Clinical trial NCT04137289
Conditions: Gastrointestinal Neoplasms Cholangiocarcinoma Pancreatic Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2020-03-11; Completion date: 2023-11-27
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 1a - Explore safety and establish the maximum tolerated dose (MTD)/recommended dose levels for phase Ib expansion phase of BI 905711 based on the frequency of patients experiencing dose limiting toxicities (DLTs) during the MTD evaluation period. The MTD evaluation period is defined as the first two treatment cycles (from first dose administration until the day preceding the third dose administration or end of REP in case of discontinuation before start of Cycle 3).

Phase 1a - Explore pharmacokinetics/pharmacodynamics, and efficacy to guide the determination of a potentially effective dose range for phase Ib in the absence of MTD.

Phase 1b - Evaluate efficacy and safety of BI 905711 at a potentially effective dose range and determine the Recommended Phase 2 Dose (RP2D)

Detailed description:

Arms: arm 1: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.02 milligram/kilogram (mg/kg) of BI 905711 intravenously as a powder for solution for infusion, on Day 1 of each 14-day cycle treatment, once every two weeks. arm 2: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.06 mg/kg of BI 905711 intravenously as a powder for solution for infusion, on Day 1 of each 14-day cycle treatment, once every two weeks. arm 3: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.2 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. arm 4: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.6 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. Participants in both the dose escalation and dose expansion phases at this dose were pooled together for baseline analysis. arm 5: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 0.6 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every week for 3 weeks and then 1 week off (3 weeks on, 1 week off). arm 6: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 1.2 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. Participants in both the dose escalation and dose expansion phases at this dose were pooled together for baseline analysis. arm 7: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 2.4 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. Participants in both the dose escalation and dose expansion phases at this dose were pooled together for baseline analysis. arm 8: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 3.6 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks. arm 9: Patients with confirmed, advanced unresectable or metastatic GI cancers received a single administration (Cycle 1) and multiple administrations (Cycle 3) of 4.8 mg/kg of BI 905711 intravenously on Day 1 of each 14-day cycle treatment, once every two weeks.
Interventions: intervention 1: BI 905711
Intervention descriptions: intervention 1: BI 905711

Protocol documents:
Prot_000.pdf: 




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Secondary endpoints: 
Phase Ia:
∀
The following PK parameters of BI 905711 will be evaluated 
after the first and after the third administrations of BI 
905711:
o
Cmax: maximum measured concentration of BI 
905711 in plasma
o
AUC0-t2: area under the concentration-time curve of 
BI 905711 in plasma
∀
Objective response based on RECIST 1.1 criteria
Phase Ib:
∀
The following PK parameters of BI 905711 will be evaluated 
after the first and after the third administrations of BI 
905711:
o
Cmax: maximum measured concentration of BI 
905711 in plasma
o
AUC0-t2: area under the concentration-time curve of 
BI 905711 in plasma 
∀
Number of patients with treatment-emergent AEs
∀
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 overall response is measured from the time 
measurement criteria are first met for Complete Response 
(CR)/ Partial Response (PR) (whichever is first recorded) 
until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive 
disease the smallest measurements recorded on study) 
according to RECIST 1.1.
∀
Disease control, defined as CR, PR, or stable disease 
according to RECIST 1.1 from the start of treatment until the 
earliest of progression disease, death or last evaluable tumor 
assessment and before start of subsequent anti-cancer 
therapy.
Trial design
Phase Ia is an open-label, dose escalation study of BI 905711 
administered intravenously. The eligible patient population will be 
patients with advanced refractory gastrointestinal cancers. Dose 
escalation will be guided by a Bayesian logistic regression model 
with overdose control. Pharmacokinetics and efficacy will be 
evaluated to guide determination of a potentially effective dose 
range for phase Ib.
Phase Ib is a randomised, open label study to determine safety and 
efficacy of BI 905711 in the expansion cohorts of colorectal cancer 
(CRC) patients and pancreatic cancer (PDAC) patients. CRC 


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patients will be randomised into four cohorts (three dose levels in 
biweekly regimen and one dose level in weekly regimen (3 weeks 
on, 1 week off). PDAC patients will be enrolled into one cohort (3 
weeks on, 1 week off).  
Total number of 
patients 
Approximately 140 evaluable patients 
Number of patients on 
each treatment
Phase Ia (dose escalation): approximately 40 evaluable CRC patients
and 20 non-CRC GI cancer patients.
Phase Ib (dose expansion): approximately 60 evaluable CRC 
patients in 3 dose levels with 4 cohorts, and approximately 20 
evaluable PDAC patients in 1 cohort.
Diagnosis
Patients with advanced, refractory gastrointestinal cancers of 
following histologies:
∀
Colorectal adenocarcinoma
∀
Gastric adenocarcinoma
∀
Esophageal adenocarcinoma
∀
Pancreatic adenocarcinoma
∀
Cholangiocarcinoma and gallbladder carcinoma
∀
Small intestine adenocarcinoma
In- and exclusion 
criteria
Inclusion Criteria
1. a. Phase Ia (dose escalation only)
Histologically or cytologically confirmed, advanced unresectable 
or metastatic gastrointestinal cancers of following histologies:
∀
Colorectal adenocarcinoma
∀
Gastric adenocarcinoma
∀
Esophageal adenocarcinoma
∀
Pancreatic adenocarcinoma
∀
Cholangiocarcinoma and gallbladder carcinoma
∀
Small intestine adenocarcinoma
b. Phase Ib (expansion phase)
Histologically or cytologically confirmed, advanced unresectable 
or metastatic gastrointestinal cancers of following histologies:
∀
Colorectal adenocarcinoma
∀
CDH17 positive pancreatic adenocarcinoma (in tumour 
tissue as assessed by central testing)
2. Patient who has failed all available conventional therapies 
known to confer clinical benefit for their disease based on local 
approved standards. For patients with colorectal cancer, prior 
treatment with regorafenib or TAS-102 is optional.
3. a. Phase Ia (dose escalation) only: 
•
Patient with either measurable or non-measurable/non-
evaluable disease. 


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b. Phase Ia (expanded cohort) and Phase Ib (expansion phase) 
only: 
•
At least one target lesion that can be accurately measured per 
RECIST v.1.1.
4. Availability and willingness to provide archived tumor tissue 
specimen and to undergo tumor biopsy before treatment. Pre-
treatment fresh tumor biopsy collections for biomarker analyses 
are considered optional in phase Ia and mandatory in phase Ib. 
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 due to 
before mentioned reasons an archived tumor tissue specimen 
obtained within ≤6 months of screening must be submitted. In 
case the patient undergoes baseline tumor biopsy, an archived 
tumor tissue specimen must be submitted regardless of date of 
collection.
5. Adequate hepatic, renal and bone marrow functions as defined 
by all of the below:
a.
Total bilirubin ≤1.5x institutional ULN (≤ 3 x ULN for 
patient with Gilbert’s syndrome)
b. ALT and AST ≤2.5 x institutional ULN (≤5x institutional
ULN for patients with known liver metastases) 
c. Serum creatinine ≤1.5x institutional ULN. If creatinine is > 
1.5 x ULN, patient is eligible if concurrent creatinine 
clearance ≥ 50 ml/min (≥0.05 L/min) (measured or 
calculated by CKD-EPI formula or Japanese version of 
CKD-EPI formula for Japanese patients).
d. ANC ≥1.0x 109/L (≥ 1.0 x 103/μL, ≥ 1,000/mm3)
e. Platelets ≥ 100x109/ L (≥ 100 x 103/μL, ≥ 100 x 103/mm3)
f. Hemoglobin (Hb) ≥8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 mmol/L
(without transfusion within previous week)
g. Phase Ia, and Phase Ib CRC cohort: Serum lipase ≤ 1.5 
institutional ULN
h. Phase Ib PDAC cohort: Serum lipase >1.5 - 2.0 x ULN or 
asymptomatic >2.0 - 5.0 x ULN if related to PDAC
6. Recovery from any adverse events according to CTCAE v5.0 of 
previous anti-cancer therapies to baseline or CTCAE grade 1, 
except for alopecia CTCAE grade 2, sensory peripheral 
neuropathy CTCAE grade ≤2 or considered not clinically 
significant.
7. ECOG performance status ≤ 1
8. Life expectancy ≥ 3 months in the opinion of the investigator
9. Of legal adult age (according to local legislation) at screening.
10. Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.
11. Male or female patients. Women of childbearing potential 
(WOCBP) and men able to father a child must be ready and able 


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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 the protocol.
Exclusion criteria:
1. Previous systemic anti-cancer therapy within the specified 
timeframe from the last dose intake to the first dose of trial 
treatment as shown below: 
∀
Any non-investigational drug, including anti-
angiogenic antibodies (bevacizumab or ramucirumab) 
and anti-EGFR antibodies (cetuximab or 
panitumumab), within 14 days.
∀
Any investigational drug or other antibodies including 
immune checkpoint inhibitors, within 28 days. 
2. 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 but must be discussed with the sponsor.
3. 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. Any history of stroke or 
myocardial infarction within 6 months prior to screening.
4. Known pathological condition of GI tract, liver and pancreas,
excluding the disease under study, that may interfere with 
assessment of drug safety or 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 grade ≥2
according to CTCAE v5.0.
5. Known history of human immunodeficiency virus infection. 
6. 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


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7. Active concomitant malignancies, other than the one treated in 
this trial.
8. 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.
9. 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 to within 30 days after the last study treatment.
10. 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.
11. Patients who are under judicial protection and patients who are
legally institutionalized
12. Major surgery (major according to the investigator’s assessment) 
performed within 3 weeks prior to treatment start or planned 
within 3 months after screening, e.g. hip replacement.
13. Any of the following cardiac criteria:
∀
Resting corrected QT interval (QTc) >470 msec
∀
Any clinically important abnormalities (as assessed by the 
Investigator) in rhythm, conduction, or morphology of 
resting ECGs, e.g., complete left bundle branch block, third 
degree heart block.
∀
Patients with a known 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, 
multigated 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.
14. Known hypersensitivity to the trial medication and/or its 
components i.e. polysorbate 20, sodium citrate, lysine 
hydrochloride, sucrose, citric acid.
Test product(s)
BI 905711
dose
Phase Ia: starting dose of 0.02 mg/kg


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Phase Ib: 
CRC patients - Three dose levels with four cohorts: 
Biweekly dosing: 0.6mg/kg; 1.2 mg/kg; 2.4mg/kg
Weekly dosing: 0.6mg/kg
PDAC patients – One dose level with one cohort:
Weekly dosing: 0.6mg/kg
method and route of 
administration
Intravenous
Duration of treatment
BI 905711 will be administered until disease progression, 
unacceptable toxicity, or other reasons requiring treatment 
discontinuation.
Safety criteria
Safety and tolerability of BI 905711 by evaluation of the incidence 
and severity of adverse events according to CTCAE v5.0 and DLTs,
safety laboratory parameters, vital signs, and electrocardiograms 
(ECGs); and the determination of the MTD. 
Statistical methods
Phase Ia: Dose escalation is guided by a Bayesian Logistic 
Regression Model (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. At the end of 
the dose escalation, the toxicity probability at each dose level will be 
calculated to determine an estimate of the MTD if applicable.
Phase Ib: Primary and secondary endpoints will be analyzed
descriptively. Bayesian hierarchical models will be applied to the 
multiple dose levels..


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FLOW CHART: PHASE IA – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
Screen
Cycle 1*
Cycle 2
*β
Cycle 3 *β
Cycle 4 * β
Cycle 5 
and 
beyond *β
EOT**
EOR
*** 
FU for
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
2
1
(+2)
2
3
8
(± 3)
1
(+2)
2
1 
(+2)
Day 0-7 after 
last dose
30 (+5) days
after last dose
Informed Consent1
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Eligibility for re-treatment2
x
x
x
x
Physical Examination3
x
x
x
x
x
x
x
x
x
Height
x
Body weight4
x
x
x
x
x
x
x
ECOG performance score5
x
x
x
x
x
x
x
x
Pregnancy test6
x
x
x
x
x
12-lead-ECG7
x
x
x
x
x
x
x
Echocardiography (or 
multigated acquisition scan) 17
x
Administration of BI 9057118
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
x
x
Safety lab parameters9
x
x
x9
x
x
x
x
x
x
x
x
Pharmacokinetics
10
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA sampling
10
x
x
x
x
x
x


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FLOW CHART: PHASE IA (CONT.) – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
Screen
Cycle 1*
Cycle 2 
*β
Cycle 3 *β
Cycle 4 * β
Cycle 5 
and 
beyond *β
EOT**
EOR
*** 
FU 
for 
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
2
1
(+2)
2
3
8
(± 3)
1
(+2)
2
1 
(+2)
Day 0-7 after 
last dose
30 (+5) days 
after last dose 
Fresh tumor biopsy
(optional)11
x
Archival tumor tissue 
(mandatory)12
x
[18F]FDG-PET/CT 13
x13
x13
Adverse Events14
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
Tumor assessment by 
CT/MRI RECIST 1.115
x15
x15
Termination of study 
medication
x
Patient vital status
x
Brain MRI (in phase Ia 
only)16
x




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12For phase Ia, an archival tumor tissue is mandatory.
13In CRC patients, [18F]FDG-PET/CT should be performed at baseline within 14 days (±7 days) prior to treatment start (Cycle 1 Day 1). A second [18F]FDG-PET/CT will be performed at the 8-
week tumor assessment timepoint. It may be performed together with standard CT assessment if feasible.
14After the individual patient’s end of the trial, the investigator should report only any occurrence of cancer, related SAEs and related AESIs of which the investigator may become aware of and 
only via the SAE form, see Section 5.2.6.2.1.
15Tumor 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: 
Repeat imaging at > 4 weeks to confirm response. 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’s cancer is being monitored with a specific tumor marker (e.g. CEA, CA19.9, etc.), tumor marker levels should be obtained at baseline, and at 
every protocol-specified tumor assessment timepoint.
16During phase Ia only, a brain MRI should be performed at baseline and repeated as clinically indicated. Brain MRI does not need to be performed at screening if there are results available 
from a brain MRI performed within 12 weeks prior to start of treatment. In case of contraindication for MRI, a brain CT scan can be performed after agreement between the investigator and 
Sponsor.
17To evaluate Exclusion criteria #13, only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the ejection fraction (EF), the EF 
will be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multigated 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. Echocardiography (or multigated acquisition scan) may be performed at any time during the study if clinically indicated.


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FLOW CHART: PHASE IB- BIWEEKLY DOSING  – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
Screen
Cycle 1*
Cycle 2 
*β
Cycle 3 *β
Cycle 4 * β
Cycle 5 
and 
beyond *β
EOT**
EOR
*** 
FU 
for 
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
3
1
(+2)
2
3
8
(± 3)
1
(+2)
2
1 
(+2)
Day 0-7 after 
last dose
30 (+5) days 
after last dose 
Informed Consent1
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Eligibility for re-treatment2
x
x
x
x
Physical Examination3
x
x
x
x
x
x
x
x
x
Height
x
Body weight4
x
x
x
x
x
x
x
ECOG performance score5
x
x
x
x
x
x
x
x
Pregnancy test6
x
x
x
x
x
12-lead-ECG7
x
x
x
x
x
x
x
Echocardiography (or 
multigated acquisition scan) 8
x
Randomization4
x
Administration of BI 9057119
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
x
x
Safety lab parameters10
x
x
x9
x
x
x
x
x
x
x
x
Pharmacokinetics
11
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA sampling
11
x
x
x
x
x
x


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FLOW CHART: PHASE IB- BIWEEKLY DOSING (CONT.) – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
Screen
Cycle 1*
Cycle 2 
*β
Cycle 3 *β
Cycle 4 * β
Cycle 5 
and 
beyond *β
EOT**
EOR
*** 
FU 
for 
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
3
1
(+2)
2
3
8
(± 3)
1
(+2)
2
1 
(+2)
Day 0-7 after 
last dose
30 (+5) days 
after last dose 
Fresh tumor biopsy12
x12
x12
x12
Archival tumor tissue 12
x12
[18F]FDG-PET/CT 13
x13
x13
Adverse Events14
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
Tumor assessment by 
CT/MRI RECIST 1.115
x15
x15
Tumor marker16
x16
x16
Termination of study 
medication
x
Patient vital status
x
(*) 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 Visit. 




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12Pre-treatment fresh tumor biopsy collections for biomarker analyses are considered mandatory in phase Ib. Only non-significant risk procedures per the investigator’s judgment will be used to 
obtain any biopsies specified in this study. For each biopsy, a minimum of 2 core needle biopsies needs to be freshly taken between screening and before first study treatment (Cycle 1 Day 1)
after eligibility has been confirmed. In case a fresh pre-treatment tumor biopsy cannot be obtained due to before mentioned reasons an archived tumor tissue specimen obtained within ≤6 months 
of screening must be submitted. In case the patient undergoes baseline tumor biopsy, an archival tumor tissue must also be submitted (mandatory) regardless of the date of collection. An additional 
fresh tumor biopsy should be taken on Cycle 2 Day 3 (optional) and/or at disease progression (optional) for a patient in which a fresh biopsy has been successfully obtained before first study 
treatment (refer to Section 5.4.1).13[18F]FDG-PET/CT should be performed at baseline within 14 days (±7 days) prior to treatment start (Cycle 1 Day 1). A second [18F]FDG-PET/CT will be 
performed at the 8 week tumor assessment timepoint. It may be performed together with standard CT assessment if feasible.
14After the individual patient’s end of the trial, the investigator should report only any occurrence of cancer, related SAEs and related AESIs of which the investigator may become aware of and 
only via the SAE form, see Section 5.2.6.2.1.
15Tumor 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. At least one prior pre-study digital scan of the target lesion should be sent to the central imaging facility of an independent vendor 
if available. 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: 
Repeat imaging at > 4 weeks to confirm response. 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. 
16Patient’s cancer will be monitored with a specific tumor marker (e.g. CEA, CA19.9, etc.). Tumor marker levels should be obtained at baseline, and at every protocol-specified tumor 
assessment timepoint.


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FLOW CHART: PHASE IB- WEEKLY DOSING  – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
SV118
SV218 / 
Screen
Cycle 1*
Cycle 2 
*β
Cycle 3 *β
Cycle 4 *
β
Odd cycles 
(e.g. 5, 7, 9, 
etc) *β
Even cycles
(e.g. 6, 8, 10, 
etc) *β
EOT**
EOR
*** 
FU for 
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
Any
time 
before 
SV2
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
3
1
(+2)
2
3
8
(± 3)
1
(+2)
2
1 
(+2)
8
(± 3)
1 
(+2)
Day 0-7 
after last 
dose
30 (+5) 
days after 
last dose 
Tissue analysis consent
x18
CDH17 status analysis
x18
Informed Consent1
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Eligibility for re-
treatment2
x
x
x
x
x
Physical Examination3
x
x
x
x
x
x
x
x
x
x
Height
x
Body weight4
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
x
12-lead-ECG7
x
x
x
x
x
x
x
x
Echocardiography (or 
multigated acquisition 
scan)8
x


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FLOW CHART: PHASE IB- WEEKLY DOSING (CONT.) – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
SV118
SV218 / 
Screen
Cycle 1*
Cycle 2 *β
Cycle 3 *β
Cycle 4 * β
Odd cycles 
(e.g. 5, 7, 9, 
etc) *β
Even 
cycles (e.g. 
6, 8, 10, 
etc) *β
EOT**
EOR
*** 
FU for 
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
Any
time 
before 
SV2
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
3
1
(+2)
2
3
8
(± 
3)
1
(+2)
2
1 
(+2)
8
(± 3)
1 
(+2)
Day 0-
7 after 
last 
dose
30 (+5) 
days 
after last 
dose 
Randomisation4
x
Administration of BI 
9057119,17
x17
x17
x17
x17
x17
x17
x17
x17
x17
Vital Signs
x
x
x
x
x
x
x
x
x
x
x
x
x
Safety lab parameters10
x
x
x1
0
x
x
x
x
x
x
x
x
x
x
x
Pharmacokinetics
11
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA sampling
11
x
x
x
x
x
x
x
Fresh tumor biopsy12
x12,18
x12
x12
x12
Archival tumor tissue12
x12,18
x12
[18F]FDG-PET/CT 13 
x13
x13
Adverse Events14
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


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FLOW CHART: PHASE IB- WEEKLY DOSING (CONT.) – No longer applicable per CTP v7.0
Treatment Period
Post-Treatment
Visit
SV118
SV218 / 
Screen
Cycle 1*
Cycle 2 *β
Cycle 3 *β
Cycle 4 *
β
Odd 
cycles (e.g. 
5, 7, 9, etc) 
*β
Even cycles 
(e.g. 6, 8, 
10, etc) *β
EOT*
*
EOR
*** 
FU for 
PDǂ
FU for 
survival 
statusǂ
Day
(day range)
Any
time 
before 
SV2
-28 
- 1
1
(+3)
2
3
8
(± 3)
1
(+2)
3
1
(+2)
2
3
8
(± 3)
1
(+2)
2
1 
(+2)
8
(± 3)
1 
(+2)
Day 
0-7 
after 
last 
dose
30 (+5) 
days after 
last dose 
Tumor assessment by 
CT/MRI RECIST 1.115
x15
x15
Tumor marker16
x16
x16
Termination of study 
medication
x
Patient vital status
x
(*) 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 Visit. 
(***) The 30-Day Safety Followup 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). 
ǂAdditional follow-up visits for progression after the 30-Day safety follow-up visit will be performed for patients who discontinue for reasons other than progression or death. Follow-up 
continues until progression per the imaging schedule (see Section 5.1).  The follow-up visits for survival status will be performed every 12 weeks (+/-7 days)(in person or by telephone) until 
death, lost to follow-up, withdrawal of consent, or end of the whole trial (see Section 6.2.3.3).
βThe interval between two dose administrations must be always at least 7 days with the exception of the interval between dose administration on Day 1 of an even-numbered cycle and Day 1 of 
the subsequent odd-number cycle which must always be at least 14 days (e.g. Cycle 2 Day 1 and Cycle 3 Day 1, Cycle 4 Day 1 and Cycle 5 Day 1, etc.). 
1Written 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.




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14After the individual patient’s end of the trial, the investigator should report only any occurrence of cancer, related SAEs and related AESIs of which the investigator may become aware of and 
only via the SAE form, see Section 5.2.6.2.1.
15Tumor 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. At least one prior pre-study digital scan of the target lesion should be sent to the central imaging facility of an independent 
vendor if available. 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: 
Repeat imaging at > 4 weeks to confirm response. 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. 
16Patient’s cancer will be monitored with a specific tumor marker (e.g. CEA, CA19.9, etc.). Tumor marker levels should be obtained at baseline, and at every protocol-specified tumor 
assessment timepoint.
17A patient will receive BI 905711 as a single administration every week for 3 weeks on, 1 week off (refer to Section 4.1.2.2).
18Required only for phase Ib PDAC cohort. SV1 and SV2 can occur in parallel. 


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FLOW CHART: PHASE 1B – BIWEEKLY - REDUCED SCHEDULE PER CTP V7.0 – ONGOING PATIENTS 
Treatment Cycle 6and 
subsequent cycles*
Post-Treatment
Visit
CxD1a
EOT**
EOR / EOS***
Day
(day range)
1
(+2)
Day 0-7 after last dose
30 (+5) days after last dose 
Physical Examination and Vital Signs
Per institutional practice6
Safety lab parameters 
Per institutional practice6
Tumor assessment by CT/MRI RECIST 1.11
Per institutional practice
Pregnancy test2
Per institutional practice6
12-lead-ECG
Per institutional practice6
Body weight
x
Administration of BI 9057113
x
Adverse Events4
x
x
x
Concomitant therapy5
x
x
x
Termination of study medication
x
(*) 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. Only overall response and disease progression
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. 
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 4.1.4.1.1 and 4.1.4.1.2. 


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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.
6 The results of these assessments will be documented in the source data, but will not be collected in the eCRF. Findings which qualify as an (S)AE will be reported in the 
eCRF, and in case of an SAE, on the SAE form. 


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FLOW CHART: PHASE 1B – WEEKLY - REDUCED SCHEDULE PER CTP V7.0 – ONGOING PATIENTS
Treatment Cycle 6 and subsequent cycles*
Post-Treatment
Visit
Even cycles (e.g. 6, 8, 10)
Odd cycles (e.g. 7, 9, 11)
EOT**
EOR / EOS***
Day
(day range)
1
(+2)
1 
(+2)
8
(± 3)
Day 0-7 after last dose
30 (+5) days after 
last dose 
Physical Examination and Vital Signs
Per institutional practice6
Safety lab parameters 
Per institutional practice6
Tumor assessment by CT/MRI RECIST 1.11
Per institutional practice
Pregnancy test2
Per institutional practice6
12-lead-ECG
Per institutional practice6
Body weight
x
x
Administration of BI 9057113
x
x
x
Adverse Events4
x
x
x
x
x
Concomitant therapy5
x
x
x
x
x
Termination of study medication
x
(*) 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 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). 
1Tumor assessment will be performed according to institutional practices. Images no longer need to be sent to imaging vendor. Only overall response and disease progression
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. 
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 4.1.4.1.1 and 4.1.4.1.2. 
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.


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5Concomitant medications that are used to treat adverse events.
6 The results of these assessments will be documented in the source data, but will not be collected in the eCRF. Findings which qualify as an (S)AE will be reported in the 
eCRF, and in case of an SAE, on the SAE form. 
Applicable to all patients ongoing patients: 
After implementation of CTP v7.0, 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).
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)


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TABLE OF CONTENTS
 
...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART: PHASE IA – No longer applicable per CTP v7.0....................................9
FLOW CHART: PHASE IB- BIWEEKLY DOSING  – No longer applicable per CTP 
v7.0........................................................................................................................13
FLOW CHART: PHASE IB- WEEKLY DOSING  – No longer applicable per CTP v7.017
FLOW CHART: PHASE 1B – BIWEEKLY - REDUCED SCHEDULE PER CTP V7.0 
– ONGOING PATIENTS...................................................................................22
FLOW CHART: PHASE 1B – WEEKLY - REDUCED SCHEDULE PER CTP V7.0 –
ONGOING PATIENTS......................................................................................24
TABLE OF CONTENTS ......................................................................................................26
ABBREVIATIONS................................................................................................................30
1.
INTRODUCTION...............................................................................................33
1.1
MEDICAL BACKGROUND.............................................................................33
1.2
DRUG PROFILE................................................................................................34
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................40
1.4
BENEFIT - RISK ASSESSMENT.....................................................................40
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................45
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........45
2.1.1
Main objectives....................................................................................................45
2.1.2
Primary endpoint(s)............................................................................................45
2.1.3
Secondary endpoint(s) ........................................................................................46
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................48
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................48
3.1.1
Phase Ia: dose escalation (Part A) .....................................................................48
3.1.1.1
Recruitment in CRC escalation cohorts................................................................48
3.1.1.2
Recruitment in non-CRC GI cancer cohorts.........................................................49
3.1.1.3
MTD determination/recommended dose range for expansion..............................49
3.1.2
Phase Ib: expansion cohorts (Part B)................................................................50
3.1.2.1
Randomized CRC expansion cohort.....................................................................51
3.1.2.2
Single Arm PDAC expansion cohort....................................................................51
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................51
3.3
SELECTION OF TRIAL POPULATION .......................................................52


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3.3.1
Main diagnosis for trial entry ............................................................................52
3.3.2
Inclusion criteria .................................................................................................53
3.3.3
Exclusion criteria ................................................................................................54
3.3.4
Withdrawal of patients from treatment or assessments..................................56
3.3.4.1
Discontinuation of trial treatment .........................................................................56
3.3.4.2
Withdrawal of consent to trial participation .........................................................57
3.3.4.3
Discontinuation of the trial by the Sponsor ..........................................................57
3.3.4.4
Replacement of patients for MTD determination and PK evaluation in phase Ia 58
4.
TREATMENTS...................................................................................................59
4.1
INVESTIGATIONAL TREATMENTS ...........................................................59
4.1.1
Identity of the Investigational Medicinal Products..........................................59
4.1.2
Selection of doses in the trial and dose modifications......................................59
4.1.2.1
Dose(s) selection for Phase Ia...............................................................................59
4.1.2.2
Dose(s) selection for phase Ib...............................................................................61
4.1.2.3
Dose modification.................................................................................................62
4.1.3
Method of assigning patients to treatment groups...........................................63
4.1.4
Drug assignment and administration of doses for each patient......................63
4.1.4.1
Management of toxicities......................................................................................64
4.1.5
Blinding and procedures for unblinding...........................................................68
4.1.5.1
Blinding.................................................................................................................68
4.1.5.2
Unblinding and breaking the code ........................................................................68
4.1.6
Packaging, labelling, and re-supply...................................................................68
4.1.7
Storage conditions...............................................................................................68
4.1.8
Drug accountability.............................................................................................68
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................69
4.2.1
Other treatments and emergency procedures..................................................69
4.2.2
Restrictions ..........................................................................................................69
4.2.2.1
Restrictions regarding concomitant treatment ......................................................69
4.2.2.2
Restrictions on diet and lifestyle...........................................................................70
4.2.2.3
Contraception requirements..................................................................................71
4.3
TREATMENT COMPLIANCE........................................................................71
5.
ASSESSMENTS..................................................................................................72
5.1
ASSESSMENT OF EFFICACY........................................................................72
5.2
ASSESSMENT OF SAFETY.............................................................................72
5.2.1
Physical examination ..........................................................................................72
5.2.2
Vital signs.............................................................................................................72
5.2.3
Safety laboratory parameters ............................................................................72
5.2.4
Electrocardiogram ..............................................................................................74
5.2.5
Other safety parameters.....................................................................................74
5.2.6
Assessment of adverse events.............................................................................74
5.2.6.1
Definitions of AEs ................................................................................................74
5.2.6.2
Adverse event collection and reporting ................................................................81
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................83


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5.3.1
Assessment of pharmacokinetics .......................................................................83
5.3.2
Methods of sample collection .............................................................................83
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................84
5.4
..............................................................84
5.4.1
Methods of sample collection .............................................................................85
5.4.1.1
Tumor tissue..........................................................................................................85
5.4.1.2
Plasma samples .....................................................................................................86
5.5
BIOBANKING (OPTIONAL) ...........................................................................89
5.5.1
Methods and timing of sample collection..........................................................89
5.6
OTHER ASSESSMENTS...................................................................................90
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................90
6.
INVESTIGATIONAL PLAN.............................................................................91
6.1
VISIT SCHEDULE.............................................................................................91
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................91
6.2.1
Screening period..................................................................................................91
6.2.2
Treatment period(s)............................................................................................93
6.2.3
Follow up period and trial completion..............................................................93
6.2.3.1
End of treatment (EOT) visit ................................................................................93
6.2.3.2
Follow-up visits.....................................................................................................93
6.2.3.3
Extended follow-up period....................................................................................94
6.2.3.4
Trial completion for an individual patient ............................................................94
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE95
7.1
STATISTICAL DESIGN - MODEL.................................................................95
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................99
7.3
PLANNED ANALYSES.....................................................................................99
7.3.1
Primary endpoint analyses.................................................................................99
7.3.2
Secondary endpoint analyses ...........................................................................100
7.3.4
Safety analyses...................................................................................................100
7.3.5
Pharmacokinetic and pharmacodynamic analyses........................................101
7.4
INTERIM ANALYSES ....................................................................................101
7.5
HANDLING OF MISSING DATA .................................................................101
7.6
RANDOMISATION .........................................................................................102
7.7
DETERMINATION OF SAMPLE SIZE .......................................................102
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......104


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8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................104
8.2
DATA QUALITY ASSURANCE ....................................................................105
8.3
RECORDS.........................................................................................................105
8.3.1
Source documents .............................................................................................105
8.3.2
Direct access to source data and documents...................................................106
8.3.3
Storage period of records .................................................................................107
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................107
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......107
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................107
8.6
TRIAL MILESTONES.....................................................................................108
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................108
9.
REFERENCES..................................................................................................110
9.1
PUBLISHED REFERENCES..........................................................................110
9.2
UNPUBLISHED REFERENCES....................................................................115
10.
APPENDICES...................................................................................................116
10.1
PHARMACOKINETIC ANALYSES.............................................................116
10.2
TIME SCHEDULE FOR PK AND BIOMARKER BLOOD SAMPLING –
NO LONGER APPLICABLE PER CTP V7.0...............................................117
10.3
DETAILS OF BLRM SETUP AND OPERATING CHARACTERISTICS128
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................133
11.1
GLOBAL AMENDMENT 1 ............................................................................133
11.2
GLOBAL AMENDMENT 2 ............................................................................137
11.3
GLOBAL AMENDMENT 3 ............................................................................143
11.4
GLOBAL AMENDMENT 4 ............................................................................147
11.5
GLOBAL AMENDMENT 5 ............................................................................153
11.6
GLOBAL AMENDMENT 6 ............................................................................163


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ABBREVIATIONS
AE
Adverse Event
ADA
Anti-drug Antibodies
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase 
AUC
Area under the Curve
BHM
Bayesian Hierarchical Model
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
CA
Competent Authority
cfDNA
Circulating free DNA
CI
Confidence Interval
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CRS
Cytokine release syndrome
ctDNA
Circulating tumor DNA
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoT
End of Treatment
EudraCT
European 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
GMP
Good Manufacturing Practice
HA
Health Authority
HED
Human equivalent dose
HNSTD
Highest Non-Severely Toxic Dose 
i.v.
Intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemical 
INN
International Non-Proprietary Name
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LMWH
Low Molecular Weight Heparin
LPLT
Last Patient Last Treatment
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
Maximum Tolerated Dose
NGS
Next Generation Sequencing
NOAEL
No Observed Adverse Effect Level
OPU
Operative Unit
OR
Objective Response


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ORR
Objective Response Rate
PD
Progressive disease
PDAC
Pancreatic Ductal Adenocarcinoma
PFS
Progression-free survival
p.o.
per os (oral)
PK
Pharmacokinetics
PR
Partial Response
q.d.
quaque die (once a day)
Q1W
Once per week 
Q2W
Once every 2 weeks
RA
Regulatory Authority
REP
Residual Effect Period
RP2D
Recommended Phase 2 Dose
s.c.
subcutaneous
SAE
Serious Adverse Event
SMC
Safety Monitoring Committee
SOI
Start of infusion
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
ULN
Upper Level of Normal
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Tumor cell death and apoptosis can be induced by activation of the extrinsic pathway via 
targeting TRAIL receptors (R16-1878). TRAILR2 pathway represents a valid opportunity for 
cancer treatment, but it has not been successful in the clinic so far. Multiple clinical trials with 
conventional antibodies against TRAILR2 indicated minimal clinical activity with no toxicity,
and these compounds have been discontinued (P16-04691).
Targeting TRAILR2 requires agonistic properties of a potential drug candidate, and this is 
difficult to achieve with conventional antibodies (R17-2985). Available data suggest that 
activation of TRAIL receptor depends not only on binding of the ligand to the receptor but 
require formation of complex higher level receptor-ligand multimeric structures. Such
receptor clustering is critical for generation of an adequate signal capable of down-stream 
propagation and apoptosis induction (R17-2986). Agonistic properties of conventional 
TRAILR2 targeting 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). It is likely that first generation 
conventional TRAILR2 antibodies had very weak and inconsistent agonistic potential for 
TRAILR2 in human clinical trials related to the above mentioned reasons e.g. high level of 
endogenous immunoglobulins that were effectively competing for Fc gamma receptors on 
immune cells in-vivo and/or low and a variable number of immune cells in the tumor
microenvironment (P16-04691).
New pharmacological approaches are needed that would overcome above mentioned 
limitation of conventional antibodies and capable to activate TRAIL receptors independently 
of Fc interactions. BI 905711 is a tetravalent bispecific molecule targeting both TRAILR2 and 
CDH17, and it is designed to selectively induce apoptosis in CDH17 expressing tumor cells 
via the CDH17-dependent clustering of TRAILR2. CDH17 is a cell surface molecule 
expressed in adenocarcinomas of gastrointestinal origin (R18-1615). Via the CDH17-
dependent clustering of TRAILR2, BI 905711 induces the pro-apoptotic activity 
independently of additional cross-linking (R17-4112) and selectively in CDH17 expressing 
tumor cells. The L234A/L235A mutation was incorporated to specifically avoid CDH17-
independent crosslinking by ablating binding to Fc#R and complements.
BI 905711 has the potential to provide a therapeutic window and avoid hepatotoxicity 
associated with clustering of TRAILR2 and apoptosis in the liver (R16-1795) due to the lack 
of detectable CDH17 protein in non-neoplastic liver tissue (R17-2598). The limited set of 
non-neoplastic tissues with CDH17 expression (small intestine, colon, gastric mucosa, gall 
bladder and pancreas ducts) should be spared from apoptosis and tissue damage due to their 
insensitivity to TRAILR2 activation (R17-4113, R16-4563).
Potential indications for BI 905711 include gastrointestinal cancers expressing CDH17: 
colorectal cancer, gastric cancer, oesophageal adenocarcinoma, pancreatic cancer and biliary 
tract cancers as indicated in Table 1.1: 1


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Table 1.1: 1
Gastrointestinal cancers expressing CDH17.  Percentage indicate 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. For BI’s prevalence study, positive 
tumors have ≥5% CDH17 positive cells.
#only metastatic samples  
Colorectal cancer (CRC) consistently expresses CDH17 at a high or intermediate level by 
immunohistochemistry in primary tumors and metastatic sites (R17-2598, R18-1615). High 
CDH17 expression in CRC was confirmed in a BI prevalence study where metastatic CRC
samples 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 cancer, oesophageal adenocarcinoma, 
pancreatic cancer and biliary tract cancers is more variable.
The rate of positive CRC tumors with ≥5% CDH17 positive cells in 1412-0001 phase 1a was 
95%, with 78.5% being double-positive for CDH17/TRAILR2 (data on file). 
It is important to recognize that 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. Nevertheless, possible correlation between quantitative CDH17 expression and 
efficacy will be explored in this study.  
For a more detailed description of the BI 905711 profile, refer to the current Investigator’s 
Brochure (IB).    
1.2
DRUG PROFILE
Mode of action
BI 905711 is tetravalent bispecific antibody specifically designed to have potent agonistic 
activity via the CDH17-dependent clustering of TRAILR2 and therefore induces apoptosis in 
CDH17 expressing tumor cells. Refer also to the IB for additional details (c16856466).


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CDH17 is a cell surface molecule expressed in different gastrointestinal adenocarcinomas 
(R17-4114). In humans, CDH17 is also present in normal cells of stomach, intestine, pancreas 
and gall bladder, but it is not expressed in liver tissue. Normal GI tissues were shown to be 
resistant to TRAILR2 induced apoptosis (R16-4563) while the liver may be sensitive to 
TRAILR2 activation (R16-1795). BI 905711 should achieve a therapeutic window by 
avoiding liver toxicity due to lack of CDH17 on hepatocytes (R17-2598), avoiding GI toxicity 
due to high threshold for TRAILR2 mediated apoptosis in normal cells of the GI tract (R16-
4563). These expectations are supported by extensive pre-clinical data as described in the IB 
(c16856466) and summarized in the following sections.
Absorption, bioavailability, distribution, metabolism, and excretion
No human data are available. The information below is based on preclinical considerations. 
Distribution
No dedicated distribution studies have been performed. In the cynomolgus monkey, Cmax 
and AUC0-168 increased approximately dose-proportionally upon dosing for all dosing 
groups (1, 10, 30, and 100mg/kg), and it is expected that distribution of BI 905711 will be 
mostly distributed to the blood after IV administration in a manner typical of IgG molecules 
(c16856466). Once distributed from intravascular space into the tissues, BI 905711 is 
expected to bind CDH17 and TRAILR2. CDH17 in expressed in pancreas, small and large 
intestine, gall bladder, and target tumor tissue. TRAILR2 is broadly expressed in tumors and 
to some extent in normal tissues particularly liver (R18-2045, R17-4113).
Metabolism
BI 905711 is a protein and is expected to undergo protein catabolism in animals and 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 interactions
BI 905711 is a therapeutic 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 molecule drugs. Therefore, pharmacokinetic drug interaction
between BI 905711 and co-administered small molecule drugs is not expected. 
Residual Effect Period
The expected Residual Effect Period (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.


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Non-clinical studies
BI 905711 demonstrated high preclinical activity in-vitro and in-vivo for CDH17 positive 
tumor cell lines in extensive batteries of pre-clinical experiments fully described in the IB. A 
short summary is given below.
The sensitivity of a panel of 24 CDH17-positive colorectal cancer cell lines to BI 905711 
treatment was evaluated and is shown in Figure1.2: 1. A V-shaped dose-response is predicted 
for this bi-specific MoA where concentrations above the optimum will favor 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 for all of them (Figure 1.2: 1)
Figure 1.2: 1
Dose response graph of CRC cell lines classified as sensitive to BI 905711 as 
determined in the Cell Titer-Glo assay. Within the range of concentrations 
tested, different cell lines showed a V-shaped dose-response curve, and 
reduced efficacy was detected when using higher than optimal doses
(c16856466).
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 of sensitivity to TRAILR2 agonists. 
As expected for a CDH17-independent molecule, a significant effect of EX 77749 decreasing 


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cell viability was observed independently of the absence of CDH17 membrane expression 
(Figure 1.2: 2).
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 
demonstrating a statistical significant tumor growth inhibition at the end of the experiment.
Similar to the in vitro setting, reduced efficacy was observed in the GP2d xenograft model at 
both lower and higher than optimum doses, resulting in a V-shaped (evaluating in vitro 
treatment-induced cell death) or a bell-shaped (evaluating in vivo treatment induced-tumor 
growth inhibition relative to control) dose-response relationship (Figure 1.2:1, Figure 4.1.2.1: 
1).


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Anticancer activity of BI 905711 in PDAC was tested in vivo using 11 patient-derived PDAC 
xenograft models (PDX) characterized by target expression of TRAILR2 and CDH17 in the 
range of 45 to 174 TPM (transcripts per million) and 26 to 604 TPM, respectively. Upon 
treatment with BI 905711, 4/11 PDX models showed tumor growth inhibition [TGI] ranging 
from 107 to 126% and 2/11 models showed moderate response (TGI 61% and 76%).
First in vivo experiments (two PDAC PDX models) to study synergistic anticancer effect of 
BI 905711 in combination with chemotherapy (irinotecan) showed deepened response.
The pharmacokinetics (PK) and immunogenicity for BI 905711 was investigated in the
cynomolgus monkey following a single intravenous (i.v.) dose at 8 mg/kg, or 100 mg/kg by 
bolus injection, demonstrating dose-proportional PK. The well-characterized cynomolgus PK 
was subsequently used to predict the human pharmacokinetics and inform the phase Ia dose 
selection, as described in Section 4.1.2 and in full detail in the IB (c16856466).
Preclinical toxicology
Preclinical toxicology is fully described in the IB (c16856466). BI 905711 intravenously 
administered once per week (Q1W) 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, and cerebrum) 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) investigation 
(Monkey IgM, IgG, C3) did not reveal evidence of immune complex deposition, suggesting 
an absence of immune complex formation or immune complex levels below the IHC detection 
limit.
The Highest Non-Severely Toxic Dose (HNSTD) in the 6-week monkey toxicity study was
judged to be 100 mg/kg Q1W, and the No Observed Adverse Effect Level (NOAEL) was
considered to be 30 mg/kg Q1W. 
No hemolytic or local effects due to BI 905711 intravenous injection were noted. BI 905711 
did not cause in vitro cytokine release (c16856466).




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Median duration of treatment in non-CRC GI cancers patients was 35.5 days (range, 15–246) 
overall and 116.5 days (range, 15–211) in the 0.6 mg/kg group. Thirteen (13) of 22 non-CRC 
GI cancer patients had PDAC. Six (6/13) PDAC patients achieved best overall response of 
stable disease including 4 patients that remained progression-free at ≥4 months.
Safety, pharmacokinetic, and pharmacodynamic profiles, as well as preliminary antitumor 
activity of BI 905711 given biweekly at three dose levels (0.6 mg/kg, 1.2 mg/kg and 2.4 
mg/kg) or weekly at one dose level (0.6 mg/kg), will be assessed during 1412-0001 expansion 
phase 1b. 
For a more detailed description of the BI 905711 profile, refer to the current Investigator’s 
Brochure (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Efficacy of current standard therapies for gastrointestinal cancers at advanced or metastatic 
stage is limited. The majority of these patients die due to primary or secondary resistance to 
therapy, and there is a significant need to develop new approaches for their treatment. BI 
905711 represents a novel class of bispecific antibody that may be developed as a new 
treatment option for these patients.  BI 905711 showed efficacy in relevant preclinical models,
and its development is supported by extensive pharmacology and toxicology preclinical data 
(Section 1.2).
This open-label, dose-escalation study represents the first protocol for BI 905711 treatment in 
humans. Safety, pharmacokinetic, and pharmacodynamic profiles, as well as preliminary 
antitumor activity assessments, acquired in this trial will provide the basis for further 
development of BI 905711.
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 v7.0 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
Most patients with advanced or metastatic gastrointestinal cancers have limited treatment 
options, develop resistance to currently available therapies, and succumb to their disease.  BI 
905711 can potentially provide a new therapeutic option for these patients as suggested by its 
efficacy in relevant preclinical models and further supported by extensive pharmacology and 
toxicology preclinical data (Section 1.2).


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Only a minimum number of patients should be exposed to doses of BI 905711 with low 
likelihood of activity. Therefore, a Bayesian Logistic Regression Model (BLRM) design will 
be used in order to escalate the dose into a dose range where optimal efficacy may be seen 
while still minimizing the risk of undue toxicity.
Conventional anti-TRAILR2 antibodies have been extensively tested and well tolerated in 
clinic with a well-defined safety profile. The majority of these compounds did not induce 
DLTs in phase 1 trials with no established MTD. Treatment-related adverse events with such 
compounds mostly included mild elevation of AST, ALT and/or pancreatic amylase with no 
reported severe events (R16-1793, R16-1794, R17-2590, R17-2600, R17-2601, R16-4524, 
R17-2606).  There is limited clinical experience with the second generation of compounds 
inducing TRAILR2 clustering independently of FcR interactions. Recently, phase I data of 
the TRAILR2 binding tetramer (TAS 266) was reported indicating reversible liver toxicity 
at the first administered dose level leading to TAS 266 discontinuation from further 
development (R16-1795). Detailed review of published pre-clinical and clinical data 
suggest that a relatively high exposure at the starting dose in phase 1 trial may have 
contributed to the observed toxicity of this drug (R16-1800). A similar compound (ABBV-
621) is currently investigated in an ongoing phase 1 study (NCT03082209) (R18-2222). A 
bi-specific compound targeting TRAILR2 and FAP (RG 7386) has completed phase 1
(NCT02991196) with no reported DLTs and MTD (R18-1695).
The summary of observed adverse events during phase Ia is provided in previous section 1.2. 
The anticipated adverse events based on the BI 905711 mode of action, pharmacological data 
and results of preclinical toxicology studies are described below:
∀
Injury of GI tissues expressing CDH17
CDH17 is expressed in the small intestine, colon, gastric mucosa, gall bladder and pancreatic 
ducts. BI 905711 may potentially cross-link TRAILR2 to CDH17 in these tissues and induce 
apoptosis and injury (Section 1.2). No signs of GI injury were observed in preclinical 
toxicology studies in cynomolgus monkeys up to the highest administered dose (c16856466). 
There are preclinical in-vitro data suggesting that normal human colon epithelial cells are 
insensitive to TRAILR2 induced apoptosis, but their sensitivity can be increased during 
inflammation and viral infection (R16-4563, R17-2592). Patients with inflammatory bowel 
disease and bowel infection should not participate in clinical trials with BI 905711. Based on 
above considerations, possible anticipated Adverse Events of BI 905711 may include nausea, 
anorexia, diarrhea, vomiting, pancreatitis, increase in pancreatic lipase/amylase, abdominal 
pain and/or other GI tract related signs/symptoms. Guidelines for management of nausea, 
diarrhea and vomiting are provided in Section 4.1.4.1.2.
∀
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. Still, liver damage induced by BI 905711 cannot be excluded 
particularly in patients with liver metastases. Patients should be followed closely for potential 
elevation of AST, ALT, and bilirubin, and for clinical signs/symptoms of liver injury as 
described in Section 5.2.6.1.4.


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∀
Renal injury
A 6-week GLP toxicology study in monkeys showed glomerulopathy at the highest tested
dose of 100 mg/kg (c16856466). These finding were not accompanied by clinical or
biochemical changes in renal functions with no increase in serum creatinine or BUN and no
proteinuria. CDH17 has not been detected in the kidneys of monkeys or humans (c16856466).
Granular deposits containing human IgG and/or monkey IgG were identified in the kidneys of 
animals displaying glomerulopathy.  The presence of these granular deposits is consistent with 
processes of immune complex formation, deposition, and clearance in response to the test 
article.  Formation of immune complexes followed by deposition in the kidneys with resultant 
glomerulopathy has been described when monkeys form ADA in response to heterologous 
protein administration and is generally not considered predictive of similar findings in 
humans. The relevance of these observed renal findings for humans is unknown. Patients will 
be monitored for changes in renal functions by serial measurement of creatinine and urea in
blood and protein in urine as specified in Section 5.2.3.
∀
Tumor lysis
BI 905711 induces apoptosis within a short time frame in-vitro and leads to tumor regression
in-vivo in preclinical models. Theoretically, tumor lysis syndrome can occur. Patients should 
be monitored for occurrence of tumor lysis syndrome particularly after the first administration 
of BI 905711 with guidelines provided in Section 4.1.4.1.4.
∀
Infusion-related reaction
BI 905711 is a humanized bi-specific antibody with atypical format, and it may induce
infusion-related reactions due to multiple mechanisms. Recent data from a similar bi-specific 
antibody targeting TRAILR2 and FAP reported an incidence of 9% of grade 1-2 infusion 
reactions with no grade ≥3 (R18-1695). Management guidelines for infusion-related reactions 
are provided in Section 4.1.4.1.1.
∀
Cytokine release syndrome (CRS) and immune-mediated reactions
The TRAIL pathway has been implicated in inflammation in some preclinical experiments,
but the clinical relevance of these findings are 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 antibodies and TRAILR2 clustering 
agents (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 with guidelines provided in Section 4.1.4.1.2.
∀
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 the IB and in Section 5.3.  Cytoplasmic CDH17 staining was occasionally present in 
cerebral neurons of both humans and monkeys. Since CDH17 is membrane bound, the 
cytoplasmic staining is non specific and pathological findings in monkey brains are not 
considered related to BI 905711 mediated cross-linking of TRAILR2 and CDH17. TRAILR2 
have been described in human brain particularly in certain pathological conditions (R18-


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2769). There were no neurological findings described in studies with other conventional 
TRAILR2 agonists up to the highest tested dose levels (R16-1793; R16-1794), R17-2590, 
R17-2600, R17-2601, R16-4524, R17-2606). In summary, dose dependent, minimal to mild 
eosinophilic/monocyte cells infiltrations in perivascular region of the brain and spine observed 
in toxicology studies in monkeys are of unknown significance and were considered to be 
possibly secondary effects related to the immunogenicity of BI 905711 or test article platform. 
Relevance of these findings for humans is unknown. The risk of possible neurological adverse 
reactions will be closely monitored in human studies. Thus, a baseline brain MRI will be 
performed in all patients enrolled in the phase Ia part.  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 
possible neurological toxicities are provided in Section 4.1.4.1.5. The possibility of their 
relationship to ADA will be assessed.  
∀
ADA (anti-drug antibodies) related adverse reaction
BI 905711 may lead to development of ADA, and its occurrence will be explored in this study 
(refer to Section 5.3.2). The consequence of ADA occurrence for safety is currently unknown.
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 closely 
followed for development of liver injury for the whole duration of BI 905711 treatment, and 
possible contribution of ADA to liver injury will be assessed.
∀
Tumor biopsy 
As part of the screening, patients are required to have a tumor tissue biopsy. Pre-treatment 
fresh tumor biopsy collections for biomarker analyses are considered optional in phase Ia and 
mandatory in phase Ib. There is an added risk for pain, swelling, bleeding for those patients 
who will undergo tumor biopsies. For this reason, biopsies will only be performed when 
deemed safe by the investigator and if the platelet count is sufficient to allow for haemostasis. 
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 associated with the 
biopsy.
During 1412-0001 phase 1a dose escalation the Safety Monitoring Committee (SMC)
assessed trial data to ensure the overall safety of the patients treated. Based on the
accumulated data, the SMC reached joint recommendations on the next dose level of BI 
905711 to be investigated and the sample size for the next dose-escalation cohort. They also 
provided the Investigators and the Sponsor with advice about the overall conduct of the trial 
(refer to Section 8.7).
The Safety Monitoring Committee reviewed the safety data of BI 905711 up to 3.6 mg/kg in 
CRC and non-CRC GI cancer patients and concluded that no DLT was observed, no MTD 
was achieved, and there was no evidence of any dose/adverse effect relationship. In addition,
there was no evidence for drug-induced liver injury and no pattern of anticipated AEs (see
section 7 of current IB) has been observed except infusion-related reactions (see previous 
section 1.2 for details).  


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A Benefit-Risk assessment in the context of the COVID-19 pandemic for patients treated with 
BI 905711 has been performed. Based on the mode of action, BI 905711 is not expected to 
have a relevant impact on the susceptibility to or the course of a SARS-CoV-2 infection.  
In case of a confirmed infection, trial treatment will be discontinued immediately and 
appropriate measures for monitoring, treatment and quarantine will be implemented. The 
patient may resume trial treatment following recovery from a SARS-CoV-2 infection if the 
patient is expected to derive clinical benefit, as agreed between the investigator and sponsor.
Patients in this trial may be immuno-compromised and at higher risk for severe illness from 
COVID-19. In case of an increased risk of SARS-CoV-2 infection due to the physical visits to 
the sites, the visits should be avoided where the investigator judges that this is the safest 
course of action. These measures ensure the safety of the patients throughout the trial, 
maintain the integrity of the trial and will not affect the benefit-risk balance of BI 905711.
In summary, the present trial has implemented a number of safety measures to mitigate
possible risks for patients. It is concluded that participation in this study and treatment with BI
905711 may provide patients with potential 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:
∀
Explore safety and establish the maximum tolerated dose (MTD)/recommended dose
levels for phase Ib expansion phase of BI 905711 based on the frequency of patients 
experiencing dose limiting toxicities (DLTs) during the MTD evaluation period. The 
MTD evaluation period is defined as the first two treatment cycles (from first dose 
administration until the day preceding the third dose administration or end of REP in 
case of discontinuation before start of Cycle 3).
∀
Explore pharmacokinetics/pharmacodynamics and efficacy to guide the determination 
of a potentially effective dose range for phase Ib in the absence of MTD.
Phase Ib:
∀
Evaluate efficacy and safety of BI 905711 at a potentially effective dose range and 
determine the Recommended Phase 2 Dose (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. For the 
definition of DLTs, refer to Section 5.2.6.1.5.
∀
Number of patients with DLTs in the MTD evaluation period. 
A BLRM employing the escalation with overdose control (EWOC) principle will be used 
during the escalation phase for the selection of the dose levels and, if applicable, the 
estimation of the MTD. Cohorts of patients will receive escalating doses of BI 905711 until 
the MTD is reached. Each cohort will consist of newly enrolled patients. Estimation of the 
MTD during the escalation phase of the trial will be based upon the estimation of the 
probability of a DLT in the MTD evaluation period in the set of evaluable patients for MTD. 
The corresponding methodology is described in Section 7 and Appendix 10.3. The MTD 
estimate established during the dose escalation phase will be re-investigated after the 
expansion phase by re-running the BLRM including all data from escalation and expansion 
phases, including DLTs observed at all treatment cycles.
Phase Ib:
∀
Objective response based on RECIST 1.1 criteria. Objective response is defined as 
best overall response of complete response or partial response, where best overall 
response is the best response recorded from the start of the study treatment until the 
earliest of disease progression, death or last evaluable tumor assessment and before 
start of subsequent anti-cancer therapy.


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∀
Progression-free survival (PFS) is defined as the time from first treatment 
administration until tumor progression according to RECIST 1.1 or death from any 
cause, whichever occurs earlier.
2.1.3
Secondary endpoint(s)
Phase Ia:
∀
The following PK parameters of BI 905711 will be evaluated after the first and after 
the third administrations of BI 905711:
o
Cmax: maximum measured concentration of BI 905711 in plasma
o
AUC0-t2: area under the concentration-time curve of BI 905711 in plasma 
∀
Objective response based on RECIST 1.1 criteria in patients with measurable disease.
Phase Ib:
∀
The following PK parameters of BI 905711 will be evaluated after the first and after 
the third administrations of BI 905711:
o
Cmax: maximum measured concentration of BI 905711 in plasma
o
AUC0-t2: area under the concentration-time curve of BI 905711 in plasma 
∀
Number of patients with treatment-emergent AEs
∀
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 overall response is measured from the time measurement criteria are 
first met for Complete Response (CR)/ Partial Response (PR) (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements 
recorded on study) according to RECIST 1.1.
∀
Disease control, defined as CR, PR, or stable disease according to RECIST 1.1 from 
the start of treatment until the earliest of progression disease, death or last evaluable 
tumor assessment and before start of subsequent anti-cancer therapy.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will consist of two parts: phase Ia (escalation part) and phase Ib (expansion part) as 
displayed in Figure 3.1: 1 and described in Sections 3.1.1 and 3.1.2.
Note: Displayed dose levels are for illustration only. The number of patients in the dose escalation cohorts may be increased 
in case of DLT observation. Non-CRC includes any other non-colorectal GI cancers.
Figure 3.1: 1 Overall study design
3.1.1
Phase Ia: dose escalation (Part A)
Phase Ia is an open-label, dose escalation study of BI 905711 administered intravenously. 
Provisional dose escalation levels are described in Table 4.1.2.1: 1.  
Recruitment in Phase Ia is complete. 
3.1.1.1
Recruitment in CRC escalation cohorts
CRC patients represent a homogenous population regarding CDH17 expression. CRC 
preclinical models were used for prediction of dose levels to be tested in phase Ia and BI 
905711 pharmacological activity. Thus, CRC patients will be recruited as mandatory cohorts 
at all dose levels. Gastrointestinal cancers in patients of various ethnicity, including Japanese 
patients, express CDH17 to a similar extent (R18-3554), and ethnicity based differences for
BI 905711 tolerability and PK are not expected (R18-3553).  Patients of any ethnicity can be 


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enrolled into the first two dose levels.  Starting from dose level 3 onwards, at least one 
Japanese patient should be included into each dose level to establish the safety for Japanese 
patients. The possible cohort size is described in Table 4.1.2.1: 1.
3.1.1.2
Recruitment in non-CRC GI cancer cohorts
Non-CRC GI cancer patients were recruited as “back-filled” cohorts at one level below the 
current dose being investigated in the CRC cohort to confirm safety also for this population. 
The decision to open enrollment of non-CRC GI cancer cohorts and the selection of the 
starting dose were taken by the SMC. Recruitment at a specified dose level occurred once it 
was determined to be safe in CRC cohorts per SMC decision.
Once the first site in China was initiated while the phase Ia was ongoing, the first Chinese 
patient was enrolled into the non-CRC dose level that was open at the time of site initiation. 
Thereafter, at least one Chinese patient was enrolled in China at each subsequent dose level in 
phase Ia.
3.1.1.3
MTD determination/recommended dose range for expansion
The data obtained from the trial was to determine the MTD estimate based on a BLRM with 
overdose control (R13-4803). The BLRM estimates the MTD by updating estimates of the 
probability of observing a DLT in the MTD evaluation period for each dose level in the trial 
as patient information becomes available. At any time in the trial, it was not permitted to 
escalate to a dose which does not fulfil the escalation with overdose control (EWOC) 
principle (refer to Section 7). 
Recruitment at every dose level started with CRC patients. As soon as all CRC patients 
enrolled for safety evaluation on a dose level completed the MTD evaluation period, a BLRM 
with overdose control was be applied by using all available data from all dose levels assessed
(from both CRC and non-CRC GI cancer patients) to determine the next dose levels in CRC 
and non-CRC cohorts and evaluate MTD. The overdose risk was then calculated for each 
preliminary dose level from Table 4.1.2.1: 1 and escalation was permitted to a dose level which 
fulfilled the EWOC criterion. Intermediate or higher dose levels could be used as long as it 
fulfilled the EWOC criterion. Specifications and details of the BLRM are indicated in Section 
7.1 and Appendix 10.3.
The safety data from non-CRC GI cancer patients as well as data from the Japanese patients
was evaluated additionally in a descriptive manner and provided to SMC at every dose 
escalation step. If DLTs in non-CRC GI cancer patients were observed in a lower dose level 
as compared to CRC patients, some sensitivity analysis was run based on BLRM by adding 
CRC/non-CRC as a covariate to evaluate whether to reduce the dose level or recruit more 
patients at the same dose level for non-CRC GI cancer patients. The SMC made a decision 
about continuation of dose escalation for non-CRC GI cancer patients based on these data. 
The SMC also discussed whether the dose level for CRC patients should be adjusted or not. 
Decision on further recruitment, dose escalation, de-escalation or cohort expansion was made 
by the SMC.


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At each dose level, the first patient was treated and was observed for at least 1 week 
before allowing the second patient to receive BI 905711 infusion.
∀
For the initial two dose levels (dose levels of 0.02 mg/kg and 0.06 mg/kg), at least one
CRC patient was required.  In case patients have not experienced a DLT within the 
first two cycles, enrollment into a higher dose level occured. In case a DLT occured,
the number of patients was increased to four patients per dose level, and BLRM was  
performed to determine the next escalation steps. At least one Japanese patient should 
be included in the additional three patients that are enrolled. Then, all subsequent dose 
levels consisted of at least four patients. For further dose-escalation steps (dose level 
of 0.2 mg/kg and above), four CRC patients were required. However, in the case that 
only three patients were evaluable (including one Japanese patient) and none 
experienced a DLT as defined in Section 5.2.6.1.5 within the MTD evaluation period, 
then dose escalation occured based on these three evaluable patients.
If DLTs were observed in the first two consecutive patients of a previously untested dose 
level, subsequent enrollment to this dose cohort was stopped. The BLRM was to be re-run to 
confirm whether the dose level still fulfils the EWOC criterion. Based on this information, the 
SMC evaluated whether the next patients will be enrolled at the same dose level, or at a lower 
dose level.
The SMC may have recommended stopping the dose escalation phase after the criterion for 
MTD (Section 7.1) is fulfilled. Further patients may have been included to confirm this MTD 
estimate, i.e. to confirm that the EWOC criterion is still fulfilled. 
The planned highest dose to be tested in the dose escalation was 4.8mg/kg based upon the 
pharmacodynamic modeling (refer to Figure 4.1.2.1: 1). Based on the available safety data 
and the BLRM, exploration of doses higher than 4.8 mg/kg was considered.
3.1.2
Phase Ib: expansion cohorts (Part B)
Phase Ib is a randomised open label study to determine safety and efficacy of BI 905711 in 
the 4 expansion cohorts of patients with colorectal cancer and the 1 expansion cohort of 
patients with pancreatic cancer. 
The selection of the dose levels for phase Ib was made by the SMC with the aim to select a 
safe and potentially effective dose range of BI 905711 based on all data collected in phase Ia.
Selected dose(s) for phase Ib expansion cohorts cannot be higher than the MTD. The overall 
framework for dose selection for phase Ib is described in Section 4.1.2.2.
If any DLTs are observed during cohort expansion, the BLRM will be run to confirm if that
dose level still fulfils the overdose risk control. Further expansion to 15 patients for the CRC 
cohorts or 20 patients for the PDAC cohorts may be stopped due to over toxicity. 
The SMC can declare any dose fulfilling the EWOC criterion as RP2D by considering all 
available efficacy (OR), PK/PD, biomarker and safety data, independent of the MTD estimate. 


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To determine the RP2D, the MTD estimate established during the dose escalation phase will 
be re-investigated after the expansion phase by re-running the BLRM including all data from 
escalation and expansion phases.
Furthermore, continuation of the trial using the optimal dose and selected patient population 
will be considered and further specified in a protocol amendment if appropriate. 
Recruitment in this trial was discontinued during Phase I expansion, and no PDAC patients 
were enrolled in this expansion cohort. 
3.1.2.1
Randomized CRC expansion cohort
Approximately 60 evaluable CRC patients can be enrolled into phase Ib into 3 dose levels 
with 4 cohorts of 15 evaluable CRC patients. Statistical justification for the number of patients 
per dose level is indicated in Section 7.7. 
Patients will be randomised into three dose levels in four cohorts (three dose levels in 
biweekly regimen and one dose level in weekly regimen (3 weeks on, 1 week off)) of BI 
905711 for a total of approximately 60 evaluable patients.  
3.1.2.2
Single Arm PDAC expansion cohort
Approximately 20 evaluable patients with CDH17-positive PDAC will be enrolled into phase 
Ib. Patients will be enrolled on one dose level in weekly regimen (3 weeks on, 1 week off) of 
BI 905711. 
CDH17 analysis must be performed by a designated vendor and results reviewed prior to 
patient enrollment. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The primary objective of this trial is to determine the MTD and the RP2D. The secondary 
objective is to explore efficacy and safety at a potentially effective dose range of BI 905711 
monotherapy. 
The phase Ia dose escalation and cohort size was determined based upon the recommendation 
of the SMC, guided by a BLRM with overdose control. An escalation with overdose control
design would increase the chance of treating patients at efficacious doses while reducing the
risk of overdosing. This design was based on practical experience and was a preferable 
algorithmic method due to its superior ability to identify the dose with the desired toxicity rate 
and its allocation of a greater proportion of patients to doses at, or close to, that dose (R13-
4802, R13-4804, R13-4805). The use of BLRM for phase I studies has also been advocated by 
the EMA guideline on small populations (R07-4856) and by the FDA (R13-4881).
The phase Ib expansion part will serve for early evaluation of anti-tumor effect of BI 905711 
at a potentially effective dose range (0.6mg/kg, 1.2mg/kg, 2.4mg/kg) and to explore anti-cancer 
effect of BI 905711 at 0.6mg/kg dose given weekly (3 weeks on, 1 week off) and at 0.6mg/kg, 




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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.
Should the patient not sign consent or be determined to be a screen failure, the site needs to 
notify the BI team as soon as possible so the slot may be re-opened to other potential patients. 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrollment), the Sponsor should be contacted immediately.
Refer to Section 8.3.1 (Source Documents) for the documentation requirements pertaining to 
the in- and exclusion criteria.
A patient who has been declared as a “screening failure” may be re-screened once, after
Sponsor agreement. A new informed consent must be signed by the patient, and all eligibility
criteria must be re-assessed, including all safety laboratory parameters within the screening
time period specified in the Flow Chart, to confirm the patient’s eligibility.
3.3.2
Inclusion criteria
1. a. Phase Ia (dose escalation only)
∀
Histologically or cytologically confirmed, advanced unresectable or metastatic
gastrointestinal cancers of following histologies:
o
Colorectal adenocarcinoma
o
Gastric adenocarcinoma
o
Esophageal adenocarcinoma
o
Pancreatic adenocarcinoma
o
Cholangiocarcinoma and gallbladder carcinoma
o
Small intestine adenocarcinoma
b. Phase Ib (expansion phase)
∀
Histologically or cytologically confirmed, advanced unresectable or metastatic 
gastrointestinal cancers of following histologies:
o
Colorectal adenocarcinoma.
o
CDH17 positive pancreatic adenocarcinoma (in tumour tissue as assessed by 
central testing)
2. Patient who has failed all available conventional therapies known to confer clinical benefit 
for their disease based on local approved standards. For patients with colorectal cancer, 
prior treatment with regorafenib or TAS-102 is optional. 
3. a. Phase Ia (dose escalation) only: 
•
Patient with either measurable or non-measurable/non-evaluable disease.
b. Phase Ia (expanded cohort) and Phase Ib (expansion phase) only: 
•
At least one target lesion that can be accurately measured per RECIST v.1.1
4. Availability and willingness to provide an archived tumor tissue specimen and undergo 
tumor biopsy before treatment. Pre-treatment fresh tumor biopsy collections for biomarker 
analyses are considered optional in phase Ia and mandatory in phase Ib. Only non-


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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 due to 
before mentioned reasons an archived tumor tissue specimen obtained within ≤6 months 
of screening must be submitted. In case the patient undergoes baseline tumor biopsy, an 
archived tumor tissue specimen must be submitted regardless of the date of collection.
5. Adequate hepatic, renal and bone marrow functions as defined by all of the below:
a.
Total bilirubin (≤1.5 x institutional ULN (≤3 x institutional ULN for patient 
with Gilbert’s syndrome)
b. ALT and AST ≤2.5 x institutional ULN (≤5 x institutional ULN for patients 
with known liver metastases) 
c.
Serum creatinine ≤1.5x institutional ULN. If creatinine is > 1.5 x ULN, patient 
is eligible if concurrent creatinine clearance ≥ 50 ml/min (≥ 0.05 L/min) 
(measured or calculated by CKD-EPI formula or Japanese version of CKD-EPI 
formula for Japanese patients).
d. ANC ≥1.0x 109/L (≥ 1.0 x 103/μL, ≥ 1,000/mm3)
e.
Platelets  ≥ 100x109/ L (≥ 100 x 103/μL, ≥ 100 x 103/mm3)
f.
Hemoglobin (Hb) ≥8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 mmol/L (without transfusion
within previous week)
g. Phase Ia, and Phase 1b CRC cohort: Serum lipase ≤ 1.5 institutional ULN
h. Phase Ib PDAC cohort: Serum lipase >1.5 - 2.0 x ULN or asymptomatic >2.0 
- 5.0 x ULN if related to PDAC 
6. Recovery from any adverse events according to CTCAE v5.0 of previous anti-cancer 
therapies to baseline or CTCAE grade 1, except for alopecia CTCAE grade 2, sensory
peripheral neuropathy CTCAE grade ≤ 2 or considered not clinically significant.
7. ECOG performance status ≤ 1
8. Life expectancy ≥ 3 months in the opinion of the investigator
9. Of legal adult age (according to local legislation) at screening.
10. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
11. 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 4.2.2.3.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
1. Previous systemic anti-cancer therapy within the specified timeframe from the last dose 
intake to the first dose of trial treatment as shown below: 
∀
Any non-investigational drug, including anti-angiogenic antibodies 
(bevacizumab or ramucirumab) and anti-EGFR antibodies (cetuximab or 


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panitumumab), within 14 days.
∀
Any investigational drug or other antibodies including immune checkpoint 
inhibitors, within 28 days. 
2. 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 but must be discussed with the sponsor.
3. 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.  Any history 
of stroke or myocardial infarction within 6 months prior to screening.
4. 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 grade 
≥2 according to CTCAE v5.0.
5. Known history of human immunodeficiency virus infection.
6. 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
7. Active concomitant malignancies, other than the one treated in this trial.
8. 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.
9. 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 to within 30 days after the last study treatment. 
10. 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.
11. Patients who are under judicial protection and patients who are legally institutionalized
12. Major surgery (major according to the investigator’s assessment) performed within 3 
weeks prior to treatment start or planned within 3 months after screening, e.g. hip 
replacement.
13. Any of the following cardiac criteria:
a.
resting corrected QT interval (QTc) >470 msec


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b. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, 
conduction, or morphology of resting ECGs, e.g., complete left bundle branch 
block, third degree heart block.
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, multigated 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.
14. Known hypersensitivity to the trial medication and/or its components i.e. 
polysorbate 20, sodium citrate, lysine hydrochloride, sucrose, citric acid.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications (refer to Sections 3.3.4.1 and
3.3.4.2).
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data. Measures to control the withdrawal rate include careful 
patient selection, appropriate explanation of the trial requirements and procedures prior to trial 
enrollment, 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 the reason for treatment 
discontinuation is death, this should be reported on the SAE form as well, regardless of causal 
relationship.
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 drug.
∀
The patient can no longer receive trial treatment for medical reasons (such as cancer 
progression, surgery, adverse events, other intercurrent diseases, or pregnancy, or 
nursing).
∀
The patient experiences an infection with SARS-CoV-2. The patient may resume trial 
treatment following recovery from SARS-CoV-2 infection if the patient is expected to 
derive clinical benefit, as agreed between the investigator and sponsor.


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Additional patients may be recruited to replace patients who discontinued their participation 
early for non-safety related reasons (e.g. unable to attend the protocol defined visits for to 
personal reason), or trial disruption e.g.  measures to control the spreading of COVID-19. 
Patients may only be replaced after an agreement with the sponsor.
The patient may continue treatment beyond initial RECIST progression if:
∀
The patient is clinically benefiting,
∀
The criteria described below are met,
∀
It is agreed between the Investigator and the Medical Monitor of the Sponsor, 
∀
The patient has signed an informed consent describing this circumstance.
Criteria required to continue treatment through 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
Even if the trial treatment is discontinued, the patient remains in the trial and, given his/her
agreement, will undergo the procedures for treatment discontinuation and follow up as 
outlined in the Flowchart and Section 6.2.3.
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, 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 enrollment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information that could significantly affect the 
continuation of the trial.
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
.


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The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.4.4
Replacement of patients for MTD determination and PK evaluation in phase Ia
Patients who experience a DLT during the MTD evaluation period were not replaced. 
The following patients without DLT during the MTD evaluation period were considered non-
evaluable for MTD determination and were not included in the BLRM analysis:
∀
Patients who withdrew consent or who were lost from follow-up before completing 
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
∀
Patients who missed 2 or more partial or complete visits during the first two cycles of 
study treatment.
∀
Patients with missing PK and evaluation of safety parameters.
These patients were replaced for DLT evaluation during the MTD evaluation period if not 
decided otherwise by the SMC (e.g. if the number of evaluable patients for the current dose 
cohort is considered sufficient for a dose escalation decision or MTD determination).
Of note, the dose escalation was determined based on all the safety information of all treated 
patients including those who were not included in the BLRM analysis.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1
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 two weeks for a patient 
enrolled in a biweekly regimen. 
Single administration every week for 3 weeks on, 1 
week off for a patient enrolled in a weekly regimen.
Method and route of administration:
intravenous 
4.1.2
Selection of doses in the trial and dose modifications
4.1.2.1
Dose(s) selection for Phase Ia
A detailed description of the methods and considerations to determine a safe starting dose and 
the phase Ia dose levels, taking into account the available nonclinical information, including 
PK/PD and toxicity data, is described in the current IB (c16856466).
In summary, human pharmacokinetics of BI 905711 upon intravenous administration were 
predicted based on cynomolgus monkey PK data. Dose-normalized, concentration-time data
were scaled to human by means of elementary Dedrick scaling (scaling factors d=1 and 
b=0.85) with mean body weights of 2.9 and 70 kg for monkeys and humans, respectively.
PK and tumor growth inhibition data from both the COLO205 and GP2d xenograft models
were incorporated into dose–response models and used, by means of plasma exposure 
matching over the proposed 2 week dosing interval (AUC0-336h), to predict the efficacious 
human dose and relevant dose-range to be investigated in phase Ia. (Figure 4.1.2.1: 1).


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Figure 4.1.2.1: 1
Simulated BI 905711 exposure vs. response at 14 days after a single i.v.
administration. Cavg (AUC0-336h divided by 336h) vs % Tumor Growth 
Inhibition relative to untreated control-curves for GP2d (blue) and Colo-205 
(black) xenograft PK/PD models. Predicted Cavg (μg/mL) values at the 
projected human doses levels (mg/kg) are shown as overlay
The recommended starting dose for phase Ia is based on an integrated evaluation of the 
predicted exposure-response relationship, the HNSTD exposure in the 6-week toxicology 
study in cynomolgus monkeys, literature review of other TRAILR2 agonists and the proposed 
patient population (c16856466).
A starting dose of 0.02 mg/kg of BI 905711 with following characteristics has been selected:
∀
The starting dose is a human equivalent dose (HED) based on matching 14 day 
predicted plasma exposure with the simulated PK/PD relationship in two xenograft 
models. This exposure level corresponds to an activity of ~ 30% tumor growth 
inhibition as compared to maximally active dose in those two models (25% for COLO 
205 and 34% for GP2d) as shown in Figure 4.1.2.1: 1.
∀
The starting dose is 30-fold lower as compared to the modelled maximally active 
human equivalent dose in the studied xenografts models (0.6 mg/kg).
∀
The predicted exposure in humans at the starting dose is 1045- and 650-fold below the 
Cmax and AUC0-336, respectively, at the NOAEL, and >3600-fold below both 
parameters at the HNSTD in monkeys. Therefore, this starting dose is supported by the 
6-week repeat-dose toxicity study in cynomolgus monkeys. 
For further starting dose details, refer to the Investigator’s Brochure (c16856466).
The dose is planned to be escalated in cohorts at the pre-defined dose levels in Table 
4.1.2.1:1. In-between or higher dose levels may be investigated as long as they fulfill the 
EWOC criterion. Rationale for the provisionally selected dose levels in phase Ia is based 
on the predicted human pharmacologically active dose and ensures a complete coverage 
and investigation of the projected BI 905711 dose-response relationship as shown in 
Figure 4.1.2.1: 1. At any time during the trial, it will not be permitted to escalate to a dose


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which does not fulfill the EWOC criterion (refer to Section 7.1). Dose escalation rules are 
described in protocol Section 3.1.1 and Section 7.1.
Table 4.1.2.1: 1
Provisional dose levels for dose escalation of BI 905711 in phase Ia
Dose level
Dose 
(mg/kg)
Increment 
from 
previous dose
Minimum number of CRC 
patientsǂ
Number of Non –
CRC GI cancer 
patientsǂ#
1
0.02
1 (any)
1
2
0.06
200%
1 (any)
1
3
0.2
230%
4 (include at least 1 
Japanese patient)
Up to 4
4
0.6*
200%
4 (include at least 1 
Japanese patient)
Up to 4
5
1.2
100%
4 (include at least 1 
Japanese patient)
Up to 4
6
2.4
100%
4 (include at least 1 
Japanese patient)
Up to 4
7
3.6
50%
4 (include at least 1 
Japanese patient)
Up to 4
8
4.8
33%
4 (include at least 1 
Japanese patient)
Up to 4
*Predicted optimal biological dose.
ǂThe number of patients in the dose escalation cohorts may be increased in case of DLT observation.
# If the first site in China is initiated while the phase Ia is ongoing, it is planned the first Chinese patient will be 
enrolled into the non-CRC dose level that is open at the time of site initiation. Thereafter, at least one Chinese 
patient will be enrolled in China at each subsequent dose level in phase Ia.
At the end of the MTD evaluation period for each treatment cohort, BI convened a meeting 
with the SMC. At the SMC meeting, the safety data including DLTs during and beyond the 
MTD evaluation period and PK/PD data as available for each patient in the current dose 
cohort was presented. Based on that, a decision on the next dose level to be tested was made. 
Dose escalation continued until identification of the MTD, safety concerns arose, or the trial 
was terminated for other reasons. Further escalation steps above 4.8 mg/kg could occur if 
deemed appropriate by the SMC.
4.1.2.2
Dose(s) selection for phase Ib
Dose(s) selection for phase Ib was made by the SMC with the aim to select a safe and 
potentially effective dose range of BI 905711 and is based on integrated analysis of all data 
collected in phase Ia (including safety, PK, biomarker, tumor response) 
Selected dose(s) cannot be higher than the MTD observed in phase Ia, if the MTD was 
determined.
A patient will receive BI 905711 either as a single administration every two weeks or as a 
single administration every week for 3 weeks on, 1 week off depending on which dose 


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level and regimen the patient is randomised to. Each treatment Cycle has a duration of 14 
days.
Table 4.1.2.2: 1 Dose levels of BI 905711 in phase Ib
Dose 
(mg/kg)
Dose regimen
Treatment Cycle
Treatment Day
0.6
Biweekly (Q2W)
Cycle 1
Every Cycle thereafter
Day 1
1.2
2.4
0.6
Weekly (Q1W)
Cycle 1
Every odd-numbered Cycle thereafter
Day 1, Day 8
Cycle 2
Every even-numbered Cycle 
thereafter
Day 1
4.1.2.3
Dose modification
Patients who experience DLT (Section 5.2.6.1.5) or any grade 3-4 AE possibly related to BI 
905711 should interrupt or delay treatment until recovery to CTCAE grade 1 or baseline 
condition.  Restart of BI 905711 treatment can be considered at reduced dose if toxicity is 
adequately managed and there is approval from the medical representative of Sponsor. 
For phase Ia, the subsequent dose level was reduced to the next lower dose level as specified 
in Table 4.1.2.1: 1 after approval by the Sponsor and provided SMC has agreed the lower dose 
level is considered safe.
Patients on the first 3 dose levels who continued treatment after completion of Cycle 4, were 
considered for intra-patient dose escalation to a higher dose level that was determined as 
being safe and appropriate by the SMC. More than one dose-escalation was considered if 
deemed appropriate by the Investigator.
For phase Ib, restart of BI 905711 treatment can be considered at a reduced dose by 25% to 
50%, if there is approval from the medical representative of the Sponsor.
No more than 2 dose reductions will be allowed. After a dose reduction, no dose re-escalation 
will be permitted.
At the time the recommended doses for expansion are determined by SMC, patients that are 
on any other dose levels may be adapted to the recommended dose at investigator's discretion.


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The dose cannot be escalated if the dose has been previously reduced for toxicity reason.
4.1.3
Method of assigning patients to treatment groups
For phase Ia, treatment slots were assigned to recruiting sites that have identified a potentially 
eligible patient in consultation with the Clinical Trial Leader (CT Leader) to the current 
enrolling dose level cohort. Slots were assigned on a competitive basis based upon 
availability. 
Patients enrolled for safety evaluation were assigned to their dose levels by the SMC based on 
available data on toxicity, PK, PD, and anti-tumor activity, refer to Section 4.1.2.1. 
Patients enrolled for efficacy evaluation were assigned to safe dose levels at which objective 
responses were observed. 
Enrollment into the current dose level cohort for dose escalation should have been always 
prioritized. 
If more than one dose cohort for efficacy evaluation was enrolling patients at the same time, 
the patient should have been enrolled into the dose level which had the lowest patient number
(if ties happened, the patient should have been enrolled into the lower dose level first). 
For phase Ib, each eligible patient will be assigned to an appropriate expansion cohort, and the 
appropriate medication number will be assigned via Interactive Response Technology (IRT). 
Patients will be randomised via IRT into five cohorts (three dose levels in biweekly regimen 
and one dose level in weekly regimen (3 weeks on, 1 week off)) of BI 905711.
4.1.4
Drug assignment and administration of doses for each patient
The study drug will be prepared and handled according to the ‘Preparation and Handling of BI 
905711 for 1412-0001 instructions which will be filed in the ISF. Upon notification that a 
patient will be treated in the study, the pharmacy will prepare the study drug at the assigned 
dosage for administration to the patient.
The Cycle 1 Day 1 dose will be calculated using the Cycle 1 Day 1 weight 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.
BI 905711 will be given as an intra-venous infusion by authorised site staff in a specialised
unit where emergency care can be provided (e.g. intensive care unit available, medical
personnel trained in advanced life support). 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.


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The 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. 
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. 
Post-infusion observation period for phase Ia and phase Ib:
∀
Patients will remain under surveillance for at least 8 hours after 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, eg. 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). 
∀
On the first day of treatment, although patients will not be required to stay overnight at the 
hospital, they should be advised to remain close to the study site where medical coverage 
will be ready to support them, if required. Thereafter, patients will be assessed at regular 
safety visits. 
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please see 
Section 6), physical patient visits to the sites may not be feasible or may need to be restricted 
to ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue trial treatment. 
4.1.4.1
Management of toxicities
4.1.4.1.1
Management of infusion-related reactions
Infusion-related reactions 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 infusion 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.


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If an infusion-related reaction of ≥ CTCAE Grade 3 occurs, study treatment must be
permanently discontinued. If symptoms of an infusion-related reaction of CTCAE Grade 2 
occur, which do not qualify as DLT according to Section 5.2.6.1.5, the infusion should be 
temporarily stopped. Upon recovery, the following guidance should 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 3 days after the original planned dose. Refer to Section 10.2 for details 
regarding PK and biomarker sample 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 8 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’s decision, but any adaption of the infusion rate must be agreed with the
Sponsor. It must not exceed 150 minutes in total as outlined in Section 4.1.4.
If infusion reactions and/or hypersensitivity reactions occur in a substantial proportion of
treated patients without premedication, the SMC may decide that all future patients treated in
the study must receive premedication (as described above) prior to BI 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.
4.1.4.1.2
Management of Cytokine Release Syndrome (CRS)
CRS is a disorder characterised by fever, tachypnea, headache, tachycardia, hypotension,
rash, and/or hypoxia caused by the release of cytokines. As outlined above in Section 
4.1.4.1.1, clinical manifestations of CRS and other forms of infusion-related reactions are 
difficult to distinguish (especially at first occurrence) and require rapid diagnosis and 
immediate management to avoid severe adverse events, including fatality.
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 8 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 


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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 4.1.4.
In case of suspected or confirmed CRS, patients will be appropriately treated according to 
institutional standards and/or medical publications (e.g. R16-2323). Supportive therapy 
including antipyretics, intravenous fluids, and low dose vasopressors may be used. In patients 
who do not respond to 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 4.1.4.1.1).
4.1.4.1.3
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 4.1.4.1.3: 1 and 4.1.4.1.3: 2.
Table 4.1.4.1.3: 1
Management of diarrhea
CTCAE Grade
Action for anti-diarrheal treatment
Action for  BI 905711
Grade 1
Anti-diarrheal treatment according to 
the local standard e.g. loperamide 
p.r.n. and hydration
Continue BI 905711 treatment
Grade 2 > 7 days 
despite optimal 
medical 
management
Anti-diarrheal treatment according to 
the local standard e.g. loperamide 
p.r.n, and hydration
Delay BI 905711 treatment until 
recovery. Consider a colonoscopy.
Consider BI 905711 treatment at the 
reduced dose after recovery to Grade 
≤ 1 based on clinical findings
Grade ≥3
Anti-diarrheal treatment according to 
the local standard e.g. loperamide 
p.r.n, and hydration
Delay BI 905711 treatment until 
recovery. Perform colonoscopy.
Consider BI 905711 treatment at the 
reduced dose after recovery based on 
colonoscopy and other clinical 
findings.


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Table 4.1.4.1.3: 2
Management of nausea and vomiting
CTCAE Grade
Anti-emetic treatment
Action for  BI 905711
Nausea Grade 1
Anti-emetic treatment may be considered 
according to the local standard e.g. 
metoclopramide p.r.n.
continue BI 905711 treatment
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.
continue BI 905711 treatment
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
Delay BI 905711 until recovery.
Consider a gastrofibroscopy, 
biochemistry tests (lipase, liver 
function tests, abdominal imaging 
(X Ray, ultrasound, CT scan).  
Consider BI 905711 treatment at 
the reduced dose only after 
recovery to Grade ≤ 1 according to 
clinical findings
4.1.4.1.4
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).
4.1.4.1.5
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. Patients should be monitored 
for possible neurological toxicity. During dose escalation phase (phase Ia), patients will 
undergo baseline brain MRI and should be followed for possible new neurological signs and 
symptoms at each visits of the study drug administration and at end of treatment. 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.


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4.1.4.1.6
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 protein in urine followed by 24 hours quantitative proteinuria in patients with protein + in 
urine. Patients with proteinuria ≥CTCAE grade 3 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.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
CRF will contain information on randomised treatment.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They will 
be packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).  Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A temperature 
log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the Sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee
∀
Availability of a signed and dated clinical trial contract between the Sponsor and the 
investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,


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∀
Availability of a signed and dated clinical trial protocol,
∀
Availability of the proof of a medical license for the Principal Investigator,
∀
Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the Sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the Sponsor
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the 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 by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Rescue medications to reverse the actions of BI 905711 are not available. Potential adverse
events should be treated symptomatically with concomitant medications to provide adequate 
supportive care as clinically necessary. Section 4.1.4.1 provides guidance for management of 
toxicities.
Radiotherapy for local symptom control of non-target lesions may be allowed if agreed
between the investigator and Sponsor.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
No experimental or approved anti-cancer treatment including chemotherapy, targeted therapy, 
immunotherapy, hormone therapy (except hormone replacement), or radiotherapy (other than 
described in Section 4.2.1) is allowed throughout the study treatment period.
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.


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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.
Heparin is incompatible with many injectable preparations e.g. some antibiotics, opioid 
analgesics, antihistamines and cytotoxics (R20-1190, R20-1191).It has been reported in the 
literature that many incompatibilities are concentration-dependent (R20-1196, R20-1190). At 
high concentrations, BI 905711 showed in-vitro incompatibility with heparin but not at 
clinically relevant concentrations (See IB section 4 for more details). Thus, 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. 
In phase Ia, hematopoietic growth factor agents were not allowed for use as primary 
prevention during the first 2 cycles. Thereafter hematopoietic growth factor agents may have 
been 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 guidelines.  In Japan, erythropoietic therapy is not approved for anemia caused by 
cancer chemotherapies.
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.
4.2.2.2
Restrictions on diet and lifestyle
There are no restrictions regarding diet and lifestyle.


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4.2.2.3
Contraception requirements
WOCBP (for the definition 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 3 
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.
4.3
TREATMENT COMPLIANCE
BI 905711 will be administered as an i.v. infusion under the supervision of the investigator or 
designated personnel at the investigative site. Dosing will be recorded in the eCRF. Missed or 
interrupted doses will be recorded in the eCRF with the associated reasons. Compliance may 
also be verified by pharmacokinetic assessment.


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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 Tumours (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 5.2.6.1.5.
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 and body weight will be performed at the time points 
specified in the Flowchart. The results must be included in the source documents available at 
the site. 
5.2.2
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 5 minutes of rest. The results 
must be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points, these are performed as per institutional practice.
All analyses will be performed at local laboratory, and the respective reference ranges will be 
provided in the ISF. Patients do not have to be fasted for the blood sampling for the safety 
laboratory. 
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 (refer to 
Section 5.2.6).


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In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (refer to Section 5.2.6.1 and the DILI Checklist provided in the EDC system). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
Table 5.2.3: 1
Safety laboratory tests
Category
Parameters
Haematology
Haemoglobin, red blood cell count (RBC), white blood cell count
(WBC) with differential, platelets (PLT) count.
Biochemistry
Glucose, sodium, potassium, total calcium, inorganic phosphate, 
creatinine, aspartate amino transferase (AST), alanine amino transferase 
(ALT), alkaline phosphatase (AP), amylase1, lactate dehydrogenase 
(LDH), total bilirubin (direct and indirect bilirubin in case of elevated 
total bilirubin values or if required per local guidelines), urea or blood 
urea nitrogen (BUN), total protein, albumin, uric acid, lipase.
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).
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin time
(PT) or, if applicable, international normalised ratio (INR)
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.
Infectious 
disease
Hepatitis B surface (HBs) antigen, presence of HBc antibody together 
with HBV-DNA, and presence of hepatitis C RNA. Results for hepatitis 
virus infection obtained in routine diagnostics are acceptable if done 
within 14 days before the informed consent date.
Pregnancy
A 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.
1Applicable only to Phase Ib patients
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.


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5.2.4
Electrocardiogram
The 12-lead ECGswill be performed per institutional practice . ECGs may be repeated for 
quality reasons and the repeated recording used for analysis. ECGs will be performed locally. 
If necessary, additional ECGs may be recorded for safety reasons. 
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 or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀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,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,


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-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
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 further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the EDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since the discontinuation of the trial medication and must be reported as 
described in Section 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 hepatic function at baseline:
∀
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
ALT and / or AST elevations ≥10 fold ULN


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∀
For patients with abnormal aminotransaminase levels; ALT and AST are both between 
>1 and <3 x ULN at baseline: 
o
An elevation of AST and/or ALT ≥3 fold the baseline value combined with an 
elevation of bilirubin ≥2 fold ULN (if bilirubin is normal at baseline) 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
o
Aminotransferase elevations (ALT and/or AST ≥5 fold the baseline value). 
∀
For patients with abnormal aminotransaminase levels; ALT and/or AST between ≥3 
and <5 x ULN at baseline: 
o
An elevation of AST and/or ALT ≥2 fold the baseline value combined with an 
elevation of bilirubin ≥2 fold ULN (if bilirubin is normal at baseline) and/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
o
Aminotransferase elevations (ALT and/or AST ≥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 eDC 
system. In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analyzed, 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.


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Figure 5.2.6.1.4: 1 
Potential severe DILI reporting
Dose Limiting Toxicity
Any medical event fulfilling the criteria of DLT (see Section 5.2.6.1.5) should be reported as 
an AESI.
Infusion-related reactions and cytokine release syndrome (CRS)
The following terms describe those events that are to be considered infusion-related reactions
or CRS. Regardless of grade, these events, when occurring within 72 hours of study drug
administration, are considered AESIs and must be reported as such:
∀
Allergic reaction
∀
Anaphylaxis
∀
Cytokine-release syndrome (see description below)
∀
Serum sickness (may include skin rashes, joint stiffness, and fever).
∀
Infusion reactions
∀
Infusion-like reactions
∀
Any other event which the investigator determines may be a potential infusion-related 
AE
Treatment of infusion-related reactions and the handling of subsequent trial dosing are
described in Section 4.1.4.1.1.
The initial clinical sign of a CRS is fever that can rise to high temperatures and is often
associated with flu-like symptoms (e.g. nausea, fatigue, headache, myalgias, malaise, chills,
rigor, tremor, hypoxia, tachypnea, rash, vomiting, diarrhea, abdominal pain, muscle and joint 


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pain, and generalised weakness). CRS may occur quickly during or after administration, or 
after several hours or days.
Management guidelines and treatment of CRS are described in Section 4.1.4.1.2.
AESIs are to be reported in an expedited manner similar to SAEs, even if they do not meet 
any of the seriousness criteria – for details please see Section 5.2.6.1.4.
5.2.6.1.5
Dose limiting toxicities
Any of the following AEs will be classified as DLTs, unless unequivocally due to underlying 
malignancy or an extraneous cause:
Table 5.2.6.1.5: 1
Dose limiting toxicities
Category
Criteria and CTC AE Grade defining a DLT
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 x 109/L, <
1.0 x 103/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 (platelet count ≥ 25,000/m3 (≥25 x 109/L, ≥25 x 
103/μL) and <50,000/m3(< 50 x 109/L, < 50 x 103/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.


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Table 5.2.6.1.5: 1
Dose limiting toxicities (cont.)
Category
Criteria and CTC AE Grade defining a DLT 
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 
SMC.
∀
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).
Non laboratory
∀
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 SMC, 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.
Treatment delay
∀
Any toxicity that result in a treatment delay >14 days 
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 SMC 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 SMC. 
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.


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Replacement of patients for DLT evaluation during MTD evaluation period
For the definition of DLT, it is essential that patients were sufficiently treated according to
supportive care standards described in Section 4.1.4.1. Patients with treatable AEs (nausea, 
vomiting, and diarrhea) that were not sufficiently treated did not qualify for DLT and needed
to be replaced, if this occurred in Cycle 1 or 2. Dose escalation was determined based on all 
the safety information of all treated patients including those who do not complete the first 2 
cycles for reasons other than a DLT. Criteria for replacement of patients during the MTD 
evaluation period is described in Section 3.3.4.4.
5.2.6.1.6
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF
according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE)
(R18-1357).
5.2.6.1.7
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship could 
be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.


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∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
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 follow-up visit 1 (including the Residual 
Effect Period, REP):
•
all AEs (non-serious and serious) and all AESIs.
•
After Follow Up visit 1 until the individual patient’s end of trial:
cancers of new histology and exacerbations of existing cancer, all related SAEs and all 
related AESIs.
•
After the individual patient’s end of the trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
report any occurrence of cancer and trial treatment related SAEs and trial treatment related 
AESIs of which the investigator may become aware of by any means of communication, 
e.g. phone call. Those AEs should be reported on the BI SAE form (see section 5.2.6.2.2), 
but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply please see Section 5.2.6.2.4.
Vital Status Data Collection
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed as described in Section 3.3.4.1, withdrawal 
from trial treatment. From then on until the individual patient’s end of the trial the investigator 
must report all deaths/fatal AEs regardless of relationship, and trial treatment related SAEs 
and trial treatment related AESIs the investigator becomes aware of. 
For description of trial completion for an individual patient, refer to Section 6.2.3.4. 
5.2.6.2.2
AE reporting to the Sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.


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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the Sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner; in
the event that consent cannot be obtained, information will be collected and reported in 
accordance with regulatory requirements. The ISF will contain the trial specific information 
and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is 
to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form 
must be completed in addition.
5.2.6.2.4
Exemption to (S)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. Only if it meets standard 
seriousness criteria (see ‘Serious adverse event’ definition) it will also be recorded on the AE 
page in the eCRF and on the BI SAE form and SAE reporting process will be followed.
Clinical symptoms and/or signs of PD will be recorded on the AE page in the eCRF. If signs 
and symptoms of progressive disease (PD) of the patient's underlying malignancy meet 
standard seriousness criteria, they will additionally be reported on the BI SAE form and SAE 
reporting procedures will be followed.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
BI 905711 PK parameters will be calculated according to the relevant BI internal procedures.
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 WinNonlinTM (version 8.1.1 or higher, 
) or 
SAS Version 9.4 (or later version).
. 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 violations 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 the criteria specified 
below). Reasons for exclusion of a patient’s data will be documented in the Clinical Trial 
Report (CTR). 
PK data may additionally be analyzed using population PK approach. If required, modelling 
activities will be planned and documented separately according to internal and external 
guidelines and SOP.
Preliminary PK analyses can be performed as necessary, e.g. for SMC decisions. In contrast to 
the final PK 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 
discrepancies between preliminary and final results may therefore occur.
5.3.2
Methods of sample collection
Effective from CTP v7.0, PK and ADA samples are no longer collected for ongoing patients.
The timepoints for collection of PK and ADA samples are given in Appendix 10.2. Details of 
the sample collection, preparation, storage and shipment are described in the ISF/laboratory
manual.
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 by the medical 
personnel or sent as electronic files to the Trial Data Manager. 
The samples may be used for further methodological investigations, e.g. for further 
investigations to characterise ADA response or to address Health authority questions 
regarding the results/methodology, stability testing, however, only data related to the analyte 
and anti-drug antibodies will be generated by these additional investigations. 






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-
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. In case 
a tissue block cannot be collected as indicated, the site needs to contact the Sponsor for 
agreement regarding fresh biopsy collection. Potential prioritization of the biomarker 
analyses might be made according to the available tissue amount.
-
Archival tumor tissue sample should be provided as FFPE-preserved tissue, preferably as 
an embedded block and less preferably as mounted tissue sections prepared under RNase 
free conditions. In case tissue cannot be collected as indicated, the site needs to contact the 
Sponsor for agreement regarding tissue collection.
-
Timepoints for fresh tumor biopsy collection are detailed in the Flowchart.
5.4.1.2
Plasma samples


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5.5
BIOBANKING (OPTIONAL)
The therapeutic benefit or occurrence of specific adverse events in patients cannot always be 
anticipated during the trial setup. Later on there may be new scientific knowledge about 
biomarkers and other factors contributing to diseases or the action of a drug. In order to be 
able to address future scientific questions, patients will be asked to voluntarily donate 
biospecimens for banking. If the patient agrees, banked samples may be used for future drug 
development projects, e.g. to identify patients that are more likely to benefit from a treatment 
or experience an adverse event, and thereby better match patients with therapies or to gain 
mechanistic understanding of drug effects and/or to identify genetic or other factors associated 
with response to therapy or the risk of adverse drug reactions. Participation in biobanking is 
voluntary and not a prerequisite for participation in the trial. Biobanking samples will only be 
banked after a separate biobanking informed consent has been given in accordance with local 
ethical and regulatory requirements.
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, see Section 8.5.1.
The leftovers of the following biomarker samples as specified in Section 5.4 might be banked:
∀
Leftover tumor tissue or derivatives (e.g., RNA, DNA)
∀
Leftover from patient’s plasma
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see the Flowchart.
All leftover biomarker samples (except for sample for genomic DNA), as specified in Section
5.4, may be banked if the biobanking consent has been signed by the patient. Samples will be 
stored at an external biobanking facility contracted by the Sponsor. If the patient has not 
consented to optional biobanking (see Section 5.5) trial samples left over after primary 
analysis will be discarded after completion of these additional investigations but not later than 
5 years after the final trial report has been signed.


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5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
Measurements performed during this trial are in accordance with measurements in phase I 
oncology trials in order to monitor safety and determine efficacy and PK parameters. 
Toxicities will be graded according to CTCAE V5.0 (R18-1357), and tumor response will be 
evaluated according to RECIST 1.1 (R09-0262).


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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 enrollment 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.
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and 
assessments, and home healthcare nurse visits. The implementation of these measures will 
depend on patient’s consent, operational feasibility, local law and regulations. If alternative 
methodology is implemented, the deviations from the original plan will be precisely 
documented.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening for Phase Ia, and Phase Ib CRC patients
The examinations required for the screening visit may be conducted within a time interval of
28 days prior to the first study drug administration. Tumor assessments performed prior to 
informed consent as part of routine clinical practice will be accepted if they meet the 
requirements of the protocol and are performed within 28 days prior to treatment start.
Screening for Phase Ib PDAC patients 
There are two screening visits for PDAC patients in Phase Ib: screening Visit 1 (SV1) for 
CDH17 status, and screening Visit 2 (SV2) for entry into the treatment period and treatment. 
Screening visit 1 (SV1) for CDH17 status
The purpose of SV1 for CDH17 status is to offer testing for CHD17 status in archival 
tumour tissue or in fresh biopsy before proceeding into SV2 for entry into the 
treatment period. 
This procedure will require a separate informed consent (Tissue Analysis Consent) for 
assessment of CHD17 expression via a central laboratory designated by the sponsor. 
No maximum time between SV1 for CDH17 status and SV2 for entry into the 
treatment period is defined, and the two screening visits can occur in parallel. 


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Therefore, patients can be enrolled in the SV1 for CDH17 status at any time, even 
while ongoing on other treatments and/or clinical trials.
Screening visit 2 (SV2) for entry into the treatment period
The purpose of SV2 is to check full patient eligibility according to in/exclusion 
criteria. Following informed consent for main study, patients will undergo screening 
assessment as indicated in the Flowchart. 
The SV2 assessments should be performed after CDH17 status is known within 28
days prior to start of treatment (screening visit window) but do not need to be 
performed on the same day. 
For patients whose eligibility was based on archival tissue that is more than 6 months 
old during SV1, a confirmatory test will be performed on a fresh biopsy that should be 
collected during SV2. SV2 fresh biopsy analysis will not prevent patient enrolment, 
should SV1 analysis show CDH17 positivity. SV2 analysis will be only used as a 
retrospective confirmation of CDH17 positivity.
Figure 6.2.1:1 Selection of PDAC patients for study treatment based on SV1 for CDH17 
status and on SV2 for entry into the treatment period.
Baseline Conditions
Any new clinically relevant findings assessed during the screening visit should be included in 
the eCRF. Baseline conditions including demographics, sex, birth date, race, and ethnicity (in 
accordance with local laws and regulations), and concomitant diagnoses and/or therapies 
present during screening, will be recorded in the eCRF.
Medical History


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Oncological and relevant non-oncological baseline conditions should be recorded in the 
eCRF. 
For oncological history, the following parameters will be reported on the eCRF:
∀
The type of tumor, the date of the first histological diagnosis (month and year may be 
sufficient), and the primary tumor site. 
∀
Any known genomic alterations such as BRAF, KRAS, HER2, BRCA...etc, and the 
immune markers status such as microsatellite instability and/or DNA mismatch repair 
deficiency...etc. 
∀
The differentiation grade (not specified, undifferentiated, poorly differentiated, 
moderately differentiated, well differentiated) obtained at the time of diagnosis and 
the location of metastatic sites will be provided as obtained at diagnosis and at study 
screening. 
∀
Previous treatment for the cancer, including any surgery, radiotherapy, and or 
systemic therapy will be reported.
∀
Previous tumor response data (i.e. from prior treatment) if available. At least one prior 
pre-study digital scan of the target lesion should be sent to the central imaging facility 
of an independent vendor if available.
Date of tumor progression after previous lines of treatment will be recorded, if known, 
including start and end dates and the outcome.
6.2.2
Treatment period(s)
If a patient is eligible for trial participation, the Cycle 1 Day 1 assessments may be performed 
as listed in the Flowchart.
Subsequent visits during the treatment period are performed as described in the Flowchart.
Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment
are met (see Section 3.3.4).
6.2.3
Follow up period and trial completion
6.2.3.1
End of treatment (EOT) visit
The EOT visit will be performed as soon as possible but not later than 7 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 assessments of the EOT visit will then be performed instead of at the next planned visit.
6.2.3.2
Follow-up visits
The REP is defined in Section 1.2. The first follow-up visit corresponds to the End of REP
(EOR) visit and may not be performed earlier than 30 days (+ ≤ 5 days) after permanent 
discontinuation of the trial medication. The information collected at this visit must include all 
new AEs that occurred after EOT and a follow-up of AEs ongoing at EOT.


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6.2.3.3
Extended follow-up period 
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
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
STATISTICAL DESIGN - MODEL
The trial will be performed as an open-label trial. There will be 2 parts phase Ia and Ib, which 
have different objectives and designs. 
Phase Ia: 
The primary objective of phase Ia is to determine the MTD of BI 905711 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 will be guided by a two-parameter Bayesian Logistic Regression 
Model (BLRM), escalating with overdose control (EWOC) (R13-4803; R13-4806).
The Bayesian logistic regression model (BLRM) is formulated as follows:
logit(πd) = log(α) + β*log(d/d*), 
where logit(π) = log(π/(1-π)).
πd represents the probability of having a DLT in the MTD evaluation period at dose d, d* =  
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. 
However, according to the dose selection scheme in Table 4.1.2.1:1, the maximum allowable 
dose increment for each escalation step shall not be more than 230%. 
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 15 patients have been treated in phase Ia, of which at least 6 at the MTD. 
The SMC may recommend stopping the dose escalation phase after the criterion for MTD is 
fulfilled. 


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Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter vector 
θ needs to be specified. This prior distribution used in the BLRM will be specified as a mixture 
of three multivariate normal distributions, i.e.
а(θ) = a1f1(θ) + a2f2(θ) + a3f3(θ)
with
ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 1)
and
fi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Prior derivation:
For the current trial, no relevant information in the form of human data was available, since 
no trial has been conducted before. Therefore, the three mixture components are established as 
follows:
1. A weakly informative prior was derived to reflect a priori assumption that the median DLT 
rate at the starting dose of 0.02 mg/kg would equal 1%, and the median DLT rate at 
4.8mg/kg would equal 15%. This yields μ1 = (-1.885, -0.650). The standard deviations were 
set such that large uncertainty about the parameter means is reflected, and the correlation 
was set to 0, thus yielding σ1,11 = 2, σ1,22  = 1 and ρ1 = 0, respectively. The prior weight a1
for the first component was chosen as 0.9.
2. A high-toxicity weakly informative prior was derived to reflect the case that the compound 
would be much more toxic than expected. For this prior component, it was assumed that the 
median DLT rate at the starting dose of 0.02mg/kg would equal 20%, and the median DLT 
rate at 4.8mg/kg would equal 60%. These assumptions yield μ2 = (0.311, -1.118). The 
standard deviations and correlations were set identical to the weakly informative prior, i.e. 
σ2,11 = 2, σ2,22  = 1 and ρ2 = 0, respectively. The prior weight a2 for the second component 
was chosen as 0.05.
3. A low-toxicity weakly informative prior was derived to reflect the case that the compound 
would be much less toxic than expected. For this prior component, it was assumed that the 
median DLT rate at the starting dose of 0.02mg/kg would equal 0.1%, and the median DLT 
rate 4.8mg/kg would equal 2%. These assumptions yield μ3 = (-4.050, -0.598). The standard 
deviations and correlations were set to σ3,11 = 5, σ3,22  = 0.01, therefore almost fixing the 
slope parameter to its mean. The correlation was set to 0, i.e. ρ3 = 0. The prior weight a3 for 
the third component was chosen as 0.05.
A summary of the prior distribution is provided in Table 7.1: 1. Additionally, the prior 
probabilities of DLTs at different doses, as well as the corresponding probability of under-, 
targeted and overtoxicity, are shown in Table 7.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1: 1. As can be seen from both, 


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the table and the figure, the prior medians of the DLT probabilities are in-line with the prior 
medians derived from the weakly informative prior, and the uncertainty around the medians is 
large, showing the low amount of information this prior provides. This is also supported by 
the prior sample size, i.e. the information contained in the prior. This is approximately equal 
to 1.5 patients. A detailed evaluation of the model using hypothetical data scenarios and 
operating characteristics is provided in the statistical Appendix 10.3.
Table 7.1: 1
Prior distribution
Prior Component
Mixture Weight
Mean vector
SD vector
Correlation
1: Weakly inf.
0.900
-1.885 -0.650
2.000, 1.000
0.000
2: High Tox
0.050
0.311  -1.118 
2.000, 1.000
0.000
3: Low Tox
0.050
-4.050 -0.598
5.000, 0.010
0.000
Table 7.1: 2
Prior probabilities of DLT at selected doses
Dose
Probability of true DLT rate in
Quantiles
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
SD
2.5%
50%
97.5%
0.02
0.862
0.063
0.075
0.076
0.165
0.000
0.007
0.653
0.06
0.832
0.075
0.093
0.092
0.180
0.000
0.012
0.714
0.2
0.785
0.096
0.119
0.116
0.200
0.000
0.023
0.778
0.6
0.725
0.115
0.160
0.149
0.222
0.000
0.043
0.830
1.2
0.670
0.134
0.196
0.178
0.239
0.000
0.067
0.865
2.4
0.591
0.157
0.252
0.220
0.258
0.001
0.103
0.902
3.6
0.533
0.169
0.298
0.253
0.273
0.002
0.137
0.922
4.8
0.488
0.174
0.338
0.282
0.286
0.002
0.169
0.940
Doses printed in bold face meet the overdose criterion (P (overdose) < 0.25))


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Figure 7.1: 1 Prior medians and 95% credible intervals
Beyond the abovementioned BLRM that considers mainly DLT probability, in order to select 
the dose(s) for phase Ib, we will also consider plasma PK data, biomarker and efficacy data as 
available. For example, a BLRM that computes the posterior probability of the plasma PK 
(AUC) falling in a target range (e.g. 80% maximal efficacy exposure) if applicable.
Phase Ib:
In this phase, patients will be randomised into five cohorts of BI 905711 with approximately 
80 patients (see section 4.1.2.2).  Dose(s) selection for phase Ib was made by a SMC with the 
aim to select a safe and potentially effective dose range of BI 905711 based on all data 
collected in phase Ia.  
Data collected during this phase Ib will be recorded and presented by descriptive statistics. 
If applicable, we may use Bayesian hierarchical models incorporating biomarker information
to support decision-making in selecting the RP2D.
If the trial is terminated due to unexpected causes, only descriptive analysis will be provided.


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7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. All analyses in this trial are descriptive 
and exploratory in nature.
7.3
PLANNED ANALYSES
Analysis of efficacy and safety will be based on the treated set, which will consist of all 
patients who receive at least one dose of BI 905711.
For the determination of the MTD, only DLT evaluable patients will be considered. Patients 
will be analyzed according to their starting doses. Any other analysis sets will be defined in 
the TSAP. No per protocol set will be used in the analysis. However, important protocol 
violations will be summarised. The TSAP will specify the important protocol violations in 
detail.
7.3.1
Primary endpoint analyses
Phase Ia: In order to determine the MTD, the number of patients with DLTs will be assessed 
per dose level in phase Ia. The MTD will be determined as described in Section 7.1. Patients 
with DLTs that occurred during the first two treatment cycles and later cycles may be 
tabulated separately.
For doses that will be recommended for phase Ib, totality of data will be considered including 
efficacy and PK. Details are described in Section 3.1.1.
Time frame: Database lock (DBL) will occur when either MTD is found or the recommended 
dose range for phase Ib is determined, and all the patients have had at least 2 post-baseline 
tumor assessment timepoints excluding patients who have discontinued earlier. 
Phase Ib: 
The primary endpoints in the dose-expansion part are objective response (OR) and PFS 
derived from the data of all cycles. The PFS will be summarized using PFS4 rate, defined as 
the proportion of patients with PFS >= 4 months, and will be presented descriptively.
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 observed response rate and PFS4 rate for different dose levels will be compared to 
recommend the optimal dose level (RP2D). If applicable, a Bayesian hierarchical model will 
be used to get the adjusted response rate for each dose level, and comparisons will be made 
among different dose levels to make a recommendation on the optimal dose level (RP2D). 
Time frame: The database lock will occur after all treated patients have had at least three post-
baseline tumor assessment timepoints (unless patients discontinue the treatment early due to 
any reasons). A clinical trial report will follow. 


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7.3.2
Secondary endpoint analyses
Secondary endpoints will be analyzed by descriptive statistics. PK analyses are specified in 
Section 7.3.5 and Section 5.3.
Time frame: the same as the primary endpoint analyses time frame. 
Details will be provided in the TSAP.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 30 days (+ ≤ 5 days) 
after the last dose of trial medication, will be assigned to the on-treatment period for 
evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analyzed 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.


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7.3.5
Pharmacokinetic and pharmacodynamic analyses
The PK parameters will be calculated by means of non-compartmental analysis. Descriptive 
statistics will be used to evaluate plasma concentration data and PK parameters. PK 
parameters will be calculated according to the relevant BI internal procedures.
Further details on analysis will be described in the TSAP.
7.4
INTERIM ANALYSES
The Sponsor will continuously monitor the safety. The dose escalation design foresees that the 
Sponsor and the SMC perform regular safety evaluations. These evaluations will be 
unblinded.
For efficacy, in phase Ib, an arm might be terminated early due to futility if lack of efficacy 
signal (in terms of OR, PFS and PD-modulation) observed among evaluable patients. 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 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.
7.5
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory values 
will be imputed by the respective values from the screening visit. No other imputations will be 
performed on missing data although every effort will be made to obtain complete information 
on all adverse events, with particular emphasis on potential DLTs.
Pharmacokinetcis:
Handling of missing PK data will be performed according to the relevant BI internal
procedure.
PK parameters that cannot be reasonably calculated based on the available drug concentration-
time data will not be imputed.


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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).
7.6
RANDOMISATION
For phase Ib, patients will be randomised into four cohorts of BI 905711 with approximately 
60 patients.  BI will arrange for the randomisation and the packaging and labelling of trial
medication. The randomisation list will be generated using a validated system, which involves 
a pseudo-random number generator so that the resulting treatment will be both reproducible 
and non-predictable. Access to the randomisation list will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for this 
trial. In total, approximately up to 140 patients are planned (approximately 40 evaluable CRC 
patients and 20 non-CRC GI cancer patients for phase Ia, approximately 60 evaluable CRC 
patients and 20 PDAC patients for phase Ib) for this study. 
For phase Ia:
Given the pre-specified possible dose levels (Table 4.1.2.1: 1) and the number of patients per 
dose level, approximately 28 CRC patients will be needed to complete dose escalation. 
The actual number of patients will depend on the number of dose cohorts and the cohort sizes 
actually tested. Based on the simulation studies to evaluate operating characteristics of the 
BLRM (see Appendix 10.3), on average 20-36 evaluable patients are expected to be treated in 
the dose escalation part for safety evaluation for the model to have reasonable operating 
characteristics relating to its MTD recommendation.
In addition, 12 CRC patients are planned for efficacy evaluation in phase Ia. Thus, for 
planning purpose, a total of 40 CRC patients and 20 non-CRC patients are planned for phase 
Ia.
For phase Ib (Part B):
For planning purposes, up to 15 CRC patients per each dose group for up to 4 cohorts, i.e. 
total of up to 60 CRC patients, and up to 20 PDAC patients for the single arm cohort will be 
enrolled for this part.
A Bayesian Hierarchical Model (BHM) approach (R13-4803) will be used to analyze the 
PFS4/ORR rate based on all data from different arms. The simulation results in Table 7.7: 1
show that with the proposed sample size per arm, the BHM approach has reasonable 
performance under a wide range of scenarios. The probability of passing the positive 
boundaries under a negative scenario is well controlled per arm (<= 3%). The probability of 
passing the positive boundaries under a positive/mix scenario is at least 75% per arm. 


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Table 7.7: 1
Operating characteristics of the BHM approach in dose expansion 
arms under different scenarios 
Prob. = Probability. PFS4BHM = Shrinkage estimator of the PFS4 rate based on the BHM. ORRBHM = Shrinkage estimator of 
the ORR rate based on the BHM. Probabilities of PFS4BHM/ORRBHM ≥ positive boundaries are based on 1000 simulations per 
scenario. Positive boundaries represent pre-specified PFS4/ORR rates. 
If DLTs are observed at a certain dose level during phase 1b and the BLRM shows that the 
dose level does not fulfill the overdose risk control, it may be considered to stop that dose 
level due to over toxicity.
Scenario: PFS4 (%)/ORR (%)
Prob. PFS4BHM ≥ positive boundaries or ORRBHM ≥ positive boundaries
Arms
0.6 mg/kg Biweekly
1.2 mg/kg Biweekly
2.4 mg/kg Biweekly
0.6 mg/kg Weekly
Prob. PFS4BHM
≥ positive 
boundaries or 
ORRBHM ≥ 
positive 
boundaries  
in at least one 
arm
Positive boundaries
50%/15%
50%/15%
50%/15%
50%/15%
Negative scenario: PFS4/ORR
Prob. PFS4BHM ≥ boundaries
or  ORRBHM ≥ boundaries  
35%/1%
3%
35%/1%
3%
35%/1%
3%
35%/1%
3%
10%
Mixed scenario: PFS4/ORR
Prob. PFS4BHM ≥ boundaries 
or  ORRBHM ≥ boundaries  
60%/20%
75%
40%/10%
27%
40%/1%
19%
40%/1%
18%
79%
Positive scenario: PFS4/ORR
Prob. PFS4BHM ≥ boundaries 
or  ORRBHM ≥ boundaries  
60%/15%
95%
60%/15%
94%
60%/15%
95%
60%/15%
95%
99%


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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 
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.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the Sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the CTR. 
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The investigator
or delegate obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator or
 


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delegate must sign (or place a seal on) and date the informed consent form. If a trial
collaborator has given a supplementary explanation, the trial collaborator also signs (or places 
a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the Sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment of 
critical data and processes for trial patient protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk Management 
Plan documents the rationale and strategies for risk management during trial conduct 
including monitoring approaches, vendor management and other processes focusing on areas 
of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the Sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow 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 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 necessary for CT/MRIs or ECGs may be provided for safety 
review. 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 will also monitor compliance with the protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please see 
Section 6), site access may be restricted thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralized 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the Sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular
∀
Sample and data usage has to be in accordance with the separate biobanking informed 
consent
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
∀
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
∀
Samples and/or data may be transferred to third parties and other countries as specified 
in the biobanking ICF


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”) 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.
The “Last Patient Last Visit Primary Endpoint (LPLV PE)” is defined as the date at which 
the last patient was examined or received an intervention for the purposes of final collection 
of data for the primary endpoint (according to the protocol specified schedule or after 
premature discontinuation) for each part of the trial. Patient treatment and follow up may 
continue after this time point. For phase Ia, if the last patient is enrolled for dose escalation 
evaluation, this is the date when the patient has had Cycle 3 Day 1 visit or EOR visit (if the 
patient is discontinued early). If the last patient is enrolled for efficacy evaluation in phase Ia 
or Ib, this is the date when the patient has had at least three tumor assessment timepoints 
(unless the patient discontinues the treatment early due to any reasons). 
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
Sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed the 
trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The Sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient (EU 
or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 


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The following committees will be established to evaluate data and allow transition between 
components of the study.
SMC (Safety Monitoring Committee)
The SMC served for decision regarding dose escalation in phase Ia and dose(s) determination 
for phase Ib. SMC will be composed of participating investigators in dose escalation and 
members of the BI trial team. SMC reviewed individual and aggregated safety data at regular 
intervals to determine the safety profile and risk/benefit ratio and recommend next dose level
and appropriateness of further enrollment into dose level cohorts following escalation rules as 
described in the CTP. Details of the SMC responsibilities and procedures were described in 
the SMC charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) were filed in the ISF. The investigators had access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a CT Leader, responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation of 
the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF. An IRT vendor will be used in this trial. Details will be provided in the IRT 
Manual, available in the ISF.


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al. Implication of TNF-related apoptosis-inducing ligand in inflammatory 
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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)
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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)
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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)
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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)
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Death Differ 22, 1727 - 1741 (2015)
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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 
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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)
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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 - 137 (2014)
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2017).
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date: 9 April 2017); U.S. Department of Health and Human Services, 
National Institutes of Health, National Cancer Institute (2017)
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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)
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Frey N. Cytokine release syndrome: who is at risk and how to treat.
Baillieres Best Pract Res Clin Haematol 30, 336-340 (2017)
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acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 
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Bendell J, Blay JY, Cassier P, Bauer T, Terret C, Mueller C, et al.
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patients with solid tumors. AACR-NCI-EORTC Int Conf on Molecular 
Targets and Cancer Therapeutics: Discovery, Biology, and Clinical 
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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, BI 905711 PK parameters will be calculated according to the relevant BI internal 
procedures.
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 
[e.g. 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.
10.2
TIME SCHEDULE FOR PK AND BIOMARKER BLOOD SAMPLING –
NO LONGER APPLICABLE PER CTP V7.0
Table 10.2: 1
Time schedule for PK and Biomarker blood sampling for phase Ia -
No longer applicable per CTP v7.0
Treatment
Course 
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Pre-Cycle 1
Screenin
g
001
-28 
to -5
0:00
0:00
Blood 
sampling 
Cycle 1 
C01_D01
101
1
Just before 
start of 
infusion 
(SOI)
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before end of 
infusionb
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
C01_D02
102
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the 
further 
infusionf
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusion f
24:30
Blood 
sampling
f
X
C01_D03
103
3
48 hours post 
SOI
48:00
Blood 
sampling
X
C01_D08
108
8
168 hours 
post SOI
168:00
Blood 
sampling
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 v7.0
Treatment
Course 
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Cycle 2 
and 4 
C02_D01
/C04_D0
1
201/
401
1
Just before 
SOI
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
end of 
infusionb
0:30
Blood 
sampling
X
C02_D02
/C04_D0
2
202/
402
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the 
further 
infusionf
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusion f
24:30
Blood 
sampling
f
X
Cycle 3 
C03_D01
301
1
Just before 
SOI
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
end of 
infusionb
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
C03_D02
302
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the 
further 
infusionf
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusion f
24:30
Blood 
sampling
f
X
C03_D03
303
3
48 hours post 
SOI
48:00
Blood 
sampling
X
C03_D08
308
8
168 hours 
post SOI
168:00
Blood 
sampling
X




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Table 10.2: 2
Time schedule for PK and Biomarker blood sampling for phase Ib-
Biweekly dosing - No longer applicable per CTP v7.0
Treatment
Course 
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Pre-Cycle 1
Screenin
g
001
-28 
to -5
0:00
0:00
Blood 
sampling 
Cycle 1 
C01_D01
101
1
Just before 
start of 
infusion 
(SOI)
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before end of 
infusionb
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
C01_D02
102
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the
further 
infusione
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusione
24:30
Blood 
sampling
X
C01_D03
103
3
48 hours post 
SOI
48:00
Blood 
sampling
X
C01_D08
108
8
168 hours 
post SOI
168:00
Blood 
sampling
X


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Table 10.2: 2
Time schedule for PK and Biomarker blood sampling for phase Ib-
Biweekly dosing (cont.) - No longer applicable per CTP v7.0
Treatment
Course 
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Cycle 2 
C02_D01
201
1
Just before 
SOI
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
end of 
infusionb
0:30
Blood 
sampling
X
C02_D03 203
3
48 hours post 
SOI
48:00
Blood 
sampling
X
Just before 
SOI of the
further 
infusione
47:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusione
48:30
Blood 
sampling
X
Cycle 3 
C03_D01
301
1
Just before 
SOI
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
end of 
infusionb
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
C03_D02
302
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the 
further 
infusione
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusione
24:30
Blood 
sampling
X
C03_D03
303
3
48 hours post 
SOI
48:00
Blood 
sampling
X
C03_D08
308
8
168 hours 
post SOI
168:00
Blood 
sampling
X






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Table 10.2: 3
Time schedule for PK and Biomarker blood sampling for phase Ib-
Weekly dosing - No longer applicable per CTP v7.0
Treatment
Course 
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Pre-Cycle 1
Screenin
g
001
-28 
to -5
0:00
0:00
Blood 
sampling 
Cycle 1 
C01_D01
101
1
Just before 
start of 
infusion 
(SOI)
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before end of 
infusionb
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
C01_D02
102
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the 
further 
infusione
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusione
24:30
Blood 
sampling
X
C01_D03
103
3
48 hours post 
SOI
48:00
Blood 
sampling
X
C01_D08
108
8
Just before 
start of 
infusion 
(SOI)
167:55
Blood 
sampling
X
168:00
168:00
SOI
---


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Table 10.2: 3
Time schedule for PK and Biomarker blood sampling for phase Ib –
Weekly dosing (cont.) - No longer applicable per CTP v7.0
Treatment
Course 
Visit
Visit 
No. 
Day
Time Pointa
[hh:min]
CRF 
Time
/PTM
Event
PK
ADA
Cycle 2 
C02_D01
201
1
Just before 
SOI
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
end of 
infusionb
0:30
Blood 
sampling
X
C02_D03 203
3
48 hours post 
SOI
48:00
Blood 
sampling
X
Just before 
SOI of the
further 
infusione
47:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusione
48:30
Blood 
sampling
X
Cycle 3 
C03_D01
301
1
Just before 
SOI
-0:05
Blood 
sampling
X
X
0:00
0:00
SOI
---
Immediately 
before
end of 
infusionb
0:30
Blood 
sampling
X
7 hours post 
SOI
7:00
Blood 
sampling
X
C03_D02
302
2
24 hours post 
SOI
24:00
Blood 
sampling
X
Just before 
SOI of the
further 
infusione
23:55
Blood 
sampling
X
Immediatel
y before
end of further 
infusione
24:30
Blood 
sampling
X
C03_D03
303
3
48 hours post 
SOI
48:00
Blood 
sampling
X
C03_D08
308
8
Just before 
start of 
infusion 
(SOI)
167:55
Blood 
sampling
X
168:00
168:00
SOI
---






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10.3
DETAILS OF BLRM SETUP AND OPERATING CHARACTERISTICS
The BLRM was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics. The simulations for scenarios and operating characteristics 
were produced using R version 3.4.2 and Jags version 4.3.0. Both the hypothetical data 
scenarios and the operating characteristics are based on the CRC patients data for safety 
evaluation only. Note that in the real trial more data will be available from the non-CRC GI 
cancer patients and also from additional patients enrolled for efficacy evaluation which will 
lead to improved data scenarios and operating characteristics
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.3: 1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model. For each scenario, the 
probability of overdose for the current dose is shown, as well as the next optimal dose 
recommended by the model in terms of the probability of target dose, and the related 
probabilities of under-dosing, target dose, and overdosing for the next optimal dose. The actual 
dose chosen for the next cohort, not shown in Table 10.3: 1, will be determined by the SMC 
after taking into consideration of the recommended dose from the model as well as other 
relevant data from this study.
For example, scenario 1 represents the case that no DLT is observed in the first patient at the 
starting dose of 0.02 mg/kg. In this case, the next dose permitted by the model and by the 
escalation rule is 0.06 mg/kg. Similarly scenarios 3 and 6 represent cases where no DLTs are 
observed, and the model will recommend escalating to the next dose level that is permitted by 
escalation rule. In scenario 2, one DLT is observed already in the patient at the lowest dose 
level. In this case, the model cannot provide the next recommended dose level. However, 
according the escalation rule specified in Section 3.1.1, two more patients may be enrolled into 
this dose level. The same holds for scenario 4.
Scenarios 17 illustrate a case where dose level 2.4 mg/kg has probability of overdose exceeds 
25%, per BLRM with the given provisional dose levels, the next optimal dose recommended 
would be 1.2 mg/kg. However, BLRM has flexibility to explore intermediate dose level, in both 
scenarios, if intermediate dose levels of 1.6 mg/kg and 1.8 mg/kg are explored, 1.6 mg/kg would 
be recommended as the next dose level because it has the highest probability of target dose, and 
overdose probability less than 25%. 
Scenario 20 illustrates a case where low dose cohorts have no DLT, or 1 DLT, and the highest 
dose level 4.8 mg/kg has 1 DLT. In such cases, BLRM would continue to put patients on 4.8 
mg/kg, but if higher dose levels are allowed, higher level e.g. 6.4 mg/kg would be 
recommended. 


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Table 10.3: 1
Hypothetical data scenarios
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
0.02
1
0
0.033
0.06
0.885
0.068
0.047
2
0.02
1
1
0.591
NA
NA
NA
NA
2a
0.02
3
1
0.236
0.02
0.503
0.261
0.236
3
0.02
0.06
1
1
0
0
0.019
0.2
0.886
0.071
0.043
4
0.02
0.06
1
1
0
1
0.394
NA
NA
NA
NA
4a
0.02
0.06
1
3
0
1
0.165
0.06
0.541
0.294
0.165
5
0.02
0.06
1
4
0
1
0.114
0.2
0.477
0.308
0.216
6
0.02
0.06
0.2
1
1
4
0
0
0
0.005
0.6
0.913
0.069
0.018
7
0.02
0.06
0.2
1
1
4
0
0
1
0.108
0.6
0.470
0.305
0.225
8
0.02
0.06
0.2
1
1
4
0
0
2
0.374
0.06
0.421
0.374
0.205
9
0.02
0.06
0.2
0.6
1
1
4
4
0
0
0
1
0.053
1.2
0.565
0.299
0.136
10
0.02
0.06
0.2
0.6
1
1
4
4
0
0
0
2
0.210
0.6
0.369
0.421
0.210
11
0.02
0.06
0.2
0.6
1
1
4
4
0
0
1
1
0.198
0.6
0.369
0.432
0.198
12
0.02
0.06
0.2
0.6
1
4
4
4
0
1
1
1
0.315
0.2
0.372
0.492
0.136
13
0.02
0.06
0.2
0.6
1
4
6
4
0
1
1
1
0.232
0.6
0.258
0.510
0.232
14
0.02
0.06
0.2
0.6
1.2
1
1
4
4
4
0
0
0
0
1
0.025
2.4
0.584
0.279
0.138


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Table 10.3: 1
Hypothetical data scenarios (cont.)
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)
15
0.02
0.06
0.2
0.6
1.2
1
1
4
4
4
0
0
0
0
2
0.176
1.2
0.420
0.404
0.176
16
0.02
0.06
0.2
0.6
1.2
2.4
2
2
4
4
4
4
0
0
0
0
1
1
0.149
  2.4
0.448
0.403
0.149
17*
0.02
0.06
0.2
0.6
1.2
2.4
2
2
4
4
4
4
0
0
0
0
1
2
0.384
  1.2
1.6*
1.8*
  0.465
0.309
0.259
  0.454
0.517
0.516
  0.082
0.174
0.225
18
0.02
0.06
0.2
0.6
1.2
2.4
3.6
1
1
4
4
4
4
4
0
0
0
0
0
0
1
0.048
4.8
0.609
0.245
0.146
19
0.02
0.06
0.2
0.6
1.2
2.4
  3.6
1
4
4
4
4
4
4
0
1
0
0
0
0
1
0.027
4.8
0.665
0.291
0.044
20*
0.02
0.06
0.2
0.6
1.2
2.4
  3.6
  4.8
1
1
4
4
4
4
4
4
0
0
0
0
1
0
0
1
0.043
4.8
6.4*
0.649
0.553
0.308
0.355
0.043
0.092
*denote the cases where intermediate or higher doses are considered. 
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose with 
true DLT rate in the target interval can be approximated via simulation. Table 10.3: 2 describes 


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7 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. Scenario 1 represents the 
DLT rates that are aligned with prior means per dose level. Scenarios 2 and 3 reflect the extreme 
cases of high and low toxicity probabilities, respectively. Scenario 4 represents an even more 
extreme case with very low toxicity probability. Scenario 5 covers the case of a true dose-
toxicity relationship that does not have a logistic form. Finally, Scenarios 6 and 7 reflect the 
possibility of having non-monotonic true dose-toxicity relationship. 
Table 10.3: 2 
Assumed true dose-toxicity scenarios
Scenarios
Provisional dose levels
0.02
0.06
0.2
0.6
1.2
2.4
3.6
4.8
1: Prior
0.076 
0.092
0.116
0.149
0.178
0.220
0.253
0.282
2: High Tox
0.100
0.221
0.305
0.356
0.408
0.454
0.486
0.498
3: Low Tox
0.009 
0.018
0.057
0.100
0.122
0.160
0.174
0.180
4: Very low Tox*
0.001 
0.008
0.010
0.020
0.050
0.065
0.080
0.100
5: Non-Logis-tic
0.020 
0.050
0.065
0.090
0.130
0.250
0.321
0.508
6: Non-Monotonic 1
0.020 
0.080
0.120
0.202
0.250
0.389
0.250
0.202
7: Non-Monotonic 2
0.010 
0.050
0.090
0.210
0.327
0.389
0.327
0.210
* Additional dose level 300mg added (assumed true tox probability of 0.789) to allow R code to run
For each of these scenarios, 1000 trials were simulated. 4 patients per dose cohort were assumed 
as default cohort size for the simulations. It was then assessed how often a dose was declared 
as MTD with true DLT rate in the under-, targeted or over-dose range. Furthermore, the average, 
minimum and maximum number of patients per trial and the average number of DLTs per trial 
are reported. Results are shown in Table 10.3: 3.


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Table 10.3: 3
Simulated operating characteristics 
Scenario
% of trials declaring an MTD with true DLT 
rate in
# Patients
# DLT
underdose
target dose
overdose
stopped
Mean
(Min-Max)
Mean
(Min- Max)
1
31.6
62.7
0.0
5.7
29.8 (4 - 52)
4.6 (1 - 13)
2
4.6
63.9
16.1
15.4
19.5 (4 - 48)
4.6 (2 - 13)
3
20.9
78.4
0.0
0.7
33.3 (8 - 52)
3.4 (0 -11)
4
98.3
0.0
0.0
1.7
35.7 (12 - 52)
2.1 (0 - 7)
5
45.8
47.4
5.6
1.2
33.9 (4 - 52)
5.3 (1 - 13)
6
21.5
72.9
5.0
0.6
28.1 (4 - 52)
4.5 (1 - 14)
7
17.4
78.2
4.2 
0.2
28.0 (8 - 52)
4.7 (1 - 12)
*1 trial declared the additional dose 300mg/kg as MTD
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
62.7% of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose 
range. 
Scenarios 4 and 5 (very low-toxicity scenario) shows, that when the true DLT rate is very low, 
i.e. the majority dose levels with true DLT rate below the target interval, then more likely the 
model will declare a underdose as MTD. Since in scenario 4 none of the dose levels has an 
assumed true toxicity rate in the target interval, none of the simulated trials has declared a MTD 
with true DLT rate in the target dose range. In scenario 5 only few dose level was assumed to 
have true DLT rate in the target range, but at the upper end of the target range, therefore only a 
low number of simulated trials declared MTD at this dose with true DLT rate in the target range. 
The probability of observing a DLT at 1.2mg/kg is 0.13 and therefore close to the lower bound 
of the target interval. Adding up the corresponding probability of declaring this dose as an MTD 
(35.8% leads to a target rate of 83.2). Both scenarios have a very low percentage of trials stopped 
since no MTD was reached (either because the maximum number of patients was reached before 
declaring MTD or because too many DLTs were simulated to continue escalation).
In Scenarios 6 and 7, dose-toxicity relationship is non-monotonic. Scenarios 6 and 7 illustrates 
that the majority simulated trials (over 70%) declare the target dose levels as MTD. 
The mean patient numbers across different scenarios is around 28, though the maximum can go 
up to 52 during simulation. This shows that the planned maximum of 40 patients is reasonable 
for phase Ia. 
In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
10Dec2019
EudraCT number
EU number
2018-003268-29
BI Trial number
1412-0001 
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A first-in-human phase Ia/b, open label, 
multicentre, dose   escalation study of BI 905711 
in patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Synopsis
Description of change
Revised to clarify Exclusion #1
Rationale for change
Revision to align description of Exclusion #1 with 
Section 3.3.3. 
Section to be changed
Flowchart
Description of change
Revised to clarify that safety labs are to be 
performed at Cycle 4 Day 1. 
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Flowchart
Description of change
Revision to footnote #2
Rationale for change
Revision to clarify meaning of Eligibility for 
further treatment prior to dosing on Day 1 of each 
cycle from Cycle 2 onwards. 
Section to be changed
Flowchart
Description of change
Revision to footnotes #10 and #12
Rationale for change
Revision to clarify that pre-treatment PET scan 
and fresh biopsy is to be performed during 
screening before the first day of treatment (Cycle 
1 Day 1) after eligibility has been confirmed.
Section to be changed
Flowchart and Section 6.2.1
Description of change
Revised footnote #14 and section 6.2.1 to clarify 
use of tumor assessments performed prior to 
informed consent. 
Rationale for change
Tumor assessments performed prior to informed 
consent as part of routine clinical practice will be 
accepted if they meet the requirements of the 
protocol and are performed within the Screening 
visit window (28 days) prior to treatment start.


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Section to be changed
Section 3.1.2
Description of change
Revised to remove statement that possible 
inclusion of non-CRC GI cancer patients into 
phase Ib will be considered if efficacy (OR) is 
observed in phase Ia
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.2 and Synopsis
Description of change
Revised Inclusion criterion #2 to describe that
eligible patients must have disease progression on 
all available therapies known to confer clinical 
benefit for their disease. 
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.2 and Synopsis
Description of change
Revised inclusion criterion #5:
    a. to expand the bilirubin inclusion criterion 
from “within normal limits and ≤1.5 x ULN for 
patients with Gilbert’s syndrome” to “bilirubin 
≤1.5 x ULN; and ≤3 x ULN for patients with 
Gilbert’s syndrome”.
    b. to expand the ALT and AST inclusion 
criterion from “≤1.5 x ULN and ≤2.5 x ULN in 
patients with known liver metastases” to “ALT 
and AST ≤2.5 x ULN or ≤5 x ULN in patients 
with known liver metastases”
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.3 and Synopsis
Description of change
Revised Exclusion criterion #3 to clarify that 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.
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.3 and Synopsis
Description of change
Added Exclusion criterion #14 to provide 
guidance regarding cardiac criteria that would 
constitute a concomitant condition for exclusion 
from the study. 
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.3 and Synopsis


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Description of change
Added exclusion criterion #15 to exclude patients 
with known hypersensitivity to the trial 
medication and/or its components i.e. polysorbate 
20, sodium citrate, lysine hydrochloride, sucrose, 
citric acid. 
Rationale for change
Revision in response to PMDA (Japan) review 
comment.
Section to be changed
Section 3.3.4.1
Description of change
Revised to include specific criteria required to 
continue treatment beyond initial RECIST-
defined radiological progression of disease and to 
clarify that written informed consent should be 
obtained.  
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 3.3.4.1
Description of change
Revised to remove references to temporary 
treatment discontinuation and to early treatment 
discontinuation. 
Rationale for change
Dose modification is described in section 4.1.2.3. 
Procedures for treatment discontinuation and 
follow up are outlined in the Flowchart and 
Section 6.2.3
Section to be changed
Section 3.3.4.4
Description of change
Revised to clarify that patients without DLT 
during MTD evaluation period will not be 
included in the BLRM analysis and additional 
patient(s) will be entered at the same dose level 
according to the criteria listed. It is also clarified 
that 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.
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 4.1.4
Description of change
Revised to clarify the post-infusion monitoring 
guidelines for the first three doses of BI 905711.
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 4.1.4
Description of change
Revised to clarify that total storage time for 
ready-to-use solution. 
Rationale for change
Revised to clarify that total storage time for 
ready-to-use solution at room temperature should 
not exceed 150 minutes between preparation and 
end of infusion time.
Section to be changed
Section 4.1.4.1.1
Description of change
Revised to clarify that during the first re-
exposure, after a prior Infusion-Related Reaction 


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(IRR), a systematic hospitalisation for at least 24 
hours for observation is no longer required. 
Instead, patients must remain under observation 
for at least 8 hours post start of infusion. If 
required, patients may be hospitalised for a longer 
observation period at the investigator’s discretion.
Rationale for change
A systematic 24-hour hospitalisation is not 
justified given that Infusion-Related Reaction 
(IRR) is a rare event that typically occurs during 
or shortly after the end of the infusion, and in 
most cases, it is manageable without 
hospitalization.
Section to be changed
Section 4.1.4.1.2
Description of change
Revised to clarify the observation period for CRS. 
Rationale for change
Revision included to clarify that 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 4.1.4.
Section to be changed
Section 4.1.4.1.5
Description of change
Revised to clarify that patients who experience a 
≥ CTCAE grade 2 adverse event must undergo a 
full neurological investigation with treatment 
interruption.
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 5.2.2
Description of change
Revised to add body temperature. 
Rationale for change
Revision added to align with updates added for 
post-infusion observation period in section 4.1.4.
Section to be changed
Section 5.2.3
Description of change
Revised to clarify urinalysis. 
Rationale for change
Analysis will be performed by routine analysis. 
Section to be changed
Section 5.2.6.1.5
Description of change
Revised DLT criteria to include (a) any death not 
clearly due to the underlying disease or 
extraneous causes and (b) all Grade 4 events 
possibly related to study therapy, irrespective of 
whether patients received maximal supportive 
therapy. 
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Section 6.2.1


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Description of change
Revision to clarify the genomic alterations status 
such as BRAF, KRAS, HER2, BRCA...etc, and 
the immune markers status such as microsatellite 
instability and/or DNA mismatch repair 
deficiency...etc. will be collected in the eCRF. 
Rationale for change
Revision in response to FDA review comment.
Section to be changed
Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates that do not affect 
protocol content and will not be listed as separate 
changes.  
11.2
GLOBAL AMENDMENT 2
Date of amendment
21May2020
EudraCT number
EU number
2018-003268-29
BI Trial number
1412-0001 
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A first-in-human phase Ia/b, open label, 
multicentre, dose   escalation study of BI 905711 
in patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Synopsis
Description of change
Update of contact information for Coordinating 
Investigator
Rationale for change
Administrative update due to change in 
Coordinator Investigator
Section to be changed
Synopsis
Description of change
Clarification added for the total number of 
patients. 
Rationale for change
Revision to state up to approximately 140 
patients. 
Section to be changed
Synopsis, Section 3.3.1, Section 3.3.2
Description of change
Inclusion criteria #1


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Rationale for change
Inclusion of gallbladder carcinoma due to update 
of tumor type to be studied.
Section to be changed
Synopsis, Section 3.3.2, Section 3.3.3
Description of change
Inclusion criteria #6, Exclusion #4
Rationale for change
Clarification that Adverse Event grading is 
according to CTCAE v5.0
Section to be changed
Synopsis and Section 3.3.3
Description of change
Exclusion #8
Rationale for change
Exclusion criteria #8 has been removed due to 
heparin interaction testing results. 
Language regarding use of anticoagulation 
therapy has been moved from Exclusion criteria
#8 to Section 4.2.2.1. 
Exclusion criteria renumbered from existing #7 
onwards in the Synopsis and in Section 3.3.3.
Section to be changed
Synopsis and Section 3.3.3
Description of change
Exclusion criteria #13
Rationale for change
Removed reference to mean resting QTC as only 
one ECG reading is planned to be obtained. 
Section to be changed
Flowchart
Description of change
Footnote #3 
Rationale for change
Clarification added that Physical exam does not 
need to be repeated at Cycle 1 Day 1 if completed 
within 24hrs.
Section to be changed
Flowchart
Description of change
Footnote #4 added 
Rationale for change
If for logistical purposes patient weight may need 
to be calculated prior to Cycle 1 Day 1 in order to 
prepare the pharmacy order, the Cycle 1 Day 1 
dose may be calculated based upon a patient 
weight obtained up to 3 days before 
administration if the body weight change is by 
≤10% compared to the reference weight.
Footnotes in flowchart renumbered from #4 
onwards. 
Section to be changed
Flowchart
Description of change
Footnote #5
Rationale for change
Clarification added that ECOG does not need to 
be repeated at Cycle 1 Day 1 if completed within 
24hrs.
Section to be changed
Flowchart
Description of change
Footnote #9
Rationale for change
Removed requirement to perform safety labs at 
Cycle 1 Day 3. 


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On Cycle 1 Day 1, patients also need to have 
safety labs performed between 4-6 hours post-
dose (updated from 7-8 hours post-dose). 
Section to be changed
Flowchart and Section 5.4.1
Description of change
Revision to footnote #11 and Section 5.4.1 to add 
an on treatment biopsy in phase Ib. 
Rationale for change
An additional on treatment fresh tumor biopsy is 
mandatory in at least 20 CRC patients irrespective 
of the dose cohort and only in case a fresh biopsy 
has been successfully obtained before first study 
treatment. The biopsy should be taken on Cycle 2 
Day 2, 24h after administration of BI 905711. 
Fresh on treatment biopsies should be obtained 
from additional patients and all indications (CRC 
and non CRC) if the patient agrees (optional). 
Timepoints are detailed in the Flow Chart 
Section to be changed
Section 1.2
Description of change
Revision to remove section about BI 905711 
mixed in vitro with plasma from blood collected 
in tubes containing heparin lead to cloudiness and 
microscopic examination revealed flocculation 
(c16856466).
Rationale for change
Revision based update of heparin use.
Section to be changed
Section 1.4
Description of change
Updated toxicology results to include a 
description of immune complex formation 
resulting in renal injury (glomerulonephropathy)
Rationale for change
Toxicology update
Section to be changed
Section 2.1.3
Description of change
Added PK parameters as secondary endpoints
Rationale for change
Update
Section to be changed
Section 3.1
Description of change
Revision to Figure 3.1:1
Rationale for change
Clarification added to align with for planned 
approach for recruitment in CRC and non-CRC 
cohorts. 
Section to be changed
Section 3.1.1
Description of change
Reformatted into sub-sections 3.1.1.1 through 
3.1.1.4 
Rationale for change
Sub-sections created for ease of review. 
Additional clarifications included for planned 
approach for recruitment in CRC and non-CRC 
cohorts, MTD determination/recommended dose 
range for expansion, and expanded cohort for 
efficacy evaluation in Phase Ia. 
Section to be changed
Section 3.1.1.2 and 4.1.2.1


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Description of change
Clarification about inclusion of China into phase 
Ia.
Rationale for change
If the first site in China is initiated while the phase 
Ia is ongoing, the first Chinese patient will be 
enrolled into the non-CRC dose level that is open 
at the time of site initiation. Thereafter, at least 
one Chinese patient will be enrolled in China at
each subsequent dose level in Phase Ia.
Section to be changed
Section 3.3
Description of change
Revision to selection of trial population
Rationale for change
Clarification added to update the approximate 
number of sites and regions anticipated to 
participate in phase Ia. 
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #3
Rationale for change
Alignment with text for exclusion criteria #3 in 
Synopsis
Section to be changed
Section 4.1.2.3
Description of change
Clarification added about dose escalation
Rationale for change
More than one dose-escalation can be considered 
if deemed appropriate by the Investigator. Dose 
cannot be escalated if it was previously reduced 
due to toxicity.
Section to be changed
Section 4.1.4
Description of change
Clarification about reference weight to be used for 
dose calculation.  
Rationale for change
The Cycle 1 Day 1 dose will be calculated using 
the Cycle 1 Day 1 weight as the reference weight. 
If the patient’s weight changes by ≤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.
Section to be changed
Section 4.1.4
Description of change
Clarification regarding timeframe for the infusion 
and priming and flushing. 
Rationale for change
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. 
Priming and flushing should not be included in the 
administration duration.
Section to be changed
Section 4.1.4.1.1
Description of change
Timeframe for administration
Rationale for change
If less than 50% of the planned dose of BI 905711 
was administered due to an infusion-related 


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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 3 
days after the original planned dose.
Section to be changed
Section 4.1.4.1.5
Description of change
Clarification of guidelines for management of 
possible neurological toxicities
Rationale for change
During dose escalation phase (phase Ia), patients 
will undergo baseline brain MRI and should be 
followed for possible new neurological signs and 
symptoms at each visits of the study drug 
administration and at end of treatment.
Section to be changed
Section 4.2.2.1
Description of change
Clarification of heparin use 
Rationale for change
Language regarding use of anticoagulation 
therapy has been moved from Exclusion criteria
#8 to Section 4.2.2.1.
Based on heparin interaction testing results, 
guidance regarding use of use of heparin 
(including flushing and locking of intravenous 
catheters) or LMWH has been updated. 
Section to be changed
Section 5.1
Description of change
Revised to align with footnote #15 and section 
6.2.1 to clarify use of tumor assessments 
performed prior to informed consent.
Rationale for change
Tumor assessments performed prior to informed 
consent as part of routine clinical practice will be 
accepted if they meet the requirements of the 
protocol and are performed within the Screening 
visit window (28 days) prior to treatment start.
Section to be changed
Flowchart, Section 5.1
Description of change
Clarification about monitoring of patients with a 
specific tumor marker (also added in footnote 
#15)
Rationale for change
If the patient’s cancer is being monitored with a 
specific tumor marker (e.g. CEA, CA19.9, etc.), 
tumor marker levels should be obtained at 
baseline, and at every protocol-specified tumor 
assessment timepoint. 
Section to be changed
Section 5.2.6.1.5
Description of change
Clarification added for definition of febrile 
neutropenia 
Rationale for change
Grade ≥ 3 febrile neutropenia defined as ANC 
below ANC <1000/mm3 and a single temperature 
of ≥ 38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥ 38 degrees C (100.4 degrees F) 


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for more than one hour; or where there are life-
threatening consequences or urgent intervention 
indicated.
Section to be changed
Section 5.3.2
Description of change
Clarification about derivation of exact time points 
of plasma sampling 
Rationale for change
Exact time points of plasma sampling will be 
documented in the CRFs by the medical personnel 
or sent as electronic files to the Trial Data 
Manager.
Section to be changed
Section 5.4
Description of change
Clarification about assessment of biomarkers
Rationale for change
Wording updated for ease of review and to 
include reference to on treatment biopsy. The 
determination of cell death biomarkers will be 
performed in plasma and tumor tissue.  
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 5.5.1
Description of change
Revision to the methods and timing of sample 
collection
Rationale for change
If the patient has not consented to optional 
biobanking (see section 5.5), trial samples left 
over after primary analysis will be discarded after 
completion of these additional investigations but 
not later than 5 years after the final trial report has 
been signed.
Section to be changed
Section 7.3.1
Description of change
Clarification of the timeframe for the primary 
endpoint analysis
Rationale for change
Time frame: Database lock (DBL) will occur 
when either MTD is found or the recommended 
dose range for Phase Ib is determined, and all the 
patients have had at least 2 tumor assessment 


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timepoints excluding patients who have 
discontinued earlier.
Section to be changed
Section 9.1
Description of change
Revision to references
Rationale for change
References added for R20-1190, R20-1191, R20-
1196, R20-1209                                         
Section to be changed
Section 10.2
Description of change
Clarification of PK sampling scheduled at 24 
hours post SOI and clarification of the windows 
for PK sampling.
Rationale for change
If less than 50% of the planned dose of BI 905711 
was administered due to infusion-related 
reactions, 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.
The window for sampling at 7h has been revised 
to ± 15 min of the designated time. In 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.
Section to be changed
Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates that do not affect 
protocol content and will not be listed as separate 
changes.  
11.3
GLOBAL AMENDMENT 3
Date of amendment
29Jun2021
EudraCT number
EU number
2018-003268-29
BI Trial number
1412-0001 
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A first-in-human phase Ia/b, open label, 
multicentre, dose escalation study of BI 905711 in 
patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons




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Description of change
Body of flowchart, footnotes #3, 5, and 9, and 
Section 6.2.3.3 include adjustments to procedures 
at the Followup for progression visit
Rationale for change
ECOG, physical examination, and safety labs 
added to align with BI standard for patient 
monitoring during follow-up for progression. 
Section to be changed
Section 1.4
Description of change
Addition of language regarding potential
identification of a confirmed SARS-CoV-2
infection.
Rationale for change
Adjustment added based upon an assessment of 
the COVID-19 related risks to trial participants.
Section to be changed
Section 3.1
Description of change
Figure 3.1: 1
Rationale for change
Revision to remove references to backfill for non-
CRC patients in Dose level 1 and Dose level 2 per 
agreement with the SMC to not consider backfill 
enrollment until Dose level 3.  
Section to be changed
Synopsis, Section 3.3.1, Section 3.3.2
Description of change
Inclusion criteria #1
Rationale for change
Revision to clarify the gastrointestinal tumor 
types to be studied.
Section to be changed
Synopsis, Section 3.3.3
Description of change
Exclusion criteria #1
Rationale for change
Revision to clarify use of previous systemic anti-
cancer therapy prior to study treatment start. 
Section to be changed
Synopsis, Section 3.3.3
Description of change
Exclusion criteria #2
Rationale for change
Revision to clarify use of radiation therapy prior 
to study treatment start.
Section to be changed
Synopsis, Section 3.3.3
Description of change
Exclusion criteria #3
Rationale for change
Revision to serious concomitant disease or 
medical condition to specify that patients with any
history of stroke or myocardial infarction within 6 
months prior to screening are not eligible for 
participation.
Section to be changed
Section 3.3.4.1
Description of change
Revision to the criteria for discontinuation of trial 
treatment to address if a patient experiences an 
infection with SARS-CoV-2. 
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact to trial 
participants. 
Section to be changed
Section 4.1.4


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Description of change
Clarification of visit handling due to potential 
disrupting circumstances.
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact to trial 
participants.
Section to be changed
Section 4.1.8
Description of change
Clarification of investigational drug handling
Rationale for change
Unused and partially used trial drug may be 
destroyed onsite according to local site procedure. 
Section to be changed
Section 4.2.2.1
Description of change
Clarification of restricted medication 
Rationale for change
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.
Section to be changed
Section 4.2.2.1
Description of change
Revision to include information regarding
COVID-19 vaccination
Rationale for change
Adjustment added based upon an assessment of
the potential COVID-19 impact.
Section to be changed
Section 5.1
Description of change
Clarification of radiomics definition. Clarification 
added that FDG-PET/CT at baseline should be 
performed within 14 days (±7 days) prior to 
treatment start (Cycle 1 Day 1).
Rationale for change
Revisions included to align with current BI 
template definition.
Section to be changed
Section 5.2.6.1.4
Description of change
Clarification of hepatic injury definition 
Rationale for change
Revisions included to align with current BI 
template definition. 
Section to be changed
Section 5.2.6.2.1
Description of change
Clarification of trial completion
Rationale for change
Adjustment to include a statement to refer to the 
description of trial completion for an individual 
patient in section 6.2.3.4.
Section to be changed
Flowchart, Section 5.4, Section 10.2
Description of change
Adjustment to add determination of cell death 
biomarkers at screening (phase Ib only).
Rationale for change
Sampling added to measure the longitudinal 
variation of these markers in CRC patients in 
phase Ib.
Section to be changed
Section 5.4.1.1
Description of change
Revision to collection of archival tissue sample
Rationale for change
Archival tumor tissue sample should be provided 
as FFPE-preserved tissue, preferably as an 


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embedded block and less preferably as mounted 
tissue sections (at least 19 sections of 4-5 μm 
thickness) prepared under RNase free conditions.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 6.1
Description of change
Clarification of handling of disruption from 
planned schedule of visits and procedures. 
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact to trial 
participants.
Section to be changed
Section 8.3.2
Description of change
Clarification regarding direct access to source 
data
Rationale for change
Adjustment added based upon an assessment of 
the potential COVID-19 impact.
Section to be changed
Miscellaneous
Description of change
Clarification of laboratory units throughout
Rationale for change
Laboratory values used for determination of 
patient eligibility or other medical decisions are 
presented in SI and conventional units. 
Section to be changed
Miscellaneous
Description of change
Revisions to formatting, punctuation, and/or 
spelling. 
Rationale for change
Clarifications added as applicable to address 
minor formatting updates that do not affect 
protocol content and will not be listed as separate 
changes.  
11.4
GLOBAL AMENDMENT 4
Date of amendment
11Apr2022
EudraCT number
EU number
2018-003268-29
BI Trial number
1412-0001 
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A first-in-human phase Ia/b, open label, 
multicentre, dose escalation study of BI 905711 in 
patients with advanced gastrointestinal cancers
Global Amendment due to urgent safety reasons
Global Amendment
X


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Section to be changed
Synopsis
Description of change
Clarification added for the total number of 
patients. 
Rationale for change
Revision to state approximately 120 evaluable 
patients. 
Section to be changed
Synopsis, Section 2.1.2
Description of change
Clarification of primary endpoint
Rationale for change
Update PFS from a secondary endpoint to a 
primary endpoint for phase Ib.
Section to be changed
Synopsis, Section 2.1.3
Description of change
Addition of secondary endpoint
Rationale for change
Addition of number of patients with treatment-
emergent AEs as a secondary endpoint for phase 
Ib to align with the main objective for phase Ib. 
Section to be changed
Synopsis, Section 3.3.2
Description of change
Inclusion criteria #1
Rationale for change
Clarification of tumor types for inclusion in phase 
Ia and phase Ib. 
Section to be changed
Synopsis, Section 3.3.2
Description of change
Inclusion criteria #5
Rationale for change
Clarification of the parameters for Hemoglobin 
(Hb) ≥ 8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 mmol/L 
(without transfusion within previous week)
Section to be changed
Synopsis, Section 3.1, Section 3.1.2, Section 7
Description of change
Confirmation of the number of planned patients in 
phase Ib
Rationale for change
Phase Ib will be opened with 3 dose levels in 4 
cohorts
Section to be changed
Synopsis, Section 1.2, Section 3.1, Section 3.1.2, 
Section 4.1.1, Section 4.1.2.2, Section 4.1.3, 
Section 7
Description of change
Confirmation of dose levels for phase Ib 
Rationale for change
Three dose levels for phase Ib will be 
administered on a biweekly regimen and 1 dose 
level for phase Ib will be administered on a 
weekly regimen (3 weeks on, 1 week off). 
Section to be changed
Flowchart
Description of change
Clarification of Flowchart applicable for patients 
in phase Ia and phase Ib
Rationale for change
Clarification of the label for the Flowchart 
applicable to patients enrolled in phase Ia. Update 
of the description of the procedure in the phase Ia 
flowchart to circulating tumor DNA. 


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Addition of a Flowchart applicable to patients 
enrolled in phase Ib- Biweekly dosing. Addition 
of a Flowchart applicable to patients enrolled in 
phase Ib- Weekly dosing.
Section to be changed
Flowcharts for phase Ia and phase Ib
Description of change
Clarification of echocardiography (or multigated 
acquisition scan)
Rationale for change
Procedure added to flowchart to clarify that 
measurement of ejection fraction at may be 
needed per Exclusion criteria #13.
Section to be changed
Synopsis, Section 3.3.2
Description of change
Clarification of Inclusion criteria #4 for biopsy 
collection in phase Ib
Rationale for change
Availability and willingness to provide an 
archived tumor tissue specimen and undergo 
tumor biopsy before treatment. Pre-treatment 
fresh tumor biopsy collections for biomarker 
analyses are considered optional in phase Ia and 
mandatory in phase Ib. 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 
due to before mentioned reasons an archived 
tumor tissue specimen obtained within ≤6 months 
of screening must be submitted. In case the 
patient undergoes baseline tumor biopsy, an 
archived tumor tissue specimen must be 
submitted regardless of the date of collection.
Section to be changed
Flowcharts for phase Ib, Section 5.4.1
Description of change
Clarification of biopsy collection in phase Ib
Rationale for change
Clarification added that in phase Ib an additional 
on-treatment fresh tumor biopsy should be taken 
on Cycle 2 Day 3 and/or at disease progression 
for a patient in which a fresh biopsy has been 
successfully obtained before first study treatment. 
Clarification added that in phase Ib in case a fresh 
biopsy before treatment start has been collected, 
an archival tumor tissue must also be submitted 
(mandatory).
Removal of the requirement that an on-treatment 
fresh biopsy is mandatory in at least 20 CRC 
patients in phase Ib. 
Section to be changed
Flowcharts for phase Ib, Section 6.2.1
Description of change
Addition of collection of previous tumor response 
data if available. 
Rationale for change
Support analyses relative to tumor response.
Section to be changed
Flowcharts 


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Description of change
Footnote 9 (phase Ia), Footnote 10 (phase Ib)
Rationale for change
Addition of the requirement to have safety labs 
performed post-dose after the second and third 
administrations to assess ALT and AST values for 
a patient that experiences an elevated ALT and/or 
AST value after Cycle 1 Day 1 administration.     
Section to be changed
Section 1.1
Description of change
Addition of prevalence data
Rationale for change
Addition of BI prevalence data for gastrointestinal 
cancers expressing CDH17.
Section to be changed
Section 1.2
Description of change
Update of Drug Profile
Rationale for change
Addition of updated information based upon 
phase Ia. 
Section to be changed
Section 1.3
Description of change
Update of rationale for performing the trial
Rationale for change
Addition of updated information based upon 
phase Ia. 
Section to be changed
Section 1.4
Description of change
Update of benefit-risk assessment
Rationale for change
Addition of updated information based upon 
phase Ia. 
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.1
Description of change
Update of Figure 3.1: 1
Rationale for change
Updated schematic included for phase Ib design.
Section to be changed
Section 3.1.1.4, Section 10.4
Description of change
Removal of the sections
Rationale for change
Sections 3.1.1.4 (Expanded cohort for efficacy 
evaluation in phase Ia) and 10.4 (Details of Dose 
Expansion and Operating Characteristics) were 
removed because the approach was not used in 
phase Ia. 
Section to be changed
Section 3.2
Description of change
Update of trial design 
Rationale for change
Addition of the dose levels and dose regimens 
selected for phase Ib and rationale for the weekly 
dosing regimen. 
Section to be changed
Section 3.3
Description of change
Clarification of patient population
Rationale for change
For phase Ib, approximately 60 evaluable patients 
are planned to be entered in 8 regions.








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Section to be changed
Title Page
Description of change
Update of contact information for Clinical Trial 
Leader
Rationale for change
Administrative update due to change in Clinical 
Trial Leader
Section to be changed
Synopsis, 3.3.2
Description of change
Updated inclusion criteria 1 and 5 for PDAC 
cohort in Phase Ib: serum lipase > 1.5 – 2.0 x 
ULN or asymptomatic >2.0 – 5.0 x ULN if 
related to PDAC; Cancer histology of pancreatic 
adenocarcinoma with CDH17 positive expression 
as assessed by central testing.
Rationale for change
Specific requirement added considering patient 
background.
Section to be changed
Synopsis, Figure 3.1.1
Description of change
Addition of 1 cohort of PDAC patients which will 
be treated weekly on 0.6 mg/kg dose level
Rationale for change
Addition of PDAC cohort
Section to be changed
Synopsis
Description of change
Statistical methods text for Phase Ib updated from 
“may be applied if more than one dose level is 
expanded” to “will be applied to the multiple dose 
levels.”
Rationale for change
Updated to reflect that more than one dose level 
was expanded in Phase Ib
Section to be changed
Synopsis, Miscellanous
Description of change
Total number of evaluable patients increased from 
approximately 120 to 140, updated throughout 
document
Rationale for change
Addition of 20 patients in PDAC cohort
Section to be changed
Flowcharts
Description of change
Addition of safety laboratory parameters and 
physical examination at EOR visit.  
Rationale for change
Revision implemented in accordance with French 
Health Authority (ANSM) regulatory 
recommendation. 
Section to be changed
Flowcharts
Description of change
Update of footnote to describe that 
echocardiography (or multigated acquisition scan) 
may be performed at any time during the study if 
clinically indicated. 


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Rationale for change
Revision implemented in accordance with Belgian 
Health Authority (FAMHP) regulatory 
recommendation.
Section to be changed
Flowchart: Phase Ia
Description of change
Removed the tickbox included at Cycle 2 Day 2 
for Fresh Tumor Biopsy, which is not applicable 
for phase Ia. 
Rationale for change
The tickbox was inadvertently included during 
formatting.
Section to be changed
Flowchart: Phase Ia
Description of change
Row for additional archival tumor tissue deleted 
for clarity, and footnote 12 updated.
Rationale for change
Archival tumor tissue is mandatory for Phase Ia.
Section to be changed
Flowchart: Phase Ib (Weekly Dosing)
Description of change
Added a tickbox for Adverse Events at Cycle 5 
Day 8. Added a tickbox for Concomitant Therapy 
at Cycle 5 Day 8. Updated formatting for the 
tickbox for Tumor Assessment by CT/MRI to 
apply for the full Treatment Period and Post-
treatment.
Rationale for change
The tickboxes were inadvertently not included 
when the Flowchart was formatted.
Section to be changed
Flowchart: Phase Ib (Weekly Dosing)
Description of change
Addition of screening visit 1 (SV1) and update 
footnote 12 for CDH17 status analysis by central 
vendor. Tissue must be sent to designated vendor 
for CDH17 positivity. Screening visit 2 (SV2) 
added and is for entry into main study after 
CDH17 positivity is confirmed. 
Addition of foonote 18 that this is only applicable 
for PDAC patients and that SV1 and SV2 can 
occur in parallel.
Rationale for change
CDH17 positive expression is part of inclusion 
criteria for PDAC patients. 
Section to be changed
Flowcharts: Phase Ib (Biweekly dosing) and 
Phase Ib (Weekly dosing)
Description of change
Row added for tumor markers, and footnote 16 
updated. Collection of tumor markers was 
optional and changed to mandatory.
Rationale for change
Updated based on additional procedure for better 
clarification and understanding of efficacy.
Section to be changed
Flowchart: Phase Ib (Weekly Dosing)
Description of change
Added column for even cycles; Cycle 5 and 
beyond separated into odd and even cycles for 
clarity.


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Rationale for change
Clarify difference in requirements between odd 
and even cycles.
Section to be changed
Flowcharts: Phase Ib (Weekly dosing)
Description of change
Footnote β, “The interval between two dose 
administration must be always at least 8 days” 
updated to “7 days”. 
Rationale for change
Correction to typo 
Section to be changed
Abbreviations
Description of change
Addition of PDAC Pancreatic Ductal 
Adenocarcinoma
Rationale for change
Addition of PDAC cohort
Section to be changed
1.2
Description of change
Added the following text under non-clinical 
studies “Anticancer activity of BI 905711 in 
PDAC was tested in vivo using 11 patient-derived 
PDAC
xenograft models (PDX) characterized by target 
expression of TRAILR2 and CDH17 in the
range of 45 to 174 TPM (transcripts per million) 
and 26 to 604 TPM, respectively. Upon
treatment with BI 905711, 4/11 PDX models 
showed tumor growth inhibition [TGI] ranging
from 107 to 126% and 2/11 models showed 
moderate response (TGI 61% and 76%).
First in vivo experiments (two PDAC PDX 
models) to study synergistic anticancer effect of
BI 905711 in combination with chemotherapy 
(irinotecan) showed deepened response.”
Updated AE information and median duration of 
treatment under data from clinical studies.
Rationale for change
Information update
Section to be changed
1.3
Description of change
The last statement in the section updated to state 
“Safety, pharmacokinetic, and pharmacodynamic 
profiles, as well as preliminary antitumor activity 
assessments, acquired in this trial will provide the 
basis for further development of BI 905711.”
Rationale for change
The statement was inadvertently truncated during 
formatting.
Section to be changed


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Description of change
Rationale for change
Section to be changed
2.2.2, 5.1, 5.4, 5.4.2.6
Description of change
[18F]FDG-PET should be performed for CRC 
patients and phase Ib PDAC patients. Updated 
throughout document.
Rationale for change
Addition of PDAC cohort
Section to be changed
3.1.2
Description of change
Moved CRC cohort into separate subsection 
3.1.2.1 Randomized CRC expansion cohort
Added the following text to new subsection 
3.1.2.2 Single Arm PDAC expansion cohort 
“Approximately 20 evaluable patients with 
CDH17-positive PDAC will be enrolled into 
phase
Ib. Patients will be enrolled on one dose level in 
weekly regimen (3 weeks on, 1 week off) of
BI 905711.
CDH17 analysis must be performed by a 
designated vendor and results reviewed prior to
patient enrollment.”
Rationale for change
Addition of PDAC cohort
Section to be changed
3.3
Description of change
Updated total number of patients in phase Ib from 
60 to 80 patients.
Added the following text “All PDAC patients in 
phase Ib will be required to undergo central 
testing of tumour tissue for
CDH17 status at screening visit 1 (SV1) before 
proceeding to full screening assessments at
screening visit 2 (SV2). There are no 
inclusion/exclusion criteria at screening visit 1 
except
that the patient must have tissue available for 
analysis and must be expected, as far as is
possible to determine, to meet all inclusion and 
exclusion criteria at the time of screening visit
2.”
Rationale for change
Addition of PDAC cohort




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Description of change
First bullet point updated from “Determination of 
CDH17 protein expression by IHC” to 
“Determination of target protein expression by 
IHC, including but not limited to CDH17”
Rationale for change
Updated for clarity and addition of PDAC patients
Section to be changed
5.4.1.1
Description of change
The following text was moved to section for 
Phase Ia: 
∀
In phase Ia, an archived tumor tissue 
specimen must be submitted (mandatory).
The following text was deleted: 
In phase Ia, in case a fresh pre-treatment tumor 
biopsy cannot be obtained due to before 
mentioned reasons, an archived tumor tissue 
specimen must be submitted (mandatory). 
Rationale for change
Updated for clarity, archival tissue is mandatory 
for Phase Ia and fresh tumor biopsy is optional. 
Section to be changed
5.4.1.1
Description of change
The following text was added to first bullet point 
under Tumor tissue collection in Phase Ib “For 
PDAC patients, CDH17 expression measured in 
archival tumor tissue within < 6 months or a fresh 
biopsy sample must be completed as part of 
screening visit 1 for PDAC cohort. If archival 
tumor tissue is submitted for screening visit 1, 
then a fresh biopsy must be provided prior to
treatment start on Day 1.”
Rationale for change
Addition of PDAC cohort
Section to be changed
5.4.1.1
Description of change
“Optional” added to second bullet point under 
Tumor tissue collection in Phase for timepoints 
Cycle 2 Day 3 and disease progression.
Rationale for change
Updated for consistency and clarity
Section to be changed
5.4.1.1
Description of change
The following text was moved to section Phase Ib 
∀
“In case a fresh pre-treatment tumor 
biopsy cannot be obtained due to the 
below-mentioned reasons, an archived 
tumor tissue specimen obtained within ≤6 
months of screening must be submitted 
(mandatory)."
The following text was moved to section Phase Ib 
and updated from “For phase Ib, in case the 
patient undergoes baseline tumor biopsy, an 
archival tumor tissue must also be submitted 
(mandatory) regardless of the date of collection. 








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11.6
GLOBAL AMENDMENT 6
Date of amendment
17Apr2023
EudraCT number
EU number
2018-003268-29
BI Trial number
1412-0001 
BI Investigational Medicinal 
Product(s)
BI 905711
Title of protocol
A first-in-human phase Ia/b, open label, 
multicentre, dose   escalation study of BI 905711 
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 
cycles > 6 
Rationale for change
Recruitment in this trial was discontinued 
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 v7.0 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 v7.0
Section to be changed
3.1.1 
Description of change
Added text “Recruitment in Phase Ia is complete”
Rationale for change
Recruitment in Phase Ia is complete.


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Section to be changed
3.1.2
Description of change
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 Ib discontinued prematurely. 
Section to be changed
3.3.4.3
Description of change
Updated #2: 
“Emergence of any efficacy/safety information 
with or without invalidating the earlier positive 
benefit risk assessment that could significantly 
affect the continuation of the trial.”
Rationale for change
To describe discontinuation of trial without 
changes to benefit-risk ratio. 
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., 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
5.3.1, 7.3.5, 7.5, 10.1
Description of change
Updated text related to PK to align with standard 
Phase 1 protocol language
Rationale for change
To align with standard Phase 1 protocol language
Section to be changed
5.3.2, 5.4.1
Description of change
Effective from CTP v7.0, PK, ADA, Biomarker 
and Optional Tumor Biopsy samples are no longer 
collected for ongoing patients. 
Rationale for change
Blood and optional tissue samples no longer 
collected.
Section to be changed
Description of change
Rationale for change


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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
Description of change
Section 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
7.6
Description of change
Updated five to four cohorts, and 80 to 60 patients. 
Rationale for change
Typo
Section to be changed
10.2
Description of change
Sampling tables for PK and Biomarkers no longer 
applicable per CTP v7.0
Rationale for change
To be consistent with flowchart revision.
Section to be changed
10.2
Description of change
Sampling tables updated to clarify timepoint for 
PK sample collection in case of infusion related 
reactions and further infusion is performed.
Rationale for change
Clarification 
Section to be changed
10.2
Description of change
Visit no for Tables 10.2:1 updated from 9970 to 
9961
Rationale for change
Updated for consistency with BI standards


 
 
 
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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Boehringer Ingelheim 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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

SAP_001.pdf: 
 
TRIAL STATISTICAL ANALYSIS PLAN
c26343384-01
BI Trial No.:
1412-0001
Title:
A first in humans phase Ia/b, open label, multicentre, dose   
escalation study of BI 905711 in patients with advanced 
gastrointestinal cancers
Investigational
Product(s):
BI 905711
Responsible trial 
statistician(s):
Phone:
Date of statistical 
analysis plan:
07 DEC 2023 
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 30
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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TSAP for BI Trial No: 1412.1
c26343384-01
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Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS(S) ....................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
5.4.1 
Demographics and baseline history...................................................................11
5.4.2
Exposure parameters..........................................................................................11
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENT(S)................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATION......................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
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......................................................................................................17
7.5.1.1
Main analysis.......................................................................................................18
7.5.2
(Other) secondary objective analysis.................................................................19
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................22
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23


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7.8.5
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24
9.
ADDITIONAL SECTIONS ...............................................................................25
10.
HISTORY TABLE..............................................................................................30


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LIST OF TABLES
Table 6.1:1
Analyzing Treatments.......................................................................................13
Table 10: 1
History table .....................................................................................................30


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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
DLT
Clinical Trial Report
Dose Limiting Toxicities
DM&SM
Boehringer Ingelheim Data Management And Statistics Manual
DRA
Drug Regulatory Affairs
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
SOC
System Organ Class


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Term
Definition / description
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 analyses including 
immunogenicity assessment..
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 6. 
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 would include primary and 
secondary endpoint analyses. There would be limited analyses provided for PK and 
biomarkers as detailed in section 7.5 and section 7.6.


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5.
ENDPOINTS(S)
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 
5.2.6.1.5 of the CTP.
∀Number of patients with DLTs in the MTD evaluation period.
The primary endpoints in Phase Ib are:
∀Objective response based on RECIST 1.1 criteria. Objective response is defined as best 
overall response of complete response or partial response, where best overall response is the 
best response recorded from the start of the study treatment until the earliest of disease 
progression, death or last evaluable tumor assessment and before start of subsequent anti-
cancer therapy.
∀Progression-free survival (PFS) is defined as the time from first treatment administration 
until tumor progression according to RECIST 1.1 or death from any cause, whichever occurs 
earlier.
A detailed definition of objective response and PFS is given in  section 9.1.
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:
∀The following PK parameters of BI 905711 will be evaluated after the first and after
the third administrations of BI 905711:
- Cmax: maximum measured concentration of BI 905711 in plasma
- AUC0-t2: area under the concentration-time curve of BI 905711 in plasma
∀Objective response based on RECIST 1.1 criteria in patients with measurable disease.


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The secondary endpoints in Phase Ib:
∀The following PK parameters of BI 905711 will be evaluated after the first and after
the third administrations of BI 905711:
- Cmax: maximum measured concentration of BI 905711 in plasma
-AUC0-t2: area under the concentration-time curve of BI 905711 in plasma
∀Number of patients with treatment-emergent AEs
∀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 overall response is measured from the time measurement criteria are
first met for Complete Response (CR)/ Partial Response (PR) (whichever is first
recorded) until the first date that recurrent or progressive disease is objectively
documented (taking as reference for progressive disease the smallest measurements
recorded on study) according to RECIST 1.1.
∀Disease control, defined as CR, PR, or stable disease according to RECIST 1.1 from
the start of treatment until the earliest of progression disease, death or last evaluable
tumor assessment and before start of subsequent anti-cancer therapy.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
This is an open-label, non-randomized, phase I dose escalation and dose expansion study. In 
phase 1b four CRC cohorts are randomized and a single arm PDAC cohort. For the main 
analysis the phase 1a and phase 1b data will be pooled together.
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.
Table 6.1:1
Analyzing Treatments
Analyzing Treatment Period
Start Date (including)
Stop Date (excluding)
Screening
Data of informed consent
Date of the first 
administration of BI 905711
On-treatment
Date of the first 
administration of BI 905711
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


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MTD evaluation period
Date of the first 
administration of BI 905711
Date of the second 
administration of study BI 
905711 + 35 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 DEVIATION
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 
lock for the primary analysis of the primary endpoint PFS (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. 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 3.3.4.4. The list of replaced patients will be provided by the Trial 


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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.
All analyses on immunogenicity will be based on Treated set (TS).
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 (see “Handling of 
missing and incomplete AE dates”) (3).
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.
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 study treatment. Note that for some study procedures (e.g. body weight, 
vital signs, laboratory tests), baseline may be the measurement made on the same day the 
study treatment was started. In such cases, these measurements will be assumed to have been 
taken according to the protocol, i.e. prior 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.
7.4.1
Main Analysis
The primary analyses for Phase Ia:


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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 7.1 of the CTP will be analyzed using the number of patients at each dose that had 
DLTs during the MTD evaluation period among the patients in the MTD set. The prior 
defined in Table 7.1: 1 of the CTP will be used for the analysis. The resulting posterior 
distribution of the DLT rates of the doses tested during the trial will be summarized using 
their mean, SD, 2.5% quantile, median, and 97.5% quantile. Additionally, the posterior 
probabilities of the DLT rate lying in the intervals [0, 0.16) (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.
The primary analyses for Phase Ib:
The primary endpoints in the dose-expansion part are objective response (OR) and PFS 
derived from the data of all cycles. The PFS will be summarized using PFS4 rate, defined as 
the proportion of patients with PFS >= 4 months, and will be presented descriptively together 
with 95% confidence intervals. 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.
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.
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1.1
Main analysis
There is no key secondary analysis as no key secondary endpoint has been specified in the 
protocol.


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7.5.2
(Other) 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 7.3.5 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
Phase Ia:
The Objective response will be analyzed the same way as the primary endpoint in Phase Ib.
Phase Ib:
The Number of patients with treatment emergent AEs, 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.
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 would include primary and 
secondary endpoint analyses. There would be limited analyses provided from statistics and 
programming for PK and this would only include listing of consistency checking PK data. 
The PK group (TMCP) would provide analyses for Cmax and AUC. 
Additional PK analysis
The analysis of standard PK parameters is performed according to BI internal standards (2).
Attainment of steady state
The attainment of steady state will be inspected graphically. The attainment of steady state 
will be explored using the trough plasma concentrations before the Nth administration of BI 
905711 in each cycle. Pair-wise comparisons of the differences between time points will be 
explored by using a repeated measures linear model on the logarithmic scale of trough plasma 
concentration including ‘subject’ as a fixed effect, and 'time' as a repeated effect in the model. 
This analysis will be done for the dose groups at 0.2 mg/kg,  0.6 mg/kg, 1.2 mg/kg, 2.4 
mg/kg, 3.6 mg/kg and 4.8 mg/kg where each dose group is analysed separately. The structure 
of the within-subject covariance matrix generally is not known in advance and will be chosen 
to be "unstructured", in case of convergence problems Huynh-Feldt, Toeplitz or 
Autoregressive (AR1) will be chosen (based on Akaike's information criterion).
On the logarithmic scale, the linear model equation for the investigation of steady state is:


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Yij = μ + #i + ∃ij
where
Yij
logarithm of the trough plasma concentrations of BI 905711 for subject j at time i, 
where i = 1, 2, 3, 4 indexing time point and j=1, 2, …, n indexing subject
%
the overall mean
#i
the effect associated with time i (discrete repeated effect) )
∃ij
random error associated with subject j at time i (assumed to be independent and 
identically normally distributed).
This analysis will be accomplished by fitting the repeated measures model (MIXED 
procedure). For the approximation of the degrees of freedom the Kenward and Roger  method 
will be used. The Akaike information criterion (AIC) will be used to select the best fitting 
covariance structure. 
Subsequently, adjusted least square means and two sided 95% confidence intervals will be 
calculated and back transformed by exponentiation. Furthermore pairwise comparisons of the 
log-transformed differences between all subsequent time points (log(trough concentration at 
time i/trough concentration at time k) = log(trough concentration at time i) - log(trough 
concentration at time k) where k>i) will be performed including the calculation of two sided 
95% confidence intervals using residual error from ANOVA.
Dose proportionality analysis
Dose proportionality will be explored using the power model that describes the functional 
relationship between the dose and pharmacokinetic endpoints as follows.
exp(Yij) = α’ * exp(Xi)β * ε’ij
Putting α’ = exp(α)  and ε’ij = exp(εij)  , after taking natural logarithms this model is converted 
to a linear form as follows.
Yij = α + β* Xi + εij
Yij = logarithm of the pharmacokinetic endpoint (i.e. Cmax, AUC0-tz, AUC0-∞for Cycle 1 and, 
if applicable, Cmax and AUC0-tz for Cycle 2) for subject j at dose level i, where i = 1, 2, … 
indexing dose level and j = 1, 2, … indexing subject
α = intercept parameter
β = slope parameter
Xi = logarithm of dose level i
εij = residual error associated with subject j at dose level i (assumed to be independent and 
identically normally distributed).


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This equation can be fit as a linear regression model. A 95% confidence interval for the slope 
will be computed. In the ideal sense, dose proportionality would correspond to a value of 1 for 
the slope parameter β in the power model. Dose proportionality would be assumed when the 
95% CI for β includes 1. 
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 would not include any 
analysis in this section of steady state or dose proportionality etc.
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.


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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.
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


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∀
Transitions of the CTCAE grade from baseline to the worst lab values, from baseline to 
the last lab values, and from the worst to last values during the on-treatment period
∀
Possible clinically significant laboratory values
∀
Transitions for laboratory values without CTCAE grade based on reference ranges
Note: For calculating the change in CTCAE grade from baseline, patients with a CTCAE 
grade of -9 (no CTCAE grade defined) or CTCAE grade of -5 (overlapping reference ranges ) 
will be treated as a CTCAE grade 0 for all analyses. In laboratory listings, the CTCAE grade 
is displayed as -9 and -5, respectively.
For Uric Acid, Hypokalemia, amylase, bicarbonate, eosinophils, glucose (high direction), INR 
of prothrombin time, lipase, methemoglobin, sodium (low direction) the CTCAE grade cannot 
always be assigned by the laboratory parameter itself as two different CTCAE grades have the 
same laboratory constellation, but are distinguished by additional clinical parameter. In this 
case a CTCAE grade of -1 will be assigned. These will not be considered for laboratory 
analyses. In laboratory listings, the CTCAE grade is displayed as -1, respectively.
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 7.4 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 1b there will be a continuous monitoring of the efficacy in terms of PFS4 and 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; 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
6.
001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current version; 
IDEA for CON.


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9.
ADDITIONAL SECTIONS


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections changed
Brief description of change
Initial
09-SEP-22
None
This is the initial TSAP with 
necessary information for trial conduct
Version 1
03-NOV-22
2, 
4, 
5.3, 5.4.1, 5.4.2, 5.4.3, 
6.1-4, 6.6, 
7, 7.3, 7.5.2, 7.5.3,
7.6, 7.8.1, 7.8.5,
9.1
TSAP updated according to comments 
and feedback during review period.
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, 5.3, 5.4, 5.4.2, 7.4.1, 
7.5.2 , 7.8.1 and 7.8.2.
TSAP updated according to final 
comments.