1 trial of RO6874813, a novel bispecific FAP-DR5 antibody, in 
patients with solid tumors. AACR-NCI-EORTC Int Conf on Molecular 
Targets and Cancer Therapeutics: Discovery, Biology, and Clinical 
Applications, Philadelphia, 26 - 30 Oct 2017 Mol Cancer Ther 17 (1) 
(Suppl), Abstr A092/92 (2017)
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Smith AW, Mitchell SA, De Aguiar CK, Moy C, Riley WT, Wagster MV,
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Morgan-Lappe SE. ABBV-621: a best-in-class TRAIL-receptor agonist 
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Cancer Research (AACR), Washington, 1 - 5 Apr 2017 Cancer Res 77 (13) 
(Suppl), Abstr DDT01-03 (2017)
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Altree-Tacha D, Tyrell J, Haas T. CDH17 is a more sensitive marker for 
gastric adenocarcinoma than CK20 and CDX2. Arch Pathol Lab Med 141, 
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Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et 
al. Chimeric antigen receptor T-cell therapy - assessment and management 
of toxicities. Nat Rev Clin Oncol 2018;15:47-62.


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Calvo E, Jonge MJ de, Rasco DW, Moreno V, Chang YW, Chiney M, et al. 
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tumors: dose-optimization cohorts. 44th Ann Cong of the European Society 
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Restellini S, Chazouilleres O, Frossard JL. Hepatic manifestations of 
inflammatory bowel diseases. Liver Int 2017;37(4):475-489.
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(access date: 26 May 2021); 2021.
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Wu XX, Kakehi Y. Enhancement of lexatumumab-induced apoptosis in 
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R21-2041
Belyanskaya LL, Marti TM, Hopkins-Donaldson S, Kurtz S, Felley-Bosco 
E, Stahel RA. Human agonistic TRAIL receptor antibodies mapatumumab 
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9.2
UNPUBLISHED REFERENCES
c16856466
BI 905711 Investigator’s Brochure, current version


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10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
If feasible, the following PK parameters of BI 905711 will be evaluated using non
compartmental analysis methods.
After the first doses:
• Cmax (maximum measured concentration)
• AUC0-∞ (area under the concentration-time curve over the time interval from zero 
extrapolated to infinity)
• AUC0-tz (area under the concentration-time curve over the time interval from 0 up to the 
last quantifiable data point)
• tz (time point of the last quantifiable plasma concentration)
• %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation)
• AUCt1-t2 (area under the concentration time curve over the time interval t1 to t2)
• tmax (time from dosing to the maximum measured concentration)
• Cpre,N (the pre-dose concentration of the analyte in plasma immediately before 
administration of the Nth dose after N-1 doses were administered)
• t1/2 (terminal half-life)
• CL (total clearance of the analyte)
• Vz (apparent volume of distribution during the terminal phase)
• Vss (volume of distribution after intravenous infusion)
If feasible, the following additional PK parameters may be determined after repeated doses 
[If steady state can reasonably be assumed, the parameters will be denoted with ss as shown; 
otherwise, they will be denoted with the dose number of the last dose]:
• Cmax,ss (maximum measured concentration at steady state)
• Cmin,ss (minimum concentration at steady state)
• tmin,ss (time to reach minimum concentration at steady state)
• Cavg (average concentration at steady state)
• Cpre, N,ss (pre-dose concentration at steady state immediately before administration of the 
next dose)
• AUCτ,ss (area under the concentration-time curve at steady state over a uniform dosing 
interval τ)
• AUCt1-t2,ss (area under the concentration time curve over the time interval t1 to t2 at 
steady state)
• tmax,ss (time from last dosing to maximum concentration at steady state)
• tz,ss (time of last measurable concentration within the dosing interval τ at steady state)
• λz,ss (terminal rate constant at steady state)
• t1/2,ss (terminal half-life at steady state)
• MRTinf,ss (mean residence time in the body after intravenous infusion at steady state)
• CLss (total clearance at steady state)
• Vz,ss (volume of distribution during the terminal phase after multiple intravascular 
administrations at steady)


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• Vss,ss (volume of distribution after multiple intravascular administrations at steady state)
• RA,Cmax (accumulation ratio based on Cmax)
• RA,AUC (accumulation ratio based on AUC0-τ)
• RA,Cpre,N (accumulation ratio based on Cpre,N)
• LI (linearity index, AUCτ,ss/AUC0-∞)
• PTF (Peak-Trough Fluctuation)
If deemed necessary, further appropriate pharmacokinetic parameters might be calculated.


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10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING NO LONGER APPLICABLE PER CTP V4.0
Table 10.2: 1
Time schedule for PK and biomarker blood sampling for Phase Ia -No 
longer applicable per CTP v4.0
Treatment
Course 
(each cycle 
is 14 days)
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Nab
Plasma for 
cell death 
biomarker
Plasma 
for 
cfDNAc
Blood 
gDNAc
Pre-Cycle 1
SCR
001
-28 
to -5
0:00
0:00
Blood 
sampling
X
Cycle 1
C01_D1 101
1
Just before 
Start of
Bevacizumab 
and/ or 
FOLFIRI
infusion
-48:05
Blood 
sampling
X
X
X
Start of 
Bevacizumab 
and/or 
FOLFIRI 
infusion
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion 
---
C01_D3 103
3
Just before
Start of
BI 905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
X
X
SOI
0:00
infusion
---
Immediately 
before end of
BI 905711 
infusion 
(EOI)b
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
X
C01_D4 104
4
24 hours post 
SOIf
24:00
Blood 
sampling
X
X
C01_D5 105
5
48 hours post 
SOI
48:00
Blood 
sampling
X
X
C01_D1
0
110
10
168 hours 
post SOI
168:0
0
Blood 
sampling
X
X
X
Cycle 2
C02_D1 201
1
Start of 
Bevacizumab 
and/or 
FOLFIRI 
infusion
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion
---
C02_
D3
203
3
Just before 
(SOI)
-0:05
Blood 
sampling
X
X
X
X
0:00
0:00
SOI
---
Immediately 
before
EOI
0:30
Blood 
sampling
X
C02_D4
204
4
24 hours post 
SOI
f
24:00
Blood 
sampling
X
X 


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Table 10.2: 1
Time schedule for PK and biomarker blood sampling for Phase Ia 
(cont) -No longer applicable per CTP v4.0
Treatment
Course 
(each cycle 
is 14 days)
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Nab
Plasma for 
cell death 
biomarker
Plasma 
for 
cfDNAc
Blood 
for 
gDNAc
Cycle 3 
C03_D1 301
1
Start of 
Bevacizumab 
and/or 
FOLFIRI 
infusion
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion
---
X
C03_D3 303
3
Just before
Start of
BI 905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
X
X
SOI
0:00
infusion
---
Immediately 
before
EOI
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
X
C03_D4 304
4
24 hours post 
SOI
f
24:00
Blood 
sampling
X
X
C03_D5 305
5
48 hours post 
SOI
48:00
Blood 
sampling
X
X
C03_D1
0
310
10
168 hours post 
SOI
168:00 Blood 
sampling
X
X
Cycle 4
C04_D1 401
1
Start of 
Bevacizumab 
and/or 
FOLFIRI 
infusion
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion
---
X
C04_D3 403
3
Just before 
start of BI 
905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
EOI
0:30
Blood 
sampling
X
C04_D4 404
4
24 hours post 
SOI
f
24:00
Blood 
sampling
X
X
Cycle 5
C05_D1 501
1
Start of 
Bevacizumab 
and/or 
FOLFIRI 
infusion
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion
---
X
Cycle 6 
C06_D3 603
3
Just before 
start of BI 
905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
X
Cycle 8
C08_D3 803
3
Just before 
SOI
-0:05
Blood 
sampling
X
X
X
Cycle 10 
C10_D3 1003
3
Just before 
SOI
-0:05
Blood 
sampling
X
X
X
Cycle 12
C12_D3 1203
3
Just before 
SOI
-0:05
Blood 
sampling
X
X
X
Cycle 14d
C14_D3 1403
3
Just before 
SOI
-0:05
Blood 
sampling
X d
X d
X d
Cycle 20, 26
C20_D3
, 
C26_D3
2003, 
2603
3
Just before 
SOI
-0:05
Blood 
sampling
X d
X d
X d


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Table 10.2: 1
Time schedule for PK and biomarker blood sampling for Phase Ia 
(cont) -No longer applicable per CTP v4.0
PTM = Planned Time; SOI=Start of [BI 905711] Infusion; EOI= End of [BI 905711] Infusion
aThe following windows of time are allowed for PK sampling:
1.
Pre-dose (PTM -0:05): within 1 hour before next drug infusion/drug administration.
2.
7h: within ± 15 min of designated time
3.
24- 48h: within ±60 min of designated time.
4.
168h ±24 hour
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of 
samples from data evaluation.
bIn the event that infusion duration is >60 minutes longer than planned, the subsequent time points for PK blood 
collection on the day of drug infusion should be adjusted accordingly. 
c One blood sample to isolate genomic DNA will be obtained at C1V1 before treatment. 6 plasma samples will 
be collected to isolate circulating nucleic acids (e.g. cfDNA) from plasma: at C1V1 before treatment, C1D10, 
C3D1, C4D1, C5D1 and EOT after treatment.
dPK, ADA and NAB sampling is to be collected pre-dose (-0:05) at Day 3 of Cycle 14 and every 3 months 
thereafter (Cycle 20, Cycle 26, etc.)..
eIf the patient will not continue treatment in the next scheduled cycle, pre-dose sampling scheduled for Day 3 of 
the next cycle needs to be performed at the EOT visit. 
fPer section 4.2.4.1, if less than 50% of the planned dose of BI 905711 was administered due to an infusion-
related reaction, 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. If this scenario occurs, the PK sample should be collected just 
before the start of the further infusion. A second PK sample should also be collected before the end of the 
further infusion.
Treatment
Course 
(each cycle 
is 14 days)
Visit
Visit 
No. 
Day Time Pointa
[hh:min]
CRF 
Time
/PT
M
Event
PK
ADA
Nab
Plasma for 
cell death 
biomarker
Plasma 
for 
cfDNAc
Blood 
for 
gDNAc
EOTe
EOT
9960
Blood 
sampling
X
X
X
X
30-Day 
Safety 
Follow-up
EOR
9970
Blood 
sampling
X
X
X


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Table 10.2: 2
Time schedule for PK and biomarker blood sampling for Phase Ib-No 
longer applicable per CTP v4.0
Treatment
Course 
(each cycle 
is 14 days)
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PKb
ADA
Nab
Plasma for 
cell death 
biomarker
Plasma 
for 
cfDNAe
Pre-Cycle 1
SCR
001
-28 
to -5
0:00
0:00
Blood 
sampling
Xd
Cycle 1
C01_D1 101
1
Just before 
Start of
standard of 
care treatment
-48:05
Blood 
sampling
X
X
Start of 
standard of 
care treatment
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion 
---
C01_D3 103
3
Just before
Start of
BI 905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
X
X
SOI
0:00
infusion
---
Immediately 
before end of
BI 905711 
infusion 
(EOI)c
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
X
C01_D4 104
4
24 hours post 
SOIh
24:00
Blood 
sampling
X
X
C01_D5 105
5
48 hours post 
SOI
48:00
Blood 
sampling
X
X
C01_D1
0
110
10
168 hours 
post SOI
168:0
0
Blood 
sampling
X
X
Cycle 2
C02_D1 201
1
Start of 
standard of 
care treatment
-48:00
Bevacizum
ab and/or 
FOLFIRI 
infusion
---
X
C02_
D3
203
3
Just before 
(SOI)
-0:05
Blood 
sampling
X
X
X
X
0:00
0:00
SOI
---
Immediately 
before
EOI
0:30
Blood 
sampling
X
C02_D5
205
5
48 hours post 
SOI
h
48:00
Blood 
sampling
X
X 


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Table 10.2: 2
Time schedule for PK and biomarker blood sampling for Phase 1b 
(cont) -No longer applicable per CTP v4.0
Treatment
Course 
(each cycle 
is 14 days)
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PKb
ADA
Nab
Plasma for 
cell death 
biomarker
Plasma 
for 
cfDNAe
Cycle 3 
C03_D1 301
1
Start of 
standard of 
care treatment
-48:00
SOC
infusion
---
C03_D3 303
3
Just before
Start of
BI 905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
X
X
SOI
0:00
infusion
---
Immediately 
before
EOI
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
X
C03_D4 304
4
24 hours post 
SOI
h
24:00
Blood 
sampling
X
X
C03_D5 305
5
48 hours post 
SOI
48:00
Blood 
sampling
X
X
C03_D1
0
310
10
168 hours post 
SOI
168:00 Blood 
sampling
X
X
Cycle 4
C04_D1 401
1
Start of 
standard of 
care treatment
-48:00
SOC
infusion
---
C04_D3 403
3
Just before 
start of BI 
905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
EOI
0:30
Blood 
sampling
X
C04_D4 404
4
24 hours post 
SOI
h
24:00
Blood 
sampling
X
X
Cycle 6 
C06_D3 603
3
Just before 
start of BI 
905711 
infusion (SOI)
-0:05
Blood 
sampling
X
X
X
Cycle 8
C08_D1 801
1
Start of 
standard of 
care treatment
-48:00
SOC 
infusion
---
X
C08_D3 803
3
Just before 
SOI
-0:05
Blood 
sampling
X
X
X
Cycle 10 
C10_D3 1003
3
Just before 
SOI
-0:05
Blood 
sampling
X
X
X
Cycle 12
C12_D3 1203
3
Just before 
SOI
-0:05
Blood 
sampling
X
X
X
Cycle 14 d,f
C14_D1 1401
1
Start of 
standard of 
care treatment
-48:00
SOC
infusion
---
X
C14_D3 1403
3
Just before 
SOI
-0:05
Blood 
sampling
X f
X f
X f
Cycle 20, 26
C20_D1
, 
C26_D1
2001, 
2601
1
Start of 
standard of 
care treatment
-48:00
SOC
infusion
---
X
C20_D3
, 
C26_D3
2003, 
2603
3
Just before 
SOI
-0:05
Blood 
sampling
X f
X f
X f


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Table 10.2: 2
Time schedule for PK and biomarker blood sampling for Phase 1b 
(cont) -No longer applicable per CTP v4.0
PTM = Planned Time; SOI=Start of [BI 905711] Infusion; EOI= End of [BI 905711] Infusion
aThe following windows of time are allowed for PK sampling:
1.
Pre-dose (PTM -0:05): within 1 hour before next drug infusion/drug administration.
2.
7h: within ± 15 min of designated time
3.
24- 48h: within ±60 min of designated time.
4.
168h ±24 hour
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of 
samples from data evaluation.
bPK sample will not be collected from CRC cohort Arm B patient
cIn the event that infusion duration is >60 minutes longer than planned, the subsequent time points for PK blood 
collection on the day of drug infusion should be adjusted accordingly. 
dAt least one pre-dose plasma sample for cell death biomarker analysis of caspase activity needs to be collected. 
e Plasma samples will be collected to isolate circulating nucleic acids (e.g., cfDNA) from plasma: at C1D1 
before treatment, C2D1, C8D1, C14D1, C20D1, C26D1 (every 6 cycle thereafter) and EOT after treatment.
fPK, ADA and NAB sampling is to be collected pre-dose (-0:05) at Day 3 of Cycle 14 and every 3 months 
thereafter (Cycle 20, Cycle 26, etc.).
gIf the patient will not continue treatment in the next scheduled cycle, pre-dose sampling scheduled for Day 3 of 
the next cycle needs to be performed at the EOT visit. 
hPer section 4.2.4.1, if less than 50% of the planned dose of BI 905711 was administered due to an infusion-
related reaction, 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. If this scenario occurs, the PK sample should be collected just 
before the start of the further infusion. A second PK sample should also be collected before the end of the 
further infusion.
Treatment
Course 
(each cycle 
is 14 days)
Visit
Visit 
No. 
Day Time Pointa
[hh:min]
CRF 
Time
/PT
M
Event
PKb
ADA
Nab
Plasma for 
cell death 
biomarker
Plasma 
for 
cfDNAe
EOTg
EOT
9960
Blood 
sampling
X
X
X
X
30-Day 
Safety 
Follow-up
EOR
9970
Blood 
sampling
X
X
X


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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. The model is 
introduced in Section 7 including prior specifications for the model. After patients in each 
cohort have completed at least the MTD evaluation period, the prior distribution will be 
updated with the accumulated DLT data from the MTD evaluation period. Posterior 
probabilities for the rate of DLTs will be summarised from the BLRM. Selection of the next 
dose level will be based on these probabilities as well as on other safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD under various 
dose-toxicity relationships through computer simulation. These results are summarised in 
Table 10.3:3. In addition, recommendations of the next dose level by the BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios to 
show how it facilitates on-trial dose-escalation decisions (see Table 10.3: 1). For simplicity 
reasons, a cohort size of 3 patients who are all evaluable is assumed.
The simulations for scenarios and operating characteristics were produced using R version 
4.0.2 and Jags version 4.3.0.
Hypothetical data scenarios for dose escalation
Hypothetical data scenarios are shown in Table 10.3: 1. These scenarios reflect potential on-
trial data scenarios and related escalation as allowed by the model, the probability of 
overdose for the current dose level, as well as the next potential dose level and related 
probabilities of DLT rate falling into the under toxicity, target toxicity and over toxicity
intervals. 
For example, Scenario 1 represents the case where 3 patients were treated in 1412-0003 trial 
with no DLTs and the current dose level in 1412-0003 trial is 0.6 mg/kg. Given this 
information, the posterior probability of over-dose for the current dose level in 1412-0003 
trial is 0.008, which is under the EWOC threshold. In this case, the BLRM recommendation 
is to escalate to 1.2 mg/kg.
Scenario 2 shows to stay at the current dose level and enroll more patients when the first DLT 
occurs out of 3 patients in the first dose level cohort. 
Similarly, in scenario 3 when no DLT occurs out of 3 patients in the first two cohorts, the 
BLRM recommends escalating to the next dose level. 
Scenarios 4, 8 and 9 show examples of staying at the current dose level with 1 DLT out of 3 
patients and continue to observe more patients. The probability of over-dose for the current 
dose level in scenario 4 trial is 0.104, which is under the EWOC threshold. 
Scenarios 6, 7 show that with 0 DLT up to the current dose level, the model's 
recommendation is to escalate to the next dose level which over-dose is under control.


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Scenario 10 shows to deescalate to the previous dose and continue the trial when 2 out of 3 
patients had DLT at the current dose level. 
Scenario 11 illustrates potentially observed data adding on to Scenario 10 can conclude the 
MTD reached at dose level 3.6 mg/kg. 
Table 10.3: 1
Hypothetical data scenario for dose escalation 
Scenario
Dose 
(mg/kg)
# 
Pat
# DLT
Current 
Dose: 
P(OD)
Next 
recommended 
dose based on 
EWOC and 
escalation rule
Next recommended dose
P(UD)
P(TD)
P(OD)
1
0.6
3
0
0.008
1.2
0.888
0.079
0.032
2
0.6
3
1
0.183
0.6
0.553
0.264
0.183
3
0.6
1.2
3
3
0
0
0.008
2.4
0.779
0.146
0.075
4
0.6
1.2
3
3
0
1
0.104
1.2
0.629
0.267
0.104
5
0.6
1.2
3
6
0
1
0.035
2.4
0.428
0.334
0.238
6
0.6
1.2
2.4
3
3
3
0
0
0
0.015
3.6
0.675
0.185
0.140
7
0.6
1.2
2.4
3.6
3
3
3
3
0
0
0
0
0.031
4.8
0.684
0.180
0.136
8
0.6
1.2
2.4
3.6
3
3
3
3
0
0
0
1
0.212
3.6
0.458
0.330
0.212
9
0.6
1.2
2.4
3.6
4.8
3
3
3
3
3
0
0
0
0
1
0.208
4.8
0.463
0.330
0.208
10
0.6
1.2
2.4
3.6
4.8
3
3
3
3
3
0
0
0
0
2
0.588
3.6
0.443
0.414
0.143
11
0.6
1.2
2.4
3.6
4.8
3
3
3
6
3
0
0
0
1
2
0.171
3.6
0.308
0.522
0.171
Operating characteristics


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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. Table 10.3:2
describes 5 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:
∀
Scenario 1: aligned with prior means
∀
Scenario 2: high-toxicity scenario
∀
Scenario 3: low-toxicity scenario
∀
Scenario 4: non-logistic dose-toxicity scenario
∀
Scenario 5: low-toxicity followed by high-toxicity
∀
Scenario 6: high toxicity followed by extremely toxic scenario
Table 10.3: 2
Probability of having a DLT under the assumed dose-toxicity scenarios
Scenario/Dose
0.6
1.2
2.4
3.6
4.8
1: Prior information (mean) 
0.06
0.1
0.18
0.28
0.38
2: High toxicity
0.1
0.2
0.25
0.39
0.45
3: Low toxicity
0.01
0.02
0.04
0.1
0.18
4: Non-logistic
0.05
0.12
0.2
0.3
0.4
5: Low-high
0.02
0.07
0.3
0.36
0.45
6: Extremely toxic
0.32
0.36
0.40
0.45
0.50
Note: Probabilities in bold indicate the true DLT rates which fall into the targeted toxicity 
interval [0.16, 0.33).
For each of the five scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rules: escalate to the dose which maximises 
the probability of the targeted toxicity region and satisfies the overdose criterion if it is ≤ 
100% increase from the current dose. 
The MTD was considered reached when the rules in Section 7.1 are fulfilled. If the MTD 
could not be reached, because already the first specified dose level was too toxic, or none of 
the dose levels revealed any DLTs, the simulated trial was stopped.
The simulation assessed how often a dose was declared as MTD with true DLT rate in the 
under-, targeted- or over-dose range. 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
Scenario
% of trials declaring MTD with true 
DLT rate in 
% of 
stopped 
trials
# Patients
# DLTs
Under dose
Target 
dose 
Over 
dose 
Mean
(Min-Max)
Mean
(Min-Max)
1.Prior
27.6    
62.1   
8.4 
1.9
15.8
(3 – 39)
2.5  
(1 - 8)
2. High
13.1
71.9
8
7
14.8
(3 – 39)
3.1  
(1 – 9)
3. Low
43.3
56.7
0
0
19
(12 – 45)
1.5
(1 – 6)
4. Non-logistic
33.9
58.7
6.4
1
15.6
(3 - 39)
2.6
(1 - 7)
5. Low-high
40.6
49.6
9.7
0.1
15
(3 – 33)
2.6
(1 – 8)
6. Extremely toxic 
0
16.3
23.1
60.6
9.2
(3 – 27)
3.2
(1 – 8)
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with the prior 
expectations regarding toxicity probabilities, 62.1% of the simulated trials choose the correct 
dose as MTD, that is a dose as MTD with the assumed true DLT rate in the target dose range.
In Scenario 2 (high-toxicity scenario), the starting dose level has 10% probability of 
observing DLTs in the first cohort. This would result in 7% of the simulated trials stopping 
due to too high toxicity. 
Scenario 3 (low-toxicity scenario) shows that only the highest dose level falls in the target 
dose range. In this case, 43.3% of the simulated trials choose a dose as MTD, which the 
assumed true DLT rate is within the under-dose range. 56.7% of the simulated trials result in
an MTD with the assumed true DLT rate in the target-dose range. And the probability of 
declaring an over toxic dose as MTD is 0%.
When the true dose toxicity curve does not follow logistic function, as shown in Scenario 4, 
the percentage of declaring a dose as MTD with the assumed true DLT rate in the target dose 
range is 58.7%.
In scenario 5, the probability of declaring MTD with the assumed true DLT rate in the target 
dose range is 49.6%. 
In scenario 6, due to extremely high toxicity, the probability of stopping the trial is 60.6%.


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The mean patient numbers range from 9.2 patients (Scenario 6) to 19 patients (Scenario 3)
and the maximum number of patients was 45. Therefore, the patient numbers are as expected 
and increase when moving away from the high-toxicity scenario.
Overall, by reviewing the OC presented in Table 10.3: 3, it can be seen that the model is 
robust to different scenarios of true dose-toxicity curves. In general, the model is 
conservative due to the overdose control criteria. In all scenarios, the probabilities of 
recommending a dose with true P(DLT) ≥ 33% as MTD are much smaller than probabilities 
of recommending a dose with true P(DLT) between 16% and 33% as MTD.
On-study recommendations based on the model are consistent with the clinical decision-
making process and should be considered in conjunction with other available clinical 
information by the BI clinical trial team and trial investigators in deciding the dose levels to 
be tested in order to determine the MTD estimate.
R version 4.0.2 and RStudio 1.3.959 version were used for the simulations.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
11 OCT 2021
EudraCT number
EU number
2021-003041-37
BI Trial number
1412-0003
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A phase Ia/b, open label, multicentre, dose 
escalation study of BI 905711 in combination with 
chemo-therapy followed by expansion cohorts in 
patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Synopsis, Section 3.3.2
Description of change
Inclusion criteria 13 was revised for better 
clarification. For CRC cohort, both Phase 1a and 
1b patient need to have PD after prior oxaliplatin-
based first line therapy or within 6 months after the 
end of oxaliplatin-based adjuvant therapy.
Oredering of other inclusion criteria were also 
revised for better clarification.
Rationale for change
Typo correction, better clarification
Section to be changed
Flowchart
Description of change
Footnote 16 added to make it clear about EF 
measument during Screening.
Rationale for change
For better understanding of procedure.
Section to be changed
Flowchart
Description of change
Safety lab testing, “x” added on C1D10 and EOT.
Rationale for change
Typo correction.
Section to be changed
Flowchart footnote 6
Description of change
Revised to clearly mention that pregnancy test is 
needed every 2 cycles.
Rationale for change
Typo correction.
Section to be changed
Flowchart, footnote 13, Section 5.4.2.6
Description of change
Required timing to conduct [18F]FDG-PET/CT 
during Screening was revised to 14 days (±7 days)
prior to treatment start.


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Deleted requirement to complete imaging with 
“contrast”.
Rationale for change
Typo correction.
Section to be changed
Section 1.2
Description of change
Detailed PK information from 1412-0001 added,
Rationale for change
Based on requirement from authority.
Section to be changed
Section 1.3, Section 1.4.2 and 1.4.3
Description of change
Detailed Safety information from 1412-0001 
added.
Rationale for change
Based on requirement from authority.
Section to be changed
Section 3.3.2
Description of change
Inclusion criteria 6 was revised to correct typo as 
below.
6. Availability and willingness to provide tumor 
tissue (fresh biopsy or and archival)
Rationale for change
Typo correction
Section to be changed
Section 4.1.5.2
Description of change
Below point was revised for better clarification
•Absence of worsening (any CTCAE grade) or 
new neurological signs/symptoms CTCAE grade 
>1 ≥ 2.
Rationale for change
Based on requirement from authority.
Section to be changed
Section 5.2.3
Description of change
Amylase added to safety lab parameter
Rationale for change
Based on authority request.
Section to be changed
Section 5.2.6.1.1
Description of change
Revised to describe more clearly, that worsening of 
pre-existing conditions other than the underlying 
disease should be reported as AE.
Rationale for change
For better clarification.
Section to be changed
Section 5.4 and 5.5
Description of change
Add explanation that China will not participate to 
Cell death biomarkers, gDNA, circulating free 
DNA and biobanking.
Rationale for change
Due to local requirement.
Section to be changed
Section 6.2.3.1
Description of change
Revised to correct typo abut rqquired timeframe 


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for EOT.
Rationale for change
Typo correction.
Section to be changed
Section 10.2
Description of change
Table 10.2 footnote “c” and “e” revised to correct 
typo.
Footnote c; …C1D810, C2D1, C3D1, C4D1, 
C5D1 and EOT after treatment.
Footnote e; …pre-dose sampling scheduled for 
Day 13 of the next cycle needs to be performed at 
the EOT visit.
Rationale for change
Typo correction.
11.2
GLOBAL AMENDMENT 2
Date of amendment
22 JUL 2022
EudraCT number
EU number
2021-003041-37
BI Trial number
1412-0003
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A phase Ia/b, open label, multicentre, dose 
escalation study of BI 905711 in combination with 
chemo-therapy followed by expansion cohorts in 
patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Synopsis, Section 1.3, Section 1.4.3
Description of change
Latest information from 1412-0001 updated.
Rationale for change
Information update
Section to be changed
Clinical Trial Synopsis and relevant section.
Description of change
Liposomal Irinotecan plus 5-FU/Leucovorin added 
as background therapy for PDAC cohort.
Rationale for change
Based on feedback from PIs
Section to be changed
Clinical Trial Synopsis
Description of change
Below sentences added in Primary endpoint for 
Phase 1b.
•In PDAC cohort safety run-in part: number of 
patients with DLTs during the MTD evaluation 
period assessed in the first 6 patients.
Rationale for change
To make consistent with Section 2.1.


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Section to be changed
Clinical Trial Synopsis and Section 3.3.2
Description of change
Inclusion criteria 8, requirement for serum lipase 
updated. Specific requirement for PDAC cohort 
added considering patient background.
Rationale for change
Based on BI internal discussion and decision.
Section to be changed
Flowchart Phase 1a
Description of change
-
Minor correction for better clarification.
-
Tumor marker measurement frequency has 
changed to every 2 cycles.
Rationale for change
For better clarification and understanding of 
efficacy.
Section to be changed
Flowchart Phase 1b and footnote 17
Description of change
-
Minor correction for better clarification.
-
Tumor marker measurement frequency has 
changed to every 2 cycles.
-
PRO-CTCAE added.
Rationale for change
For better clarification, understanding of efficacy 
and clinical utility of a medical intervention.
Section to be changed
Flowchart Phase 1b, footnote 12,
Description of change
Visit of Cycle 2 Day 4 has changed to Cycle 2 Day 
5.
Rationale for change
Based on BI internal discussion and decision.
Section to be changed
Flowchart Phase 1b, footnote 11 and 12, Section 
5.4.3.1
Description of change
Requirement for provision of biopsy samples has 
relaxed.
-
Archival tissue collected within 6 months 
can be accepted, instead of 3 months.
-
Fresh biopsy are not mandatory anymore if 
archival tissue collected within 6 months 
can be provided.
-
An on-treatment biopsy are not mandatory 
anymore and switched to optional 
requirement.
-
Other minor change for better flexibility 
and clarification
Rationale for change
Based on feedback from PIs
Section to be changed
Section 1.2
Description of change
PK characteristic description has updated based on 
recent information from 1412-0001.


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Rationale for change
Information updated
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 4.1.5, Table 4.1.5.3.1
Description of change
Dose for liposaml irinotecan added.
5-FU (infusion) dose corrected.
Rationale for change
Due to additional background therapy option and 
typo correction
Section to be changed
Section 4.1.5, Table 4.1.5.3.2
Description of change
Dose modification instruction for interstitial lung 
disease and anaphylactic reaction added.
Rationale for change
Based on BI internal discussion and decision for 
patient safety.
Section to be changed
Section 4.2.1.1
Description of change
Regimen information of Liposomal Irinotecan plus 
5-FU/Leucovorin) added.
Rationale for change
Due to additional background therapy option
Section to be changed
Section 5.1
Description of change
Tumor marker measurement frequency has 
changed to every 2 cycles.
Rationale for change
For better understanding of efficacy.
Section to be changed
Section 5.3.2 
Description of change
Description added for analysis with leftovers 
sample.
Rationale for change
Based on BI internal discussion and decision for 
better understanding of product.
Section to be changed
Section 5.4
Description of change
Plan for biomarker analysis updated.
Description which stated no sample collection for 
cell death biomarker, gDNA and cicurating DNA 
in China deleted.
Rationale for change
Based on BI internal discussion and decision for 


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better understanding of product.
Section to be changed
Section 5.4.2.1 
Description of change
Description added for analysis with leftovers 
sample.
Rationale for change
Based on BI internal discussion and decision for 
better understanding of product.
Section to be changed
Section 5.4.2.4 
Description of change
Description added for better clarification. 
Rationale for change
For better clarification,
Section to be changed
Section 5.4.2.5 
Description of change
Description added for better clarification. 
Rationale for change
For better clarification,
Section to be changed
Section 5.4.2.6 
Description of change
Description of allowance for assessment added for 
better clarification. 
Rationale for change
For better clarification,
Section to be changed
Section 5.4.3.2
Description of change
Description added about optional collection of pre-
dose plasma samples. 
Rationale for change
Based on BI internal discussion and decision for 
better understanding of product.
Section to be changed
Section 5.6 and Section 5.7
Description of change
Explanation of PRO-CTCAE added.
Rationale for change
For better understanding of clinical utility of a 
medical intervention.
Section to be changed
Section 7.2.5
Description of change
Description of further objective analyses added for 
PRO-CTCAE.
Rationale for change
For better understanding of clinical utility of a 
medical intervention.
Section to be changed
Section 7.1.8
Description of change
Safety evaluation during Phase 1b part added.
Preliminary, exploratory analysis of PK and 
immunogenicity added.
Rationale for change
For better patient safety.
Based on BI internal discussion and decision for 


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better understanding of product.
Section to be changed
Section 7.2.1
Description of change
Description of iPD added.
Rationale for change
For better clarification.
Section to be changed
Appendix 10.2 Table 10.2: 1, footnote d
Description of change
Table 10.2: 1 split into two tables, Table 10.2: 1
for Phase 1a part and Table 10.2: 2 for Phase 1b
part.
Collection of ADA and NAB sample has changed 
to continue after cycle 26, instead of stop 
collection from cycle 26.
Rationale for change
For better clarification.
Based on BI internal discussion and decision for 
better understanding of product.
Section to be changed
Appendix 10.2, Table 10.2: 2
Description of change
New table created specific for Phase 1b.
Rationale for change
For better clarification.
11.3
GLOBAL AMENDMENT 3
Date of amendment
27 Apr 2023
EudraCT number
EU number
2021-003041-37
BI Trial number
1412-0003
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A phase Ia/b, open label, multicentre, dose 
escalation study of BI 905711 in combination with 
chemo-therapy followed by expansion cohorts in 
patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Flowcharts
Description of change
Section amended to clarify visits, assessments and 
procedures that are mandatory/not mandatory for 
ongoing patients.
Rationale for change
Recruitment in this trial was discontinued 


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prematurely during the Phase I expansion cohort. 
Reduced procedures and assessments for ongoing 
patients to those needed for safety monitoring. 
Section to be changed
1.3
Description of change
Added text “Based on available preliminary data
from phase I clinical studies (1412.1 and 1412.3), 
the decision was made to terminate BI 905711 
(TRAILR2/CDH17) development program. This 
decision is not related to any safety concerns or 
unfavorable benefit/risk balance, but to the lack of 
predictive biomarkers and the limited efficacy 
particularly in the context of the evolving treatment 
landscape for advanced CRC and other GI cancers. 
The purpose of CTP v4.0 is to reduce the study 
related activities to the minimum required to 
monitor patient safety and to avoid undue burden on 
patients.”
Rationale for change
Explain rationale for CTP v4.0
Section to be changed
3.1
Description of change
Added text “Recruitment in Phase Ia is complete”
Added text “Recruitment in this trial was 
discontinued during Phase I expansion, and no 
PDAC patients were enrolled in this expansion 
cohort.”
Rationale for change
Recruitment in Phase Ia is complete.
Recruitment in Phase Ib discontinued prematurely.
Section to be changed
5.1
Description of change
Updated to reflect that tumor assessments will be 
assessed per institutional practice, and only overall 
response and disease progression will be collected 
in the eCRF. 
Rationale for change
To be consistent with flowchart revision.
Section to be changed
5.2.1, 5.2.2, 5.2.3, 5.2.4
Description of change
Physical examination, vital signs, safety labs, and 
ECGs will be done as per institutional practice.
Rationale for change
To be consistent with flowchart revision.
Section to be changed
5.3.2, 5.4
Description of change
Effective from CTP v4.0, PK, ADA/Nab, 
Biomarker, Tumor Biopsy samples and FDG-PET 


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scans are no longer collected for ongoing patients. 
Rationale for change
Blood, tissue samples and FDG-PET are no longer 
collected.
Section to be changed
6.2.3.1
Description of change
Deleted “If the patient finishes study treatment 
without having progressive disease, tumor 
assessment/imaging must be performed at the time 
of treatment discontinuation, unless it has been 
done within the past 4 weeks.”
Rationale for change
To be consistent with flowchart revision.
Section to be changed
6.2.3.3, 6.2.3.4
Description of change
Sections amended to define EOR as end of study.
No further follow-up visits after EOR are required, 
unless follow-up is for S(AE) that occurred before 
EOR period.
Rationale for change
To be consistent with flowchart revision.
Section to be changed
10.2
Description of change
Sampling tables for PK and Biomarkers no longer 
applicable per CTP v4.0
Rationale for change
To be consistent with flowchart revision.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Technical Version Number:
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Meaning of Signature  
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c40575634-01
BI Trial No.:
1412-0003
Title:
A phase Ia/b, open label, multicentre, dose escalation study of BI 
905711 in combination with chemo-therapy followed by 
expansion cohorts in patients with advanced gastrointestinal 
cancers
Investigational
Product(s):
BI 905711
Responsible trial 
statistician(s):
Phone:
Date of statistical 
analysis plan:
05 JAN 2024
the date (DD MMM YYYY) for SIGNED/REVISED must be the 
date when the TSAP is sent for approval in the EDMS
Version:
“Final” 
Page 1 of 29
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! 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT(S)...................................................................................8
5.2
SECONDARY ENDPOINT(S).............................................................................8
5.2.1
Key secondary endpoint(s) ...................................................................................8
5.2.2
Secondary endpoint(s)...........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................12
6.1
TREATMENT(S) ................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED ...........................................................................14
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................15
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........17
7.2
CONCOMITANT DISEASES AND MEDICATION......................................17
7.3
TREATMENT COMPLIANCE ........................................................................17
7.4
PRIMARY OBJECTIVE ANALYSIS ..............................................................17
7.4.1
Main analysis .......................................................................................................18
7.4.4
Supplementary analysis ......................................................................................18
7.5
SECONDARY OBJECTIVE ANALYSIS ........................................................18
7.5.1
Key secondary objective analysis.......................................................................18
7.5.1.1
Main analysis.........................................................................................................19
7.5.1.4
Supplementary analysis.........................................................................................19
7.5.2
Secondary objective analysis..............................................................................19
7.6
FURTHER OBJECTIVE ANALYSIS..............................................................19
7.7
EXTENT OF EXPOSURE .................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................20


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7.8.2
Laboratory data...................................................................................................21
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG ......................................................................................................................22
7.8.5
Others ...................................................................................................................22
8. 
REFERENCES ....................................................................................................23
10.
HISTORY TABLE..............................................................................................29


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LIST OF TABLES
Table 6.1:1
Analyzing Treatments.......................................................................................13
Table 10: 1
History table .....................................................................................................29


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
ADA
Adverse Event
Anti-Drug Antibodies
RPM
BLRM
CRC
Report Planning Meeting
Bayesian Logistic Regression Model
Colon Rectal Cancer
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DM&SM
Boehringer Ingelheim Data Management And Statistics Manual
DRA
DLT
Drug Regulatory Affairs
Dose Limiting Toxicities
DMG
Dictionary Maintenance Group
EDC
Electronic Data Capture
EMEA
European Agency For The Evaluation Of Medicinal Products
FAS
Full Analysis Set
ICH
International Conference On Harmonization
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary For Regulatory Activities
MQRM
PD
PDAC
Medical Quality Review Meeting
Protocol Deviation
Pancreatic ductal adenocarcinoma
PK
Pharmacokinetics
PPS
Per Protocol Set
PSTAT
Project Statistician
PT
Preferred Term
Q1
Lower Quartile
Q3
Upper Quartile
SA
Statistical Analysis
SD
Standard Deviation
SMQ
Standardised MedDRA Query


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Term
Definition / description
SOC
System Organ Class
TCM
Trial Clinical Monitor
TESS
Treatment Emergent Signs And Symptoms 
ToC
Table of Contents
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
SAS® Version 9.4 (or later version) will be used for all analyses including immunogenicity 
assessment.
For PK the following applies: Pharmacokinetic (PK) parameters will be calculated using 
Phoenix WinNonlinTM software (version 8.1 or higher, 
 
) or SAS Version 9.4 (or later version).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
This section is not applicable as this is the first version of the TSAP. This TSAP reflects all 
amendments in CTP up to and including Amendment 4.
As of March 2023 the study was terminated due to lack of efficacy signal and it was decided 
to produce an abbreviated report for CTR. The abbreviated CTR will include primary and 
secondary endpoint analyses. There will be limited analyses provided for PK and biomarkers 
as detailed in section 7.5.1.2 and section 7.6.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT(S)
The primary endpoints in Phase Ia are:
∀Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the 
true DLT rate being equal or above 33% during the MTD evaluation period as determined by 
the BLRM defined in section 7 of the CTP. For the definition of DLTs, refer to Section 5.2.7
of the CTP.
∀Number of patients with DLTs in the MTD evaluation period.
The MTD evaluation period is defined as a two 14-day treatment cycle from cycle 1 Day 1 
until the day before cycle 3 Day 1, or end of the REP (30 days + 5 days) in case of 
discontinuation before start of cycle 3.
The primary endpoints in Phase Ib are:
∀
Confirmed objective response (OR) as assessed by the investigator based on Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) in patients with measurable 
disease, defined as the best overall response of complete response (CR) or partial 
response (PR), from the first administration of trial treatment until the earliest of 
progressive disease (PD), death or last evaluable tumor assessment before start of 
subsequent anti-cancer therapy.
∀
In safety run-in part of PDAC cohort: number of patients with DLTs during the MTD 
evaluation period assessed in the first 6 patients.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
No key secondary endpoint is defined for this study.
5.2.2
Secondary endpoint(s)
The secondary endpoints in Phase Ia:


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The following PK parameters will be calculated after study treatment administration, as 
measured during the first cycle and after multiple cycles:
∀
Cmax: Maximum measured plasma concentration of BI 905711.
∀
AUC0-t2: Area under the concentration-time curve in plasma of BI 905711
The secondary endpoints in Phase Ib:
∀
Progression-Free Survival (PFS) defined from date of start of treatment to the date of 
disease progression or death, whichever is earlier as assessed by the investigator
according to RECIST 1.1.
∀
Radiological (CT Scan) tumor shrinkage, defined as the difference between the 
minimum post-baseline sum of longest diameters of target lesions and the baseline
sum of longest diameters of the same set of target lesions according to RECIST 1.1.
∀
The duration of OR is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements 
recorded on study) according to RECIST 1.1.
∀
Disease control, defined as CR, PR, or stable disease (SD) lasting at least 16 weeks 
according to RECIST 1.1 from the start of treatment until the earliest of PD, death or 
last evaluable tumor assessment and before start of subsequent anti-cancer therapy.
∀
The following PK parameters will be calculated after study treatment administration, 
as measured during the first cycle and after multiple cycles:
-
Cmax: Maximum measured plasma concentration of BI 905711 in plasma.
-
AUC0-t2: Area under the concentration-time curve for BI 905711 in plasma.
A detailed definition of objective response and PFS is given in appendix 10.1.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
This is a phase Ia/b, open label, multicentre, dose escalation study of BI 905711 in 
combination with chemotherapy (with or without bevacizumab) followed by expansion 
cohorts in patients with advanced or metastatic CRC and PDAC. The study will consist of two 
phases: a dose-escalation phase (Phase Ia) and a dose-expansion phase (Phase Ib). For the 
main analysis the phase Ia and phase Ib data will be pooled together.
In phase Ia, CRC patients will be administered BI 905711 + FOLFIRI + Bevacizumab 
biweekly with 20 planned patients. In phase Ib dose expansion, CRC patients will be 
randomized into two cohorts in a 2:1 ratio. Patients in cohort 1 (arm A with 40 planned 
patients) will be administered BI 905711 + FOLFIRI + Bevacizumab and patients in cohort 2 
(arm B with 20 planned patients) will be administered  FOLFIRI + Bevacizumab only. In 
addition there will be a separate single arm cohort with patients 2nd line PDAC that will be 
administered BI 905711 + FOLFIRI (or Liposomal Irinotecan + 5-FU/Leucovorin) with 20 
planned patients.
The following “analyzing treatment” (Table 6.1:1) will be used for reporting treatment 
emergent adverse events (AEs) and safety laboratory variables and the timeline criteria “start 
date ≤onset date of AE < stop date” will be used to determine if an AE will be assigned to be 
“analyzing treatment” or not. Detailed rule for assigning AEs to these time periods are listed 
below:
∀
If the date of informed consent ≤ AE onset date < date/time of the first 
administration of BI 905711, then the AE is assigned to “Screening”;
∀
If the date/time of the first administration of BI 905711 ≤ AE onset date < 
min{date of the late administration of BI 905711 + 35 days, DBL date}, then the 
AE is assigned to “On-treatment”;
∀
If AE onset date ≥ date of the last administration of BI 905711 + 35 days, then the 
AE is assigned to “Follow-up”.
AEs that have onset date during the screening or follow-up periods will be displayed in 
separate subject listings from those occurred during the on-treatment period. For the on-
treatment and follow-up periods, AE frequency tabulations will contain a “total” column, 
representing all doses of BI 905711. Subject data listings of AEs will not have a “total” 
column. To justify the MTD determination, DLTs occurring during the MTD evaluation 
period and the entire on-treatment period will be displayed separately.


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Table 6.1:1
Analyzing Treatments
Analyzing Treatment Period
Start Date (including)
Stop Date (excluding)
Screening
Date of informed consent
Date of the first 
administration of BI 905711
or chemotherapy whichever 
comes first
On-treatment
Date of the first 
administration of BI 905711
or chemotherapy whichever 
comes first
Date of the last 
administration of BI905711 
+ 35 days (for discontinued 
patients); or DBL date (for 
on-going patients)
Follow-up
Date of the last 
administration of BI 905711 
+ 35 days
Note: on-going patients do 
not have follow-up periods
Date of the last per protocol 
visit or DBL date, 
whichever comes first
MTD evaluation period
Date of the first 
administration of BI 905711
Date of the second 
administration of study BI 
905711 + 29 days; or DBL 
date; or the start date of the 
third treatment cycle, 
whichever is earlier
Note: a 35-day residual effect period is defined for this study. DBL = database lock. 29 days 
is from the criteria of DLT since any drug-related AE that causes a > 28 days of drug free 
interval is a DLT. 
The actual treatment codes and decodes, the labels for the analyzing treatment, and the 
analysis numbers are defined in the technical TSAP document of ADS Plan and Data Guide 
and stored in the same location with this document in Boehringer Ingelheim Regulatory 
Documents for Submission (BIRDS).
6.2
IMPORTANT PROTOCOL DEVIATIONS
According to (5), important safety protocol deviations (PDs) are those that potentially affect 
the rights or safety of study subjects. Important PDs (IPDs) are those that can potentially 
influence the primary outcome measure(s) for the respective patients in a way that is neither 
negligible nor in accordance with the study objectives.
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the trial master file (TMF) in the electronic document management system (EDMS). The final 
list of iPDs will be confirmed at the last report planning meeting (RPM) before the database 


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lock for the primary analysis of the primary endpoint (based on blinded central independent 
review).
Important PDs will be documented in the DV template domain with input from clinical. The 
DV template domain will then be sent to data management that will convert to a data base for 
analysis.
6.3
SUBJECT SETS ANALYSED
∀
Screened set: This patient set includes all subjects who have signed the informed 
consent. The screened set will be used for patient disposition tables.
∀
Treated set (TS): This includes all subjects who were dispensed study medication and 
were documented to have been treated with at least one dose of BI 905711 or 
chemotherapy. This TS is used for both safety and efficacy analyses. 
∀
MTD evaluation set (MTDS): This includes all patients in the TS who were not 
replaced for the MTD determination. The MTDS is used for the primary analyses of 
DLTs and MTD determination. Rules for replacement of patients are defined in the 
CTP Section 3.3.4.1.1. The list of replaced patients will be provided by the Trial 
Clinical Monitor no later than the last RPM and should be documented in the RPM 
minutes.
∀
Pharmacokinetic parameter analysis set (PKS): This includes all subjects in the treated 
set (TS) who provide at least one PK endpoint and was not excluded due to a protocol 
deviation relevant to the evaluation of PK or due to PK non-evaluability (as specified 
in the following subsection Pharmacokinetics). Descriptive and potential model based 
analyses of PK parameters will be based on the PKS.
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. If not 
specified otherwise, missing data will not be imputed and remain missing. Potential outliers
will be reported and analysed as observed.
Missing or incomplete AE dates are imputed according to BI standards in (3) (see “Handling 
of missing and incomplete AE dates”).
Missing data and outliers of PK data are handled according to BI standards. PK parameters 
that cannot be reasonably calculated based on the available drug concentration-time data will 
not be imputed.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the CTP’s flow chart.
Unless otherwise specified, baseline is defined as the time point closest to and prior to the 
first administration of any study treatment of either BI 905711 or chemotherapy. 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 the first 
administration of BI 905711.
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 BI 905711 is 
considered as baseline if and only if the examination time of the laboratory measurement is 
before the first administration of BI 905711.


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7.
PLANNED ANALYSIS
The following standards for End-Of-Text tables are defined:
∀
The set of summary statistics for continuous data is: N / Mean / Standard Deviation 
(StD) / Min / Median / Max. For tables that are provided for endpoints with some 
extreme data, median, quartiles, and percentiles should be preferred to mean, standard 
deviation, minimum, and maximum. If not otherwise specified, the abbreviation Pxx 
should be used for displaying the xxth percentile. Other than the Min and Max, all 
statistics will be presented to one more decimal place than the raw data.
∀
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). The precision 
for percentages will be one decimal place. The category “missing” will be displayed 
only if there are actually missing values.
∀
For time-to-event analysis tables the set of statistics is: number of patients [N(%)], 
number of patients with event [N(%)], <time to event> [months] followed by 25th 
percentile (P25), median, 75th percentile (P75) and number of patients censored 
[N(%)]. If not specified otherwise the duration as well as the time to event will be 
displayed in months.
Where applicable, conversion from days to weeks, months, and years will be as follows:
∀
Weeks = days ÷ 7
∀
Months = (days × 12) ÷ 365.25
∀
Years = days ÷ 365.25. 
General aspects for PK
Descriptive data analysis of PK endpoints and concentrations will be performed according to 
BI procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the criteria 
specified below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be
∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications


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Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example.
∀
Missing samples/concentration data at important phases of PK disposition curve.
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. Only 
concentration values within the validated concentration range and actual sampling times will 
be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).
7.1
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 CTR.
Concomitant diseases will be coded using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
Concomitant medications will be coded using the most current version of World Health 
Organization Drug Dictionary (WHO DD). Concomitant medications will be classified 
according to the Anatomical Therapeutic Chemical (ATC) classification system. The third 
ATC level will be used to categorize concomitant therapies 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 concomitant 
medications with more than one possible ATC level 3 category will be counted more than 
once. Explanatory footnotes will clarify the possible double counting.
Separate summaries of concomitant medications started prior to and after first administration
of trial medication will be produced.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics on the treated set are planned for this section of the CTR. The 
actual dose versus the planned dose for infusion drug administration for each patient will be 
listed. 
7.4
PRIMARY OBJECTIVE ANALYSIS
This trial will be performed as an open label. 


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7.4.1
Main analysis
The primary objective in phase Ia is to determine the MTD and the recommended dose for 
expansion (RDE) of BI 905711 in combination with FOLFIRI plus bevacizumab. MTD is 
defined as the highest dose with less than 25% risk of the true DLT rate being equal or above 
0.33 (EWOC criterion). Dose-escalation for each group will be guided by a two-parameter 
Bayesian Logistic Regression Model (BLRM), escalating with overdose control (EWOC).
In phase Ia, 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 will be presented, excluding patients who 
discontinue during the first treatment cycle for reasons other than a DLT. The BLRM as 
described in Section 7.2.3 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 7.2.3: 2 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) (under dosing), [0.16, 0.33) 
(target dosing), and [0.33, 1] (overdosing) will be computed and listed for each dose. The 
posterior probabilities of under dosing, 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.
In phase Ib the objective response will be analyzed in terms of objective response rate (ORR), 
defined as the proportion of patients with best overall response of complete response (CR) or 
partial response (PR). For each dose level, the proportion of patients with objective response 
(CR and PR) will be calculated with 95% confidence interval.
The primary endpoints in the dose-expansion part are objective response (OR). 
7.4.4
Supplementary analysis
Not applicable. 
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
There is no key secondary analysis as no key secondary endpoint has been specified in the 
protocol.


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7.5.1.1
Main analysis
Not applicable.
7.5.1.4
Supplementary analysis 
Not applicable.
7.5.2
Secondary objective analysis
Descriptive analysis of the following pharmacokinetic parameters will be performed for BI 
905711 in phase Ia and phase Ib as outlined in section 7.2.5 in CTP and according to BI 
standards if applicable and feasible
∀
Cmax : maximum measured concentration of BI 905711 in plasma
∀
AUC0-t2 : area under the concentration-time curve of BI 905711 in plasma
These parameters will be calculated after study treatment administration, as measured during 
the first cycle and after multiple cycles.
Other secondary endpoints in phase Ib include PFS, radiological (CT scan) tumor shrinkage, 
duration of OR and disease control and rate.
Kaplan-Meier estimates will be used to display the distribution of PFS for each treatment 
group on a Kaplan-Meier curve. To support the plot, estimated survival probabilities at 
specific time points of interest (scheduled imaging time points) will be tabulated along with 
95% CIs using Greenwood’s variance estimate. In addition, the Kaplan-Meier estimates will 
be used to provide estimates of the median, 25th, and 75th percentiles.
Duration of overall response and disease control will be analyzed by descriptive statistics.
Disease control rate will be analyzed the same way as ORR. Tumor shrinkage will be 
analyzed by descriptive statistics and by treatment. Waterfall and spider plots will be 
provided. 
For the abbreviated report there will be limited analyses provided from statistics and 
programming for PK and this will only include specific checks of PK data. The PK group 
(TMCP) will provide analyses for Cmax and AUC.
7.6
FURTHER OBJECTIVE ANALYSIS
PK and PD parameters will be analyzed by descriptive statistics and using standard methods. 
The Number of patients with treatment emergent AEs will be analyzed by descriptive 


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statistics. The analysis of OS will use the same methods as secondary endpoint PFS in Phase 
Ib.
ADA
ADA will be analyzed descriptively. A potential effect of ADA on PK, PD, safety and 
efficacy may be evaluated.
The abbreviated report will include listing of ADA titer. The PK group (TMCP) will provide 
analyses for ADA titer.
For the abbreviated report there will be no analysis of PRO data and PRO-CTCAE 
questionnaires.
Additional exploratory analyses of biomarker may be performed on the CDH17 expression as 
follows.
∀
Protein expression (IHC) levels for CDH17 compared to PFS (CRC)
∀
Gene expression levels for CDH17 and TRAILR2 compared to PFS (CRC)
∀
Protein expression (IHC) levels for CDH17 compared to cCasp (CRC)
∀
Gene expression levels for CDH17 and TRAILR2 compared to cCasp (CRC)
∀
Correlation between cCasp activity and PFS.
As of March 2023, the study was terminated due to lack of efficacy signal and it was decided 
to produce an abbreviated CTR. The abbreviated CTR would include a limited amount of 
biomarker outputs.
7.7
EXTENT OF EXPOSURE
Treatment exposure will be primarily summarized by the total on-treatment time and has been 
defined in section 5.4.2 of this TSAP.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
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 35 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.


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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 905711 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. In addition the number of DLTs in the MTD period and 
during the study will be provided. 
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:
∀
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 


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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.
7.8.3
Vital signs
Vital signs and physical examination, at Screening, baseline, during the course of the trial and 
at the end-of-trial evaluation will be listed with regard to possible changes compared to 
findings before start of treatment.
7.8.4
ECG
ECG data will be collected as described in CTP Section 5.2.4. Clinically significant findings 
in ECG data will be reported under “Adverse events” if applicable and will be analyzed 
accordingly. In addition, patients ECG assessments will be listed for all time points.
7.8.5
Others
Details on interim analysis are described in section 7.2.8 in CTP as follows.
No formal interim analysis is planned for PK and immunogenicity. Preliminary, exploratory 
analysis of PK and if applicable of immunogenicity will be performed prior to database lock 
during study conduct based on all evaluable data at the time of analysis. This will be 
performed to support dose escalations and e.g. in case the information is needed to inform 
other activities during the development of substance such as concomitant treatment 
restrictions in other trials. In contrast to the final calculations, the preliminary, exploratory 
analysis will be based on planned sampling times rather than on actual times, regardless of 
whether actual times were within the time windows or not. Therefore, minor deviations of 
preliminary and final results may occur. No formal preliminary PK and immunogenicity 
report will be written.
In Phase Ib there will be a continuous monitoring of the efficacy in terms of OR (and PD-
modulation). Tumor marker (CEA, CA19-9) modulations will be monitored continuously. An 
arm may be terminated early due to lack of efficacy.


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8.
REFERENCES
1. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
2. 001-MCS-36-472: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version, Group 
“Biostatistics & Data Sciences”, IDEA for CON.
3. 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON. 
4. 001-MCG-156: "Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
5. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical 
Study Reports, current version, EMA webpage.
6. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections changed
Brief description of change
Draft
03-MAY-2023
None
This is the draft TSAP 
Version 1
24-JUL-2023
3, 4, 5.3, 6.1, 6.6, 6.7, 7.6, 
10.1
Final based on reviewers 
comments.
Version 1.1
09-OCT-2023
7.4,7.5,7.6
Align sections 7.4,7.5,7.6 
heading titles with version 4 
TSAP template as applicable.
Final
30-NOV-2023
2, 5.4.2, 7.4.1 and 7.5.2
Update TSAP according to
final comments.