Conditions: Neoplasms
Allocation: NA | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
This open-label dose escalation phase I trial, 1280.15, is with the first administration of BI 836845 in Japanese patients with various types of advanced solid tumours. The rationale behind this study is to identify the maximum tolerated dose (MTD) of BI 836845 in Japanese patients with advanced solid tumours as weekly intravenous administration.

Detailed description:

Arms:
arm 1: 750 milligram Xentuzumab given weekly (days 1, 8, and 15) as an intravenous infusion over 1 hour. Patients stayed on treatment in 21-day cycles until disease progression or undue toxicities. arm 2: 1000 milligram Xentuzumab given weekly (days 1, 8, and 15) as an intravenous infusion over 1 hour. Patients stayed on treatment in 21-day cycles until disease progression or undue toxicities. arm 3: 1400 milligram Xentuzumab given weekly (days 1, 8, and 15) as an intravenous infusion over 1 hour. Patients stayed on treatment in 21-day cycles until disease progression or undue toxicities.

Interventions: intervention 1: 750 milligram Xentuzumab intervention 2: 1000 milligram Xentuzumab intervention 3: 1400 milligram Xentuzumab
Intervention descriptions: intervention 1: 750 milligram Xentuzumab given weekly (days 1, 8, and 15) as an intravenous infusion over 1 hour. Patients stayed on treatment in 21-day cycles until disease progression or undue toxicities. intervention 2: 1000 milligram Xentuzumab given weekly (days 1, 8, and 15) as an intravenous infusion over 1 hour. Patients stayed on treatment in 21-day cycles until disease progression or undue toxicities. intervention 3: 1400 milligram Xentuzumab given weekly (days 1, 8, and 15) as an intravenous infusion over 1 hour. Patients stayed on treatment in 21-day cycles until disease progression or undue toxicities.

Protocol document:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
Clinical Trial Protocol 
 
Doc. No.: c01692098-04
BI Trial No.:
1280.15
BI Investigational
Product:
Xentuzumab (BI 836845) 
Title:
An open-label phase I dose escalation trial of weekly intravenous 
administrations of BI 836845 in Japanese patients with advanced solid 
tumours
Clinical Phase:
I
Clinical Trial 
Leader: 
Tel: 
  
Fax: 
Investigator:
Tel: 
  
Fax: 
Status: 
Final Protocol (Revised Protocol (based on global amendment 2)) 
Version and Date:
Version: 
3.0           
Date: 29 Apr 2022
Page 1 of 74
Proprietary confidential information.
¤ 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not – in full or in part – be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
Trial number:
Revision date:
29 Apr 2022
28 Feb 2014
1280.15
Title of trial:
An open-label phase I dose escalation trial of weekly intravenous administrations of 
BI 836845 in Japanese patients with advanced solid tumours
investigator:
Trial site:
Clinical phase:
I
Objectives:
x Identification of the maximum tolerated dose (MTD) of BI 836845 in Japanese 
patients with advanced solid tumours
x Evaluation of safety, pharmacokinetics, pharmacodynamics, and anti-tumour
activity
Methodology:
Open-label and dose escalation, followed by expansion cohort and rollover
No. of patients: 
total entered:
Maximum 24 (to identify the MTD and to conduct an expansion cohort if needed)
each treatment:
x Three (3) to 6 patients in 750 and 1000 mg dose cohort
x Six (6) patients in 1400 mg dose cohort
x Additional 6 patients as an expansion cohort if needed
Diagnosis:
Patients with advanced solid tumours
Main criteria
for inclusion:
Patients with cytologically or histologically confirmed solid tumours that are 
refractory to standard therapy, for whom no standard therapy of proven efficacy 
exists, or who are not amenable to establish treatment options
Test product:
BI 836845
dose:
750, 1000, and 1400 mg
mode of admin.:
Weekly intravenous administrations over 1 hour
Duration of treatment:
x One treatment cycle consists of 21 days without discontinuation of study treatment.
x The study treatment may be continued until patients meet any of the criteria for 
discontinuation.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
Trial number:
Revision date:
29 Apr 2022
28 Feb 2014
1280.15
Criteria for efficacy:
The following assessments will be performed according to Response Evaluation 
Criteria in Solid Tumours (RECIST) version 1.1 as other efficacy assessments
x Objective response: number of patients whose best response is either complete 
response (CR) or partial response (PR)
x Disease control: number of patients whose best response is either CR, PR, or stable 
disease (SD)
x Duration of disease control: time from first disease control (CR, PR, or SD) to the 
time to progression or death
Criteria for 
pharmacokinetics:
Pharmacokinetic profile of BI 836845
Criteria for safety:
The following adverse events will mainly be evaluated according to Common 
Terminology Criteria for Adverse Events version 4.03
The primary endpoint:
x MTD of BI 836845 in Japanese patients with advanced solid tumours (as identified
by the number of patients with dose-limiting toxicities [DLTs])
Other safety assessments: 
x All adverse events
x Laboratory tests
x Eastern Cooperative Oncology Group (ECOG) performance status
x Vital signs
x Twelve (12)-lead electrocardiogram (ECG)
Statistical methods:
Descriptive statistics






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  7. 
Tumour assessment images taken within 28 days before start of Cycle 1 may be used as baseline scans where 
appropriate without the need to repeat scans during screening period. 
  8. 
The blood will be collected by the discretion of investigator at pre-infusion or post-infusion. 
  9. 
On Day 1 of Cycle 1, 12-lead electrocardiogram (ECG) is performed at pre-infusion, during infusion 
(30 ± 5 minutes after start of infusion), and immediately before end of infusion.  ECG will be performed before 
infusion on Day 15 of Cycle 1 and Cycle 2 onwards during study treatment.
10. 
Echocardiography (ECHO) or multiple-gated acquisition scan (MUGA) must be assessed at screening.  Further 
scans may be performed after start of study treatment if clinically indicated by the discretion of investigator. 
11. 
The blood is collected at pre-infusion on Visit 1 of Cycle 1 for evaluating insulin-like growth factor binding 
protein (IGFBP)-3 promoter polymorphism evaluation (mandatory) and optional biobanking. At least 15 slides of 
tissue section prepared from the archived sample are required for analysing imprinting/methylation status of 
insulin-like growth factor (IGF)-2 (optional). 
12. 
Blood sampling for pharmacokinetics and/or biomarker will be performed at the time points specified in 
Tables 10.1: 1, 10.1: 2 and 10.1: 3. 
13. 
All laboratory parameters specified in Section 5.2.4 should be performed.  The results from the previous laboratory 
test may be used on Visit 1 of each cycle if the examination was performed within 2 days before the visit.  On 
another visits, the examinations will be performed before infusion. In case of adverse events related to laboratory 
abnormalities, adequate and more frequent evaluation will be performed at the discretion of the investigator.
14. 
All parameters specified in Section 5.2.7 should be performed using fasting plasma and serum samples. 
15. 
Fasting plasma and serum samples may be collected within 7 days before Visit 1 of Cycle 1 and Visit 1 of Cycle 2. 
16. 
Physical examination and vital signs at FU1 visit are optional.
17. 
Not applicable for patients who continue the study treatment into the rollover part regarding biomarker analyses
18. 
Fasting plasma and serum samples are collected where possible.
19. 
All adverse events (including deaths) occurring until 42 days after the last administration of BI 836845 will be
collected and followed up until they have recovered or have been sufficiently characterised, unless the investigator 
and the sponsor agree not to pursue them further.
20. 
All adverse events (including death) occurring later than 42 days after the last administration of BI 836845 until 
end of the trial will also be collected and followed up until they have recovered or have been sufficiently 
characterised, unless the investigator and the sponsor agree not to pursue them further.
21. 
Concomitant therapies during follow-up period are only collected for cases where indicated for the treatment of 
adverse events
22. 
Not applicable for patients who continue the study treatment into the rollover part




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TABLE OF CONTENTS
TITLE PAGE ..................................................................................................... 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ............................................... 2 
FLOW CHART.................................................................................................. 4 
FLOW CHART – ROLLOVER PART........................................................... 7 
TABLE OF CONTENTS .................................................................................. 8 
ABBREVIATIONS.......................................................................................... 12 
1. 
INTRODUCTION.................................................................................... 14 
1.1 
MEDICAL BACKGROUND ............................................................................14 
1.2 
DRUG PROFILE ...............................................................................................14 
1.3 
NON-CLINICAL INFORMATION .................................................................14 
1.3.1 Pharmacology ........................................................................................14 
1.3.2 Toxicology ..............................................................................................15 
1.4 
CLINICAL INFORMATION ...........................................................................16 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT–RISK 
ASSESSMENT ......................................................................................... 18 
2.1 
RATIONALE FOR PERFORMING THE TRIAL ........................................18 
2.2 
TRIAL OBJECTIVES .......................................................................................18 
2.3 
BENEFIT–RISK ASSESSMENT .....................................................................18 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 21 
3.1 
OVERALL TRIAL DESIGN AND PLAN ......................................................21 
3.1.1 Administrative structure of the trial ...................................................22 
3.2 
DISCUSSION OF TRIAL DESIGN .................................................................23 
3.3 
SELECTION OF TRIAL POPULATION ......................................................23 
3.3.1 Main diagnosis for study entry ............................................................23 
3.3.2 Inclusion criteria ...................................................................................23 
3.3.3 Exclusion criteria ..................................................................................24 
3.3.4 Removal of patients from therapy or assessments .............................25 
3.3.4.1 Criteria for discontinuation of study treatment in the trial for
individual patients .................................................................... 25 
3.3.4.2 Criteria for discontinuation of the trial for individual patients 26 
3.3.4.3 Discontinuation of the trial by the sponsor .............................. 26 
3.3.5 Replacement of patients .......................................................................27 
4. 
TREATMENTS........................................................................................ 28 
4.1 
TREATMENTS TO BE ADMINISTERED ....................................................28 
4.1.1 Identity of BI investigational product .................................................28 
4.1.2 Method of assigning patients to treatment groups .............................28 
4.1.3 Selection of doses in the trial ................................................................28 


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4.1.3.1 Initial dose and dose levels to be evaluated ............................. 28 
4.1.3.2 Dose-limiting toxicities ............................................................ 29 
4.1.3.3 Maximum tolerated dose.......................................................... 30 
4.1.3.4 Dose escalation, cohort expansion, and/or dose de-escalation 31 
4.1.3.5 Initiation of study treatment with BI 836845 for the next cycle 
(Cycle 2 onwards) .................................................................... 32 
4.1.3.6 Dose reduction ......................................................................... 32 
4.1.3.7 Dose interruption ..................................................................... 32 
4.1.3.8 Initiation of rollover part .......................................................... 33 
4.1.4 Drug assignment and administration of doses for each patient .......33 
4.1.5 Blinding and procedures for unblinding ............................................34 
4.1.5.1 Blinding.................................................................................... 34 
4.1.5.2 Procedures for emergency unblinding ..................................... 34 
4.1.6 Packaging, labelling, and re-supply ....................................................34 
4.1.7 Storage conditions .................................................................................34 
4.1.8 Drug accountability ..............................................................................34 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT ....................................................................................................35 
4.2.1 Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................35 
4.2.1.1  Management and grading of infusion reactions ...................... 36 
4.2.1.2 Management of hyperglycaemia .............................................. 37 
4.2.2 Restrictions ............................................................................................37 
4.2.2.1 Restrictions regarding concomitant treatment ......................... 37 
4.2.2.2 Restrictions on diet and life style ............................................. 37 
4.3 
TREATMENT COMPLIANCE .......................................................................37 
5. 
VARIABLES AND THEIR ASSESSMENT ......................................... 38 
5.1 
EFFICACY .........................................................................................................38 
5.1.1 Endpoints of efficacy.............................................................................38 
5.1.2 Assessment of efficacy...........................................................................38 
5.2 
SAFETY ..............................................................................................................39 
5.2.1 Endpoints of safety ................................................................................39 
5.2.2 Assessment of adverse events ...............................................................39 
5.2.2.1 Definitions of adverse events ................................................... 39 
5.2.2.2 Adverse event and serious adverse event reporting ................. 42 
5.2.3 Dose-limiting toxicity and maximum tolerated dose .........................43 
5.2.4 Assessment of safety laboratory parameters ......................................43 
5.2.5 Electrocardiogram ................................................................................44 
5.2.6 Left ventricular ejection fraction ........................................................44 
5.2.7 Endocrine Assessments .........................................................................45 
5.2.8 Assessment of vital signs and physical examination ..........................45 
5.2.9 Pregnancy testing ..................................................................................45 
5.3 
OTHER ...............................................................................................................46 




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7.4 
HANDLING OF MISSING DATA ..................................................................58 
7.4.1 Plasma concentration–time profiles ....................................................59 
7.4.2 Pharmacokinetic assessment ................................................................59 
7.5 
RANDOMISATION ..........................................................................................59 
7.6 
DETERMINATION OF SAMPLE SIZE ........................................................60 
8. 
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS ................................................................................................ 61 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................61 
8.2 
DATA QUALITY ASSURANCE .....................................................................62 
8.3 
RECORDS ..........................................................................................................62 
8.3.1 Source documents .................................................................................62 
8.3.2 Direct access to source data and documents .......................................62 
8.3.3 Storage of records .................................................................................63 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS ..............................................................................................................63 
8.4.1 Listedness ...............................................................................................63 
8.4.2 Expedited reporting to health authorities and IRBs .........................63 
8.5 
STATEMENT OF CONFIDENTIALITY .......................................................63 
8.6 
COMPLETION OF TRIAL ..............................................................................64 
8.7 
PROTOCOL VIOLATIONS ............................................................................64 
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY ......................................................................64 
9. 
REFERENCES......................................................................................... 65 
9.1 
PUBLISHED REFERENCES ...........................................................................65 
9.2 
UNPUBLISHED REFERENCES .....................................................................66 
10. APPENDICES .......................................................................................... 67 
10.1 SAMPLING TIME POINTS FOR PHARMACOKINETICS AND 
BIOMARKERS ..................................................................................................67 
10.2 COCKCROFT–GAULT FORMULA ..............................................................69 
10.3 CLINICAL EVALUATION OF LIVER INJURY .........................................70 
10.3.1 Introduction ...........................................................................................70 
10.3.2 Procedures .............................................................................................70 
11 DESCRIPTION OF GLOBAL AMENDMENT................................... 72 
11.1 GLOBAL AMENDMENT 1 .............................................................................72 
11.2 GLOBAL AMENDMENT 2 .............................................................................74 


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ABBREVIATIONS
ADA
anti-drug antibody
ADL
activities of daily living
AFP
alpha-fetoprotein
ALT (SGPT)
alanine aminotransferase
AST (SGOT)
aspartate aminotransferase
ȕ-hCG
beta-human chorionic gonadotropin
BLQ
below the lower limit of quantification
CA
cancer antigen
CEA
carcinoembryonic antigen
CK
creatine phosphokinase
CR
complete response
CRA
clinical research associate
CRO
contract research organisation
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Leader
CTP
clinical trial protocol
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECHO
echocardiography
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
ELISA
enzyme-linked immunosorbent assay
EOT
end of treatment
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FU1/FU2
the first follow-up/the second follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HbA1c
haemoglobin A1c
HED
human equivalent dose
HIV
human immunodeficiency virus
ICH–GCP 
International Conference on Harmonisation Harmonised Tripartite 
Guideline for Good Clinical Practice
Ig
immunoglobulin
IGF
insulin-like growth factor
IGF-1R/IGF-2R
insulin-like growth factor-1 receptor/insulin-like growth factor-2 receptor
IGFBP
insulin-like growth factor binding protein
INR
international normalised ratio
IR
insulin receptor
IRB
Institutional Review Board


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ISF
Investigator Site File
LHRH
luteinising hormone–releasing hormone
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTORC1
mammalian target of rapamycin complex 1
MUGA
multiple-gated acquisition scan
NC
not calculated
NCA
non-compartmental analysis
NOA
not analysed
NOP
no peak detectable
NOR
no valid result
NOS
no sample available
NSAIDs
nonsteroidal anti-inflammatory drugs
PAS
periodic acid–Schiff
PD
progressive disease
PK–PD
pharmacokinetic–pharmacodynamic
PR
partial response
PSA
prostate-specific antigen
q3w
on every 3 weeks
qw
weekly
RDC
remote data capture
RECIST
Response Evaluation Criteria in Solid Tumours
SAE
serious adverse event
SD
stable disease
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TKI
tyrosine kinase inhibitor
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
TSH
thyroid-stimulating hormone
ULN
upper limit of normal


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The insulin-like growth factor (IGF) signalling system consists of ligands (IGF-1 and IGF-2), 
IGF-binding proteins (IGFBPs), and receptors (IGF-1 receptor [IGF-1R], IGF-2 receptor
[IGF-2R] and insulin receptor [IR]). Evidence that targeting IGF may be useful in cancer
treatment was first recognised decades ago.  Research in IGF signalling has shown that it 
controls key cellular activities, including proliferation, growth, and survival and is often
deregulated in neoplasia (R07-4212 and R10-5760).
There is experimental and clinical evidence that cancer cells express insulin and IGF 
receptors.  Expression of IGF-1R or its ligand is increased in a variety of cancers, including 
lung, colon, prostate, breast, ovarian, liver cancer and sarcoma (R10-5759, R10-5756 and 
R10-5355).  Therefore, the IGF system is a tempting target for anti-cancer drug development, 
and pharmacologic targeting strategies include inhibition of receptor function with anti-
receptor antibodies or small molecule receptor tyrosine kinase inhibitors (TKIs; R10-5760, 
R10-5758, and R10-5757). 
Most cancers express IGF-1 receptors, but there is evidence that autocrine and/or paracrine
expression of ligands, particularly IGF-2, is deranged in neoplasm (R10-5355).  In addition, 
the IGF-2 gene is an imprinted gene; loss of imprinting is one of several mechanisms leading
to IGF-2 overexpression (R10-5694). For example, IGF-2 is the most overexpressed gene in
colorectal cancer (R10-5355).  Thus, targeting IGF-1 and IGF-2 may lead to a higher 
probability of response to a therapeutic strategy that may confer an advantage. 
1.2
DRUG PROFILE
BI 836845 (xentuzumab as the generic name) is a fully human IgG1 monoclonal antibody 
(mAb) that binds to and neutralises the function of human IGF-1 and IGF-2.  The BI 836845
molecule is composed of two heterodimers.  Each of the heterodimers is composed of a heavy 
polypeptide chain of ~50 kDa (447 amino acids) and a light polypeptide chain of ~23 kDa 
(216 amino acids), and the four polypeptide chains of the antibody molecule are linked 
together by disulfide bonds.  The heavy chains are glycosylated, and there are two binding 
sites for IGF-1 and IGF-2 per antibody molecule.  The antibody has a molecular mass of 
approximately 146 kDa.
1.3
NON-CLINICAL INFORMATION
1.3.1 
Pharmacology 
BI 836845 binds with high affinity to IGF-1 and IGF-2, and potently neutralises the 
proliferative and prosurvival cellular signalling triggered by both proteins.  Mode of action 
differentiation to IGF-1R-targeted mAbs was demonstrated, in particular through inhibition 


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of IGF-2-stimulated IR-A activation, an additional proliferative and prosurvival pathway not 
inhibited by IGF-1R-targeted mAbs.  The growth of multiple cancer cell lines derived from 
different cancer types are inhibited by BI 836845. The combination potential of BI 836845 
has been demonstrated using non-clinical models of Ewing’s sarcoma.  The viability of the 
RD-ES cell line was more effectively inhibited by the combination of BI 836845 and 
rapamycin than either agent alone. Studies also indicated that the mechanism for the 
improved efficacy of the combination is through BI 836845 inhibiting the increased IGF 
ligand signalling activity that is triggered when mammalian target of rapamycin complex 1
(mTORC1) is inhibited.
BI 836845 has a potent inhibitory effect on the IGF-1R phosphorylation potential (IGF
bioactivity) of human plasma ex vivo. Due to its cross-reactivity to rat and Cynomolgus
monkey IGF-1 and IGF-2, the pharmacodynamic effect of BI 836845 on IGF bioactivity in 
both these species was demonstrated using samples from 13-week toxicity studies.  In both 
species, BI 836845 showed a clear and potent reduction in plasma IGF bioactivity for all 
doses tested (3.2–32 mg/kg human equivalent dose [HED]). 
1.3.2 
Toxicology 
Safety Pharmacology (core battery) endpoints integrated in the 13-week toxicity study in 
Cynomolgus monkey (100% sequence homology of human IGF-1 and IGF-2) indicated no 
adverse cardiovascular, respiratory, or neurological effects of BI 836845.
Repeated intravenous administration in Cynomolgus monkey for 13 weeks and in rats (the 
second relevant species based on comparable binding affinity against IGF-1 and IGF-2) for 
up to 26 weeks led to a variety of dose-related and essentially reversible effects. The 
treatment-related changes included the body as a whole (growth retardation) in both species 
and liver functions, the haematolymphatic system, kidneys, bone, teeth, and ovaries in rats 
only. 
Most if not all observed effects were attributable to the pharmacodynamic potential of 
BI 836845, i.e. reflecting the neutralisation of specific growth factors in these species during
a phase of rapid body growth.  Consequently, signs of general growth retardation, e.g. 
reduced body weight gain and body size were apparent in both species examined.  The effects 
on the haematolymphatic system and liver function seen in the rat studies were considered to 
be below toxicological significance.
Glomerulopathy (periodic acid–Schiff [PAS]-positive granules in podocytes and dilated 
Bowman’s spaces) was observed in individual rats (7–8 weeks old at the commencement of 
treatment) at all dose levels of the 13-week study, but not in those of the 26-week study (10–
11 weeks old).  This rat glomerulopathy is therefore considered an age-dependent change.  As 
there were indications that IGF has a stronger effect on younger animals due to their steep 
growth curve until about Week 10, slightly older animals were used in the 26-week toxicity 
study.  Also, the older animals did not show findings in bone and teeth.  On the other hand, a 
higher incidence and severity of interstitial structures called ‘persistent granulosa cell nests 


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within remnants of atretic follicles’ were observed in the ovaries of rats at dosages of 20 and 
200 mg/kg which was reversible after a 12-week recovery period.  However, a number of 
follicles showed normal maturation, and the incidences of the different stages of the 
menstrual cycle were not affected.
The only effects noted in rats and Cynomolgus monkeys exposed similarly to rats were a 
dose-dependent reduction of body growth and alkaline phosphatase activity.  Otherwise,
young adult monkeys did not show any of the effects observed in rats although fully 
pharmacologically active doses were achieved in both species at all dose levels in terms of
the reduced plasma IGF-1R phosphorylation activity (IGF bioactivity). 
Furthermore, glucose levels, fructosamines, and haemoglobin A1c (HbA1c) were increased 
weakly in rats and in male Cynomolgus monkeys given 30 and 100 mg/kg (equivalent to 10 
to 32 mg/kg HED).
1.4
CLINICAL INFORMATION
Boehringer Ingelheim is conducting the following two phase I trials with BI 836845 in 
patients with advanced solid tumours: 
x
Trial 1280.1: Investigating a weekly (qw) schedule in Taiwan
x
Trial 1280.2: Investigating once every 3 weeks (q3w) schedule in the United Kingdom 
At the cut-off date of July 10, 2013, a total of 81 patients were treated in two BI 836845 
phase I dose-escalation trials.
A relevant biological dose for BI 836845 monotherapy in solid tumors was determined at 
1000 mg qw, used as the recommended dose for further Phase II trials.
No relevant hyperglycaemia has been observed so far.  BI 836845 was well tolerated, with no 
relevant non-specific side effects reported. The type and pattern of adverse events observed 
to date have generally been consistent with the underlying neoplastic conditions of patients 
enrolled on the study.  The most common adverse events have been those pertaining to 
“General disorders”, “Gastrointestinal disorders”, “Respiratory, thoracic and mediastinal 
disorders” as well as “Investigations”. The reported drug-related adverse events were mostly 
ranked Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or 2 until 
1800 mg (qw schedule) and 3600 mg (q3w schedule) without any dose dependency.  CTCAE 
grade 3 pulmonary haemorrhage was the only drug-related severe adverse event reported in 
1280.1 trial.  The adverse event declared a dose-limiting toxicity (DLT) and was considered 
drug-related by the investigator due to the timely relationship, as it occurred within 36 hours 
after first administration of the study drug at a dose of 450 mg weekly.  As per the clinical 
trial protocol (CTP), 3 additional patients were therefore dosed at 450 mg (for a total of 
6 patients), with no further DLTs observed at this or subsequent dose levels. Furthermore, a 
CT revealed a metastasis adjacent to the bronchus in which the haemorrhage had occurred.  


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No DLT was reported in 1280.2 trial.  Given the safety profile of BI 836845 reported in 
1280.1 and 1280.2 trials, sufficient tolerability with BI 836845 for patients is assured until 
1800 mg (qw schedule) and 3600 mg (q3w schedule).
Maximum plasma concentrations of BI 836845 were observed at the end of infusion or 
shortly thereafter. After reaching the peak, plasma concentrations showed an at least biphasic 
decay with a terminal half-life in the order of 6 days.  The estimated volume of distribution 
was about 5.8 L (approximately twice the plasma volume) and the total plasma clearance was 
about 30 mL/h.  No deviations from dose-proportional pharmacokinetics have been observed 
in the dose range tested (10–1050 mg given qw schedule and 10–3600 mg given q3w 
schedule in 1280.1 and 1280.2 trials, respectively).  Repeated qw dosing resulted in about 
1.5-fold accumulation of BI 836845 plasma concentration at steady state, while only limited 
accumulation was observed after repeated q3w infusions.  
A dose is considered biologically relevant when concentrations of free IGF-1 and free IGF-2 
are considerably reduced over time.  Free IGF-1 and free IGF-2 plasma concentrations are 
not measured in 1280.1 and 1280.2 trials. Therefore, a semimechanistic pharmacokinetic–
pharmacodynamic (PK–PD) model was developed based on pharmacokinetics of BI 836845,
measured pharmacodynamic biomarkers (i.e. plasma concentrations of total IGF-1, total 
IGF-2, and IGFBP-3), and literature applying a physiologically-based approach.  This PK–
PD model describes the pharmacokinetics of BI 836845 and interaction between BI 836845 
and the different pharmacodynamic biomarkers, and allows the prediction of plasma 
concentrations of free IGF-1 and free IGF-2 over time. Simulations indicate that a qw dosing 
of 1000 mg reduces the population mean free IGF-1 concentration by more than 90% and in 
addition population mean free IGF-2 by 64% at trough steady-state relative to pre-treatment. 
This is considered as a relevant biological effect and a suitable dose to be taken forward.
Promising early efficacy signals have been observed with two confirmed partial responses
(PRs) according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria in a 
patient with nasopharyngeal cancer (800 mg dose cohort given qw schedule) and a patient 
with a peripheral primitive neuroectodermal tumor/Ewing sarcoma (1050 mg dose cohort 
given qw schedule).  Moreover, 12 out of 48 patients (1280.1 trial) and 4 out of 33 patients 
(1280.2 trial) confirmed stable diseases (SDs) have been observed in heavily pretreated 
patients suffering from advanced or metastatic solid tumours.
More detailed and updated information is provided in the latest version of Investigator’s 
Brochure (c01690707).


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2. 
RATIONALE, OBJECTIVES, AND BENEFIT–RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
As shown in Section 1.4, sufficient tolerability with BI 836845 for Caucasian and Asian 
patients with advanced solid tumours is assured until 1800 mg (qw schedule) and 3600 mg 
(q3w schedule).  However, insight into tolerability with BI 836845 for Japanese patients with 
advanced solid tumours is not obtained yet.
This open-label dose escalation phase I trial, 1280.15, is the first administration of BI 836845
in Japanese patients with various types of advanced solid tumours.  The rationale behind this 
study is to identify the maximum tolerated dose (MTD) of BI 836845 in Japanese patients 
with advanced solid tumours as weekly intravenous administration. Once the MTD will be 
identified, phase III trials will be planned to be conducted after tolerability with BI 836845 
and combination drugs will be assured through the safety run-in cohort. 
2.2
TRIAL OBJECTIVES
The objective of the trial is to identify the MTD of BI 836845 in Japanese patients with 
advanced solid tumours.  
In case no MTD can be identified up to the highest dose tested in this trial, a relevant 
biological dose may be recommended based on all available data (safety, pharmacokinetics, 
pharmacodynamics, and efficacy).
Safety, pharmacokinetics, pharmacodynamics, and anti-tumour activity of BI 836845 will 
also be evaluated.
2.3
BENEFIT–RISK ASSESSMENT
Despite substantial improvements in cancer therapy, there is still a need for novel therapeutic
agents.
Early evaluations of ongoing clinical trials of anti-IGF/IGF-1R agents as a single agent, as
well as pharmacodynamic studies of BI 836845 on neoplastic cell lines, indicate the 
possibility of disease stabilisation, or tumour responses in a subset of patients with advanced
and otherwise incurable cancers. In addition, targeting IGF-2, which is aberrantly 
overexpressed in certain cancers, with a ligand neutralising antibody such as BI 836845, may 
translate into an advantage over compounds further along in clinical development and which 
target the IGF-1R.
The non-clinical safety profile of BI 836845 in growing rats primarily has revealed that liver, 
peripheral blood/bone marrow, lymphoid organs, growing teeth, bone, kidneys, and the 


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ovaries are main target organs. There was full reversibility of effects except for alterations in
kidney and teeth in the 13-week toxicity study.  However, in the 26-week toxicity study, the 
findings in kidney and teeth were absent.  The effects observed are mostly to be attributed to
the direct pharmacological activity of BI 836845 and reflect the neutralisation of specific 
growth factors.
Experience to date with several anti-IGF-1 receptor antibodies or TKIs revealed that 
treatment may result in hyperglycaemia, which was rarely severe enough to cause cessation 
of treatment and often responded to metformin therapy. These findings were very rarely
observed with BI 836845 monotherapy in phase I. Other observed adverse effects with anti-
IGF-1R antibodies or TKIs included lethargy, anorexia, leukopenia, thrombocytopenia, 
elevated aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, 
diarrhoea, and hyperuricaemia.  In general, the observed adverse effects in single agent trials
were moderate and not dose-limiting. Preliminary safety and efficacy data from 81 patients 
at the end of the dose escalation part of the first-in-human studies 1280.1 (qw schedule) and 
1280.2 (q3w schedule) are available. A preliminary safety profile has been established and, 
overall, the safety data of BI 836845 in these trials is considered favourable. 
The potential risks associated with BI 836845 are unknown in Japanese patients and 
unexpected or infrequent adverse events may occur in the clinical trial.  The proposed trial 
will evaluate stepwise dose escalation of BI 836845, and the investigator should carefully be 
monitored the patients’ safety during trial participation.
Although BI 836845 is a fully human antibody given intravenously, there may be potential 
for infusion reactions (e.g. infusion-related reactions, injection site reactions, immune system 
disorders) to occur.  Such infusion reactions will be graded thoroughly and appropriate 
preventative and/or corrective actions implemented following the standard of care for such 
adverse events.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators.  Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients’
safety.
Together with the encouraging preliminary signs of anti-tumour activity observed (see 
Section 1.4 for details), this 1280.15 trial had warranted, until the negative efficacy results for 
BI 836845 in the placebo-controlled randomised Phase II 1280-0022 trial, continuation of 
clinical investigation of BI 836845 in patients with solid tumours.  The 1280-0022 Phase II
placebo-controlled, randomised trial recently completed primary endpoint analysis and 
showed no added benefit of BI 836845 compared to placebo, in patients with everolimus and 
exemestane backbone therapy, when treating trial participants with metastatic breast cancer, 
HR+, HER2– and non-visceral disease.  No new safety signals were observed with the 
addition of BI 836845 to the everolimus and exemestane combination. 
In consideration of these topline results of 1280-0022, as of 19 October, 2021, Boehringer 
Ingelheim recommended to immediately discontinue all BI 836845 treatments.  As a 
consequence of the worsening in benefit-risk for BI 836845, Boehringer Ingelheim also 


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decided to terminate all oncology drug development for BI 836845 including the cessation of
further manufacturing of investigational medicinal product BI 836845. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial is an open-label dose escalation phase I trial of BI 836845 in Japanese patients with 
various types of advanced solid tumours to identify the MTD, safety, pharmacokinetics,
pharmacodynamics, and preliminary anti-tumour activity of BI 836845. Patients will be 
administered BI 836845 weekly and continued the study treatment every 21 days without 
discontinuation of study treatment. 
Patients will be enrolled into the study at the time of obtaining written informed consent and 
will subsequently be assessed for the eligibility within a maximum 28 days screening period.
Study treatment will be started after the investigator confirms the eligibility for the study 
treatment from Cycle 1 and will be continued until patients meet any of criteria for 
discontinuation, e.g. progressive disease (PD), undue toxicity, consent withdrawal (see 
Sections 3.3.4.1 and 3.3.4.2 for definition). One treatment cycle consists of 21 days.  End of 
treatment (EOT) visit will be conducted within 5 days after patient discontinuation of study 
treatment. If patient discontinuation of study treatment falls on a scheduled visit, EOT visit 
should be conducted instead of assessments at the scheduled visit. Follow-up period will stop 
when once a patient has disease progression, is dead, is lost to follow-up, or has treatment 
with another anti-cancer drug, whichever occurs first, or patients have been willing to 
discontinue the trial. All adverse events will be collected and followed up according to 
Section 5.2.2.2.
At the time of all patients in the trial having sufficient data to answer the primary endpoint 
(see Section 5.2.1), patients continuing on study treatment will have the EOT assessments 
(except for blood collection for biomarker analyses) performed and then continue on study 
treatment into the rollover part with reduced clinical data collection. Clinical assessments 
and laboratory tests are not mandatory and appropriately performed as per the standard of 
care at the study sites or at the discretion of investigator, and only clinical relevant 
abnormalities are reported as adverse events according to Section 5.2.2.2.   Results for the 
assessments and tests should be recorded in the source data only, additional documentation in 
the electronic case report form (eCRF) is not required.
A full clinical trial report will be written based upon the data before rollover part.  At the end 
of the clinical trial, the data collected in the rollover part will be locked and the data may be 
summarised in an addendum of clinical trial report.
The trial will be supervised by the principal investigator specialised in the treatment of 
advanced solid tumours and experienced in phase I oncology trials.  The trial site will have 
available all equipment necessary for dealing with any serious side effects and potential 
emergencies.


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3.1.1
Administrative structure of the trial
The trial is sponsored by
will appoint a Clinical Trial Leader (CTL).  CTL is
responsible for coordinating theactivities required in order to manage the trial in accordance 
with applicable regulations andinternal standard operating procedures (SOPs), directing the 
clinical trial team in the preparation, conduct, and reporting ofthe trial, order the materials as 
needed for the trial, ensures appropriate training andinformation of clinical research 
associates (CRAs) and investigators.
Data management and statistical evaluation will be performed by
or a contract research organisation (CRO) appointed by 
 according to Boehringer Ingelheim SOPs.  For these 
activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to Boehringer Ingelheim SOPs.  A list of responsible persons and relevant 
local information (as protocol reference if applicable) are in the Investigator Site File (ISF) 
and the Trial Master File (TMF) document.
On-site monitoring will be performed by
or a CRO 
appointed by
Electrocardiograms (ECGs) will be recorded by digital ECG machines and centrally 
evaluated by ERT, Inc. ECG machines at study sites can be used during the rollover part 
without data transfer and evaluation by the central ECG laboratory.
A principal investigator will be nominated to coordinate investigators at study site 
participating in this trial. Documents on participating (principal) investigators and other 
important participants, especially their curricula vitae, will be filed in the TMF.
The ISF document will be kept in print-out version at the sites as far as required by local 
regulation and Boehringer Ingelheim SOP.  A copy of the ISF documents will be kept as an 
electronic TMF document according to Boehringer Ingelheim SOPs. 
An external expert who is independent of the study sites (investigators) and the sponsor, with 
expertise in oncology clinical trials, will be assigned.  The reviews by the assigned external 
expert ensure the adequacy of DLT evaluation and/or dose escalation which discussed and 
agreed between the study site (investigators) and the sponsor as an independent third party.  
In addition, an external expert can make recommendations to the sponsor regarding study 
continuation, amendment, or discontinuation as necessary when it is brought important safety 
information about the trial and/or investigational drug.
Details on handling of the trial supplies including responsible institutions are given in 
Sections 4.1.6, 4.1.7, and 4.1.8 of this CTP.


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3.2
DISCUSSION OF TRIAL DESIGN
This trial follows a traditional 3 + 3 design with dose de-escalation in oncology phase I trials.  
Dose escalation, cohort expansion, or dose de-escalation will be decided after discussion and 
agreement with the principal investigator.  Rationales for the initial dose and dose cohorts are 
described in Section 4.1.3.1.
3.3
SELECTION OF TRIAL POPULATION
Only patients with advanced solid tumours and maximum 18 patients evaluable for the 
primary endpoint will be entered. Number of evaluable patients to be entered in each dose 
cohort is described in Section 4.1.3.1.  Additional 6 patients may also be entered as an 
expansion cohort to be recommended a relevant biological dose. 
The trial will be conducted at 1 trial site 
). 
A log of all patients enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the trial site irrespective of whether they have been treated with 
BI 836845 or not. 
3.3.1
Main diagnosis for study entry
Patients with cytologically or histologically confirmed solid tumours that are refractory to 
standard therapy, for whom no standard therapy of proven efficacy exists, or who are not 
amenable to establish treatment options.
3.3.2
Inclusion criteria
Patients who meet all of the following inclusion criteria by the judgment of investigator are
eligible to receive the study treatment: 
  1. Patients with cytologically or histologically confirmed solid tumours that are refractory 
to standard therapy, for whom no standard therapy of proven efficacy exists, or who are 
not amenable to establish treatment options
  2.
$JH20 years old 
  3. Eastern Cooperative Oncology Group (ECOG) performance status (R01-0787) 0, 1, or 2 
  4. Written informed consent that is consistent with Good Clinical Practice (GCP) 
guidelines 


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3.3.3
Exclusion criteria
Patients for whom any of the following exclusion criteria apply by the judgment of 
investigator are not eligible to receive the study treatment: 
  1. Active infectious disease to be incompatible with the study treatment according to the 
CTP
  2. Patients who do not have sufficient major organ function and meet any of the following 
test results at screening period 
x
Cardiac left ventrLFXODUIXQFWLRQZLWKUHVWLQJHMHFWLRQIUDFWLRQDVGHWHUPLQHGE\
echocardiography (ECHO) or multiple-gated acquisition scan (MUGA) 
x Absolute neutrophil count <ȝL 
x Platelets <100 ȝL 
x Total bilirubin >1.5 × the upper limit of normal (ULN)
x AST (SGOT) and/or ALT (SGPT) >2.5 × ULN (in case of known liver metastases,
AST and/or ALT >5 × ULN) 
x Creatinine >1.5 × ULN
x Haemoglobin <9 g/dL 
x HbA1c DQGIDVWLQJJOXFRVH>8.9 mmol/L (>160 mg/dL)
  3. Serious illness or concomitant non-oncological disease including severe, acute, or 
chronic medical or psychiatric condition, or laboratory abnormality that may 
compromise the safety of the patient during the study, affect the patient’s ability to 
complete the study, or interfere with interpretation of study results considered by the 
investigator to be incompatible with the study treatment according to the CTP
  4. History of thrombosis (except tumour invading great vessels) within 1 year before start 
of study treatment or if concurrent anticoagulation required
  5. Patients not recovered from any therapy-related toxicities from previous 
chemotherapies, hormonal therapies, immunotherapies, molecular-targeted therapies, or 
radiotherapies to CTCAE grade 
  6. Patients who have not recovered from any previous surgery and major surgery within 
the last 4 weeks before start of study treatment
  7. Patients with untreated or symptomatic brain metastases. Patients with treated 
asymptomatic brain metastases may be eligible if there has been no change in brain 
disease status for at least 4 weeks before start of study treatment, no history of cerebral 
oedema or bleeding in the past 4 weeks before start of study treatment, and must be on a 
stable or reducing dose of dexamethasone.  Anti-epileptic therapy will be allowed 
during the study treatment if the patient is stable on antiepileptic treatment for 4 weeks 
or more without adjustments before start of study treatment.
  8. Patients who have been treated with any of the following within 4 weeks before start of 
study treatment: chemotherapies, immunotherapies, radiotherapies (within 2 weeks 
before start of study treatment for local palliative radiotherapies for the treatment of 
brain metastasis or extremities), biological therapies, molecular-targeted therapies,
hormonal therapies for breast cancer within 2 weeks before start of study treatment
(excluding luteinising hormone-releasing hormone [LHRH] agonists in prostate cancer 
or bisphosphonates), or treatment with other investigational drugs. Patients who have 


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completed the treatment with mitomycin C or nitrosoureas within 6 weeks before start 
of study treatment.
  9. Patients who have used any investigational drug within 4 weeks before start of study 
treatment or who have planned concomitantly use with the trial.
10.
Patients unable to comply with the CTP or unable to communicate or cooperate with the 
investigator 
11. Active alcohol abuse or active drug abuse 
12. Patients with unstable arrhythmias, unstable angina or severe obstructive pulmonary 
disease within the past 1 year.
13. Previous and concurrent other cancer (except for non-invasive and/or non-melanoma 
skin cancer, carcinoma in situ of the epithelium or mucosa, or mucosal gastric or 
colorectal cancer which has been curatively treated by endoscopic mucosal resection or 
endoscopic submucosal dissection).  Other tumours treated curatively and with no 
evidence of recurrence for at least 5 years before enrolment into the trial is eligible.
14.
Patients with uncontrolled diabetes mellitus
15.
Female patients who are pregnant or who do not agree the interruption of breast feeding 
from start of study treatment within 4 months after the last study treatment. Female 
patients of child-bearing potential who have a positive serum pregnancy test within 
7 days of enrolment in the trial.  Females of child-bearing potential (premenopausal 
females) are defined as the females who observed menses within 12 months except for 
an alternative medical cause.  Female patients who underwent an operation for 
sterilisation are excluded for this criterion.
16.
Female patients of child-bearing potential or male patients who do not agree to use 
adequate contraception from start of study treatment within 4 months after the last study 
treatment.  Combined oral contraceptives (approved in Japan), some intrauterine devices 
(approved in Japan), vasectomy since more than 2 months for male patients or for 
partners of female patients, etc. are accepted as contraception, and barrier methods of 
contraception are also accepted in so far as condom (approved in Japan) is used.
17. Known positive serology for human immunodeficiency virus (HIV).  HIV testing is not 
mandatory. 
18.
History of relevant allergy or hypersensitivity to ingredients of BI 836845 
19.
Other patients judged ineligible for enrolment in the trial by the investigator 
3.3.4
Removal of patients from therapy or assessments
Discontinuation of study treatment or discontinuation of the trial will be documented in the 
eCRF and the reason for discontinuation recorded and discussed in the clinical trial report if 
needed. 
3.3.4.1
Criteria for discontinuation of study treatment in the trial for individual patients 
Patients should discontinue the study treatment and initiate EOT and subsequent visits if any 
one of the following criteria is met: 


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x
Patients who withdraw consent to further study treatment
x
Patients who are no longer able to continue the study treatment (e.g. undue toxicity, 
pregnancy, surgery, concomitant diagnoses, concomitant therapies, administrative 
reasons) after discussion and agreement with the investigator and the sponsor 
x
Patients who developed PD by the discretion of investigator 
x
Patients who interrupt the study treatment more than 4 weeks as counted from the next 
planned treatment administration. If an interruption of more than 4 weeks is necessary 
and clinically justified, the patient may continue the study treatment after discussion and 
agreement between the investigator and the sponsor if there is documented clinical benefit 
(e.g., SD, disease control).
x
Patients who require more than 2 dose reductions or dose reduction less than 500 mg 
throughout the study treatment
The EOT visit should be performed within 5 days after discontinuation of study treatment
except for the rollover part.  In case an adverse event is still ongoing at the time of 
discontinuation, every effort should be made to follow-up for the adverse event according to 
Section 5.2.2.2.
3.3.4.2
Criteria for discontinuation of the trial for individual patients 
Patients should discontinue the trial if any one of the following criteria is met: 
x
Patients who withdraw consent to participation in the trial
x
Significant non-compliance with the protocol requirements.  Such patients may be 
discontinued the trial after discussion and agreement between the investigator and the 
sponsor. 
3.3.4.3 Discontinuation of the trial by the sponsor 
reserves the right to discontinue the trial overall, or at 
a trial site, at any time for the following reasons:
x
Failure to meet expected entry goals overall or at a trial site
x
Emergence of any efficacy and/or safety information that could significantly affect 
continuation of trial: As described in Section 2.3 “BENEFIT–RISK ASSESSMENT”,
Boehringer Ingelheim decided to terminate all oncology drug development for BI 836845 
in consideration of.topline results of 1280-0022. 
x
Violation of GCP, the CTP, or the contract by the trial site or the investigator, disturbing 
the appropriate conduct of the trial. 


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The trial site will be reimbursed for reasonable expenses incurred in case of trial termination, 
except for cases relevant to the third bullet point above.
3.3.5
Replacement of patients
Patients will be replaced for the analysis of primary endpoint in cases of:
x
Discontinuation during Cycle 1 for reasons other than DLT (e.g. withdrawal of informed 
consent because patients no longer wish to continue the study treatment or to participate
in the trial)
x
Patients who do not experience DLT but miss more than 1 visit during Cycle 1.  
x
Patients who are not evaluable with respect to DLT
Replacement of patients will be determined on a case by case basis and will only occur after 
discussion and agreement between the investigator and the sponsor. 


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product
Substance:
BI 836845 (fully human mAb)
Pharmaceutical form:
Liquid formulation
Source:
Boehringer Ingelheim Pharma GmbH & Co. 
KG
Route of administration:
Intravenous
Posology:
Infusion for over 1 hour. On Day 1 of Cycle 1,
the duration of infusion may be extended to 
over 1 hour and up to a maximum of 3 hours in 
FDVHVRI&7&$(JUDGHLQIXVLRQUHDFWLRQV.
Refer to the ISF for details of the preparation and handling regimen of BI 836845 including 
information on equipment, infusion procedure and process. 
4.1.2
Method of assigning patients to treatment groups
A unique patient identification number will be assigned by the sponsor after the patient has 
signed the informed consent form. The number will represent the patient number that should 
be recorded on all eCRFs and correspondence regarding the patient. Once assigned, numbers 
for any screening failures, non-treated, non-evaluable, or discontinued patients will not be re-
used. 
Only in the case in which the investigator will confirm that patients have met all inclusion
criteria and do not apply any exclusion criteria, the investigator will be able to register the 
patients (see Section 6.2.2 for details). The sponsor will assign the dose cohort for the 
registered patients. 
4.1.3
Selection of doses in the trial
4.1.3.1
Initial dose and dose levels to be evaluated
Dose cohorts of BI 836845 to be evaluated are indicated in Table 4.1.3.1: 1. Actual number 
of evaluable patients to be entered will depend on the incidence of DLTs.  To identify the 
MTD, 6 patients must enter the dose cohort. Dose escalation will proceed as outlined in 
Section 4.1.3.4 until the MTD or 1400 mg dose cohort has been reached.  Additional 
6 patients may also be entered as an expansion cohort to be recommended a relevant 
biological dose. 




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Non-haematological toxicities:
x
CTCAE grade 3 or 4 non-haematologic toxicity (except incompletely treated nausea, 
untreated vomiting, untreated diarrhoea, skin toxicity, fatigue, infusion reaction, 
electrolyte, hyperglycaemia, AST, or ALT). The following drug-related non-
haematological toxicities should be defined as DLTs:
o
CTCAE grade 2 infusion reaction despite adequate pre-medication
o
CTCAE grade QDXVHDDQGRUYRPLWLQJpersisting for 7 or more days despite 
antiemetic treatment
o
CTCAE grade VNLQWR[LFLW\GHVSLWHDGHTXDWHVXSSRUWLYHFDUHPHDVXUHVIRUXSWR
14 days if it does not reach an improvement to grade 
o
CTCAE grade K\SHUJO\FDHPLDUHVLVWDQWWRWUHDWPHQWZLWKDQti-diabetic agents
o
Any electrolyte CTCAE grade 3 adverse event which is refractory to optimal 
correction therapy
o
No recovery from a non-DLT CTCAE grade 3 toxicity to grade ZLWKLQ days 
of administered dose 
o
Sustained CTCAE grade 3 fatigue or asthenia for longer than 96 hours associated 
with deterioration of ECOG performance status
It is understood that also other drug-related adverse events (CTCAE grade 2) may carry the 
potential to be significant enough to necessitate treatment interruption or discontinuation, and 
as such qualify as DLT.  Such adverse events will be required the confirmation after thorough 
discussion between the investigator and the sponsor on a case-by-case basis.
All adverse events which are determined as DLTs occurring during Cycle 2 or later (DLT-
equivalent adverse events) will also be considered during evaluation of the overall safety in 
the trial.
All DLTs and DLT-equivalent adverse events have to immediately be reported to the 
sponsor.  DLTs and DLT-equivalent adverse events must be determined after discussion and 
agreement with the investigator and the sponsor.  The sponsor may ask for the opinion of the 
assigned external expert if needed.
4.1.3.3
Maximum tolerated dose
The MTD of BI 836845 is the highest dose tested with DLT occurring in not over 1 out of 
6 evaluable patients. 
In case the MTD will not be reached until 1400 mg, it will be deemed as a sufficient 
tolerability in Japanese patients with advanced solid tumours at 1400 mg. 






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case patients develop a DLT or a DLT-equivalent adverse event, see Section 4.1.3.6 for 
details.
During drug interruption, the scheduled BI 836845 administration will be missed and will not 
be retrospectively administered.  All the other scheduled assessments shall be performed as 
described in the Flow Chart. Patients should discontinue the study treatment when the 
duration of dose interruption exceeds 4 weeks as counted from the next planned treatment 
administration according to Section 3.3.4.1.
4.1.3.8
Initiation of rollover part
At the time of all patients in the trial having sufficient data to answer the primary endpoint 
(see Section 5.2.1), patients continuing on study treatment will have the EOT assessments 
(except for blood collection for biomarker analyses) performed and then continue on study 
treatment into the rollover part with reduced clinical data collection. 
The investigator should make efforts to keep administration of BI 836845 at intervals of 
7 days.  However, weekly administration schedule can temporarily be accelerated, delayed or 
skipped due to administrative reasons at the discretion of the investigator.
4.1.4
Drug assignment and administration of doses for each patient
A method of drug assignment for patients is described in Section 4.1.2.
BI 836845 will be administered intravenously over 1 hour with repeated administration 
weekly until patients meet any of criteria for discontinuation (see Section 3.3.4 for definition)
as per the Flow Chart.  Infusion duration on Day 1 of Cycle 1 may be extended to over 1 hour 
and up to a maximum of 3 hours in cases of CTCAE grade LQIXVLRQUHDFWLRQV (see 
Section 4.2.1.1 for grading and management of infusion reactions).  An infusion duration of 
less than 1 hour must be avoided because mannitol is used in the formulation of 
BI 836845.
Patients will be treated at the assigned dose during the study treatment unless patients are 
required the dose reduction (see Section 4.1.3.6 for definition).  Intra-patient dose escalation 
will not be allowed.
In case of a delay of infusion, the reason and the exact time of deviation must be recorded in 
the eCRF because the accuracy of this information is crucial for the proper evaluation and 
appraisal of pharmacokinetics and other data.  In case of a drug interruption, the reason must 
be recorded in the eCRF. Administration status is not recorded in the eCRF during the 
rollover part.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1 Blinding 
Not applicable because it is an open-label trial
4.1.5.2 Procedures for emergency unblinding 
Not applicable because it is an open-label trial
4.1.6 
Packaging, labelling, and re-supply
BI 836845 drug supplies will be provided from
For details of packaging and the description of the label as well as the process for resupply of 
investigational drug, see the ISF.
4.1.7 
Storage conditions 
BI 836845 will be stored in the original packaging at the temperature stated on the drug label. 
4.1.8
Drug accountability
Drug supplies which will be provided by the sponsor must be kept in a secure and limited 
access storage area in the hospital pharmacy.  Where necessary, a temperature log must be 
maintained to make certain that the drug supplies are stored at the correct temperature 
according to the ISF.
The investigational drug storage manager will receive the investigational drugs delivered by 
the sponsor when the following requirements are fulfilled: 
x
Approval of the CTP by the Institutional Review Board (IRB) 
x
Availability of a signed and dated clinical trial contract between the sponsor and the Head 
of Trial Centre
x
Approval/notification of the regulatory authority, e.g. competent authority 
x
Availability of the curriculum vitae of the principal investigator
x
Availability of a signed and dated CTP or immediately imminent signing of the CTP


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The investigational drug storage manager must maintain records of the product’s delivery to 
the trial site, the inventory at the trial site, the use by each patient, and the return of unused 
products.  
These records will include dates, quantities, batch/serial numbers, expiry (‘use-by’) dates, 
and medication numbers.  The investigational drug storage manager will maintain records 
that document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor.  
At the time of return of unused products, the investigational drug storage manager must 
verify that all unused drug supplies have been returned. 
Upon completion of the trial, the investigational storage manager submits to the sponsor a 
copy of the investigational drug dispensing and return log.  When submitting the copy, the 
investigational drug storage manager should exercise caution to preserve the anonymity of 
patients’ names.  
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Rescue medication to reverse the effects of BI 836845 is not available.  Potential side effects 
of BI 836845 should be treated symptomatically. 
Symptomatic treatments of tumour-associated symptoms are allowed.  Concomitant 
medications and/or concomitant therapies to provide adequate supportive care may be given 
as clinically necessary. Patients should receive full supportive care including transfusions of 
blood and blood products, antibiotics, analgesia etc., according to local practice or guidelines 
where appropriate.  Anti-emetic medication should be prescribed according to local practice.
Precaution should be taken to avoid extravasation.  Patients should be asked to report any 
pain or burning at the site of injection immediately. If extravasation is suspected, the 
infusion should be stopped immediately.  Treatment should be initiated according to local 
practice.
All concomitant and concomitant therapies should be recorded in the eCRF except during  the 
rollover part.  Trade name and indication of concomitant therapies will be documented.  If
patients receive parenteral nutrition during the trial, the components need not be specified in 
detail and should just be indicated as “parenteral nutrition” and the form be completed.  If a 
patient requires anaesthesia, it will be sufficient to indicate “anaesthesia” without specifying 
the details.
If surgery is considered necessary for the patient, whenever possible, at least 7 days should 
elapse after the last dose of BI 836845 before surgery is performed. Treatment can be 
resumed from 12 days after surgery. 




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4.2.1.2
Management of hyperglycaemia
In case of hyperglycaemia treatment should follow standard and local guidelines and may 
include oral antidiabetics such as metformin.  The appropriate expert advice should be 
considered in the management of hyperglycaemia. When treatment with the investigational
drug is discontinued, the need for further antidiabetic treatment has to be evaluated depending 
on the blood glucose levels of the patient. 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The use of concomitant drugs for prophylactic purpose is prohibited to prevent the expression 
of drug-related adverse events.  Additional experimental anti-cancer treatment and/or 
standard chemotherapy, immunotherapy, hormone treatment, with the exception of megestrol 
acetate and LHRH analogues, is not allowed during the trial. 
For symptom control palliative radiotherapy may be permitted after discussion and agreement
with the investigator and the sponsor on a case-by-case basis (e.g. for bone metastases).  The 
impact of any palliative radiotherapy on tumour assessments must be documented. 
Any concomitant medication should be reduced to the clinically necessary minimum on the 
days of BI 836845 infusion. 
4.2.2.2
Restrictions on diet and life style
No restrictions on diet and lifestyle apply to the trial. 
4.3
TREATMENT COMPLIANCE
BI 836845 will be administered by infusion over 1 hour in accordance with the CTP under 
supervision of the investigator or delegated study personnel.




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5.2
SAFETY
5.2.1
Endpoints of safety
The primary endpoint: 
x
MTD of BI 836845 in Japanese patients with advanced solid tumours (as identified by the 
number of patients with DLTs) 
Other safety assessments:
x
All adverse events
x
Laboratory tests
x
ECOG performance status
x
Vital signs
x
Twelve (12)-lead electrocardiogram (ECG)
5.2.2
Assessment of adverse events
5.2.2.1 Definitions of adverse events 
Adverse event 
An adverse event is defined as any untoward medical occurrence, including an exacerbation 
of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product.  The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any adverse event which results in death, is 
immediately life-threatening, results in persistent or significant disability/incapacity, requires 
or prolongs patient hospitalisation, is a congenital anomaly/birth defect, or is to be deemed 
serious for any other reason if it is an important medical event when based upon 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. 
An adverse event which possibly leads to disability will be handled as “deemed serious for 
any other reason” and reported as an SAE.
Patients may be hospitalised during selected phases of the trial for administrative reasons.  
These hospitalisations for administrative reasons and other hospitalisations as described 
below need not be reported as SAEs.  The events not considered to be SAEs are 


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hospitalisations for the: routine treatment or monitoring of the underlying disease, not 
associated with any deterioration in condition; treatment, which was elective or already 
planned at the screening visit, for a pre-existing condition that is unrelated to the indication 
under study and did not worsen; admission to a hospital or other institution for general care, 
not associated with any deterioration in condition; treatment on an emergency, outpatient 
basis for an event not fulfilling any of the definitions of serious given above and not resulting 
in hospital admission or; admission to hospice for respite care. 
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to CTCAE 
version 4.03in the eCRF. 
When no CTCAE grading is available for a specific adverse event, the intensity of the AE 
should be judged based on the following: 
x
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
x
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
x
Grade 3: Severe or medically significant but not immediately life-threatening;
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self 
care ADL
x
Grade 4: Life-threatening consequences; urgent intervention indicated
x
Grade 5: Death related to adverse event
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, and 
confounding factors such as concomitant medication, concomitant diseases, and relevant 
history.  Assessment of causal relationship should be recorded in the eCRFs. The reason for 
the decision on causal relationship needs to be provided in the eCRFs.
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the adverse event. 
No: 
There is no reasonable causal relationship between the investigational product 
administered and the adverse event. 
Worsening of underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
adverse event or a SAE in the eCRF.


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Changes in vital signs, electrocardiogram, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an adverse event or SAE in the eCRF if they are judged clinically relevant by the 
investigator.
Adverse events of special interests
DLTs and DLT-equivalent adverse events (see Section 4.1.3.2 for definition), and DILI are 
defined as “adverse events of special interests”. Adverse events of special interests are to be 
reported in an expedited manner similar to SAE even if they do not meet any of the 
seriousness criteria (see Section 5.2.2.2 for details).
If a DLT or a DLT-equivalent adverse event is observed, or the investigator determines any 
DILI is related to the study treatment, the administration of the investigational drug and/or 
application of concomitant therapy must be managed according to Sections 4.1.3.5, 4.1.3.6,
and 4.2.
The DILI is defined as followings: 
x
For patients with normal liver function (ALT, AST, and bilirubin within normal limits) at 
baseline: 
AQHOHYDWLRQRI$67DQGRU$/7 × ULN combined with an elevation of bilirubin 
 × ULN measured in the same blood draw sample
x
For patients with impaired function tests (AST and/or ALT >ULN) at baseline: 
AQHOHYDWLRQRIWUDQVDPLQDVH (baseline + 4 × ULN) combined with an elevation of total 
ELOLUXELQ × ULN measured in the same blood draw sample
Patients showing these laboratory abnormalities need to be followed up according to 
Appendix 10.3.2 of this CTP and the “DILI checklist” provided in the ISF. Patients with 
abnormal liver function tests must have their abnormalities and the etiology documented in 
detail as baseline conditions.  Every effort should be made to explain possible deteriorations 
of baseline conditions. 
Other significant adverse events 
Other significant adverse events are defined any adverse event caused by discontinuation of 
study treatment and/or dose reduction. 


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5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during any cycle of the trial (i.e. from 
signing the informed consent onwards through the follow-up period) will be collected, 
documented, and reported to the sponsor by the investigator on the appropriate eCRFs and/or 
SAE reporting forms.  Reporting will be done according to the specific definitions and 
instructions detailed in the ‘Adverse Event Reporting’ section of the ISF. 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all adverse events as 
defined in Section 5.2.2.1.
The investigator also has the responsibility to report all adverse events (including deaths) 
occurring within obtaining written informed consent and 42 days after the last administration 
of BI 836845 will be collected.  Any adverse events or SAEs reported to the sponsor during 
this phase must be documented in the safety database.
Except for the rollover part, all adverse events (including death) occurring later than 42 days 
after the last administration of BI 836845 until end of the trial will also be collected.  Any 
adverse events or SAEs reported to the sponsor during this phase must be documented in the 
safety database.
Except for the rollover part, all adverse events, including those persisting after end of study 
treatment must be followed up until recovery to CTCAE grade or baseline condition or, in 
case of persistence, sufficient characterisation of the toxic effects has been achieved and the 
investigator and the sponsor agree not to pursue them further. 
If not stipulated differently in the ISF, the investigator must report the following adverse 
events immediately (within 24 hours or the next business day whichever is shorter) to the 
sponsor: 
  1. If using paper process SAE form via telephone/fax or 
  2. If available for the trial, using the remote data capture (RDC) or electronic data capture 
(EDC)
SAEs as well as non-serious adverse events occurring at the same time as an SAE and/or 
which are medically related to the SAE(s) and adverse events of special interests must be 
reported as SAEs.  With receipt of any further information to these events, a follow-up SAE 
report has to be provided.  SAEs and non-serious adverse events must include a causal 
relationship assessment made by the investigator. This information must be also reported 
immediately to the head of the trial site.
Boehringer Ingelheim has set up a list of adverse events which are defined to be always 
serious.  In order to support the investigator with the identification of these “always serious
adverse events”, if a non-serious adverse event is identified to be serious per definition by 
Boehringer Ingelheim, a query will be raised.  The investigator must verify the description 


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and seriousness of the adverse event.  If the event description is correct, the item “serious” 
needs to be ticked and an SAE has to be reported in expedited fashion following the same 
procedure as above.  The list of these adverse events can be found via the RDC/EDC
environment. 
With receipt of any further information to these adverse events, a follow-up SAE report has 
to be provided.  SAEs and non-serious adverse events must include a causal relationship 
assessment made by the investigator. This information must also be reported immediately to 
the head of the trial site.
The SAE form is to be forwarded to the defined unique entry point identified for the Drug 
Safety Department of
(contact details will be 
provided in the ISF).  This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship.  
It also applies if new information to existing SAEs or protocol-specified adverse events of 
special interests becomes available. 
Pregnancy 
In rare cases, pregnancy might occur in clinical trials. Once a female patient has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor.  As well as once a 
male patient has been enrolled into the clinical trial, after having taken study medication, the 
investigator must report immediately any drug exposure during pregnancy for the male 
patient’s partner to the sponsor.  Drug exposure during pregnancy has to be reported 
immediately (within 24 hours or next business day whichever is shorter) to the defined 
unique entry point for SAE forms of the Drug Safety Department of
(contact details will be provided in the ISF).  The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up.  In the 
absence of an adverse events or SAE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed.  The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Dose-limiting toxicity and maximum tolerated dose
See Sections 4.1.3.2 and 4.1.3.3 for definitions of DLTs and the MTD, respectively.
5.2.4
Assessment of safety laboratory parameters
Laboratory tests specified in Table 5.2.4: 1 will be assessed at the visits indicated in the 
Flow Chart.  The results from the previous laboratory test may be used on Visit 1 of each 
cycle if the examination was performed within 2 days before the visit.  At another visits, the 




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5.2.7
Endocrine Assessments
Fasting plasma and serum samples (where possible at EOT visit) should be collected from 
patients for determination of the following as per the time points specified in the Flow Chart: 
x
Glucose 
x
Insulin
x
Thyroid-stimulating hormone (TSH)
x
Human growth hormone 
x
HbA1c
x
C-peptide  
Fasting plasma and serum samples may be collected within 7 days before Visit 1 of Cycle 1 
and Visit 1 of Cycle 2.
Further samples may be taken throughout the trial where required and deemed appropriate by 
the investigator. All analyses are to be performed by the local clinical laboratory.
5.2.8
Assessment of vital signs and physical examination
Vital signs (blood pressure, pulse, respiratory rate after 2 minutes supine rest, and 
temperature) will be recorded at the screening visit and at the time points specified in the 
Flow Chart.  On administration day of every cycle except for the rollover part, vital signs are 
performed at pre-infusion, during infusion (30 ± 5 minutes after start of infusion), and 
immediately before end of infusion.  Further vital signs to be taken at any time if clinically 
indicated and/or after discontinuation of administration.
A physical examination will be performed at screening and at the time points specified in the 
Flow Chart.  The physical examination should include a thorough cardiopulmonary 
examination, an examination of the regional lymph nodes, an examination of the abdomen 
and an assessment of the mental and neurological status. Additional symptoms which have 
not been reported during a previous examination should be clarified.  A physician or a 
clinical research coordinator should perform this examination. Measurement of height (in 
cm) and body weight (in kg) and the evaluation of the ECOG performance status will be 
performed at the time points specified in the Flow Chart.
5.2.9
Pregnancy testing
Beta-human chorionic gonadotropin (ȕ-hCG) testing in serum will be performed as outlined 
in the Flow Chart at screening (within 7 days before start of study treatment), Visit 1 of every 
odd cycle, and at the EOT visit except for the rollover part.  Methods and duration of 
contraception indicated in the latest subject information should be applied.  Should a woman 


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become pregnant or suspect she is pregnant while participating in the trial, she should inform 
her treating physician immediately.
5.3
OTHER
5.3.1
Demographic and cancer history
Demographics (e.g. sex, birth date, race) and baseline conditions will be collected during the 
screening visit.
Cancer history will also be obtained as many as possible. 
x
The type of cancer including the histological subtype and molecular markers if applicable 
or available (e.g., EGFR mutation status, KRAS/BRAF mutation status)
x
The primary tumour site 
x
The month and year of first histological diagnosis 
x
The differentiation grade (not specified, undifferentiated, poorly-differentiated, 
moderately-differentiated, and well-differentiated).
x
The TNM stage of the tumour obtained at screening visit of the trial including the number 
and location of metastatic sites
x
Previous surgeries 
x
Number and type of previously administered chemotherapies, immunotherapies, 
hormonal therapies, molecular-targeted therapies, and biological therapies including 
specification of the treatment protocol and name of treatment
x
The best response (CR, PR, SD, PD, or unknown) 
5.3.2
Medical history and concomitant therapies
Relevant symptoms due to underlying disease, pre-existing diseases, and/or the treatments 
present at screening will be recorded in patients’ eCRFs. 
Any changes of concomitant therapies from baseline to treat such symptoms will be recorded 
in patients’ eCRFs except for the rollover part. 


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5.3.4 
Pharmacogenomic evaluation 
To allow for pharmacogenomic analyses, 2 blood samples will be asked.
The first blood sample of 2 mL will be collected in an EDTA tube from all patients on Day 1
of Cycle 1 and will be stored at –20ºC or below at Boehringer Ingelheim.  It will be used for 
DNA extraction and subsequent genotyping of polymorphisms in the IGF pathway, including 
e.g. IGF-binding proteins, like IGFBP-3. In addition, analysis of the DNA sample may be 
performed in an effort to identify genetic factors predisposing to adverse events.  With regard 
to the sample, the patient’s blood sample and the extracted DNA can be disposed in response 
to the patient’s request after the patient withdraws informed consent for pharmacogenomics.
The second blood sample (8.5 mL blood in PAXgene tubes, DNA banking sample) will be 
stored at –20ºC or below at Boehringer Ingelheim for 15 years after the end of the clinical 
trial or until there is no more material available for tests. The stored DNA may be analysed 
at a later time to identify whether there are other genetic factors that could contribute to a 
better therapeutic outcome or a higher risk of developing drug-related adverse events. The 
second sample will be taken and stored after separate written informed consent is given.  
Storage as well as retrieval and analysis of banked samples take place in a strictly controlled 
environment.  With regard to the sample, the patient’s blood sample and the extracted DNA 
can be disposed in response to the patient’s request after the patient withdraws informed 
consent for pharmacogenomics until 3 months after archive of clinical trial report in the trial.  
After the samples are anonymised at the instant of 3 months after archive of clinical trial 
report, the samples cannot be disposed unless consent withdrawal.  The first and second 
blood sample will be disposed after the clinical trial report is archived and after reaching the 
maximum allowed storage duration, respectively. 


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Both blood samples will be disposed as clinical waste no way to trace back to the identity of 
the donor. 
Collection of the first sample is a mandatory part of the CTP, whereas the collection of the 
second sample is voluntary. 
If possible, tissue slides cut from archival formalin-fixed paraffin-embedded (FFPE) tumour 
tissue will be obtained from initial diagnostic surgery.  If tissue is available from more than 
1 occasion, the latest obtained tissue should be used wherever possible.  Participation in this 
pharmacogenomic investigation for archived tissue sample is voluntary and not a prerequisite 
for participation in the study. The tissue sample will be stored for 15 years after the end of 
the clinical trial or until there is no more material available for tests at 4–25ºC at CRO which 
is delegated the pharmacogenomics tests of the sample.  The tissue will be analysed for 
mRNA expression of IGF pathway related genes, e.g. tumour IGF-1 and IGF-2.  For these 
analyses, tumour tissue slide sets from FFPE tumour samples must contain a minimum of 
15 slides (RNase-free preparation).  Further mutations/deletions in genes relevant for 
response or resistance, e.g. in genes belonging to the PI3K family and in PTEN, and 
imprinting/methylation status of IGF-2 will be explored.  In an effort to fully understand 
mechanisms of drug effect, mutation and gene expression analyses may be extended to other 
important oncogenes or tumour-related genes.  With regard to the sample, the patient’s tissue 
sample can be disposed in response to the patient’s request after the patient withdraws 
informed consent for pharmacogenomics.  The tissue sample will be disposed after the 
clinical trial report is archived as clinical waste no way to trace back to the identity of the 
donor. 
The results of pharmacogenomics tests will not be disclosed to patients because they are 
exploratory analysis which is not validated for diagnostic use.  This analysis may be 
performed at a later point in time, and the results may be reported in a separate report.
5.4
APPROPRIATENESS OF MEASUREMENTS
The RECIST version 1.1 (R09-0262) to be used for evaluation of tumour response are well-
established and scientifically accepted. The CTCAE version 4.03 (R10-4848) are commonly 
used in the assessment of adverse events in cancer patients.
All measurements performed during the trial will be to identify the MTD, and to evaluate the 
safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of 
BI 836845 for the trial. 
The scheduled assessments are to monitor drug-induced changes in respect to vital signs, 
laboratory tests, and ECG.  Tumour evaluations are necessary for determination of tumour 
response to treatment and possible pharmacodynamic effects.  Biomarker analyses are 
necessary for correlation with therapeutic outcome.  Immunogenicity testing will detect any 
anti-drug antibody reactions as a result of infusion of BI 836845. 




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Details about blood sample collection, preparation of EDTA-anticoagulated plasma samples, 
storage, and shipment will be provided in a sample handling manual.
5.6
BIOMARKERS FOR EVALUATING PHARMACODYNAMICS
This trial includes biomarkers that are measured and evaluated by an explorative objective.  
These assessments are hypothesis generating and will be used to expand our understanding of 
the disease and investigational drug. 
The following biomarkers will be analysed in samples collected from patients entered into the 
trial:
x
Total IGF-1, total IGF-2, and IGFBP-3 in the serum
x
IGF bioactivity in the heparinised plasma
As medical knowledge in this field is constantly evolving, other blood biomarkers that come 
to be known as potentially relevant prognostic and/or predictive markers of treatment 
response may also be explored via available blood.  For this purpose leftover biomarker 
samples will be stored beyond end of the study for a maximum of 15 years.  Biomarkers that 
come to be known or emerge as not relevant during the trial may not be analysed. 
5.6.1
Endpoints based on biomarkers
Biomarker analysis is exploratory, and no endpoint will be based on biomarkers. 
5.6.2
Method of sample collection
Details about blood sample collection, preparation of plasma and serum samples, required 
tubes, labelling of tubes, storage and shipment (frequency and addresses) will be provided in 
the sample handling manual. 


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5.6.4
Tumour markers
In case of applicable tumour markers of the underlying disease (e.g. CA 15-3, CA-125, CEA, 
PSA, AFP), the blood sample will be obtained pre-dose and post dose at the discretion of the 
investigator. Sample type specification, sampling procedure, and sample collection will 
follow the local standard. Analysis will be performed at the trial site. 
5.7
PHARMACOKINETIC–PHARMACODYNAMIC RELATIONSHIP
No formal analysis of a PK–PD relationship is planned in the trial. 


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If the data suggest a PK–PD relationship of special parameters (e.g. IGF-1 concentration, 
IGF-2 concentration, IGFBP-3 concentration, phosphorylation of IGF-1R), a detailed analysis 
may be performed. 
Correlation between drug concentration and response may be investigated if adequate 
appropriate data are available. In addition, exploratory correlation may also be investigated 
between drug concentration and adverse events.
Data may also be used to develop PK–PD models using nonlinear mixed effect modelling 
techniques, if feasible. For this purpose data may also be combined with data from other 
trials. Modelling activities will be planned and documented separately according to internal 
and external guidelines and SOP. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Visit schedule of the trial should be conducted in the order as summarised below: 
1.
Written informed consent
2.
Screening visit
3.
Registration for eligible patients
4. 
Study treatment during Cycle 1 
5.
Eligibility assessment for continuing the study treatment of next cycle
6. 
Continuation of study treatment during the next cycle if eligible until discontinuation of 
study treatment 
7. 
Rollover part: Continuation of study treatment until discontinuation after having 
sufficient data to answer the primary endpoint
8.
EOT visit if ineligible for the study treatment
9. 
Follow-up visits 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Patients will visit as specified in the Flow Chart.  If patients could not visit on a scheduled 
day, the actual date of conducting planned investigation or evaluation will be recorded with 
the reason why patients could not visit on the scheduled day.
6.2.1
Screening period
Written informed consent must be obtained before any trial-specific evaluation is performed 
as part of screening and the trial overall.
After obtaining written informed consent, patients will attend a screening visit between
Day –28 and –1 before receiving their initial study treatment. Patients will be assessed for 
the eligibility during the screening visit by evaluating all assessments specified in the 
Flow Chart. 
Patients who meet all of the inclusion criteria (see Section 3.3.2) and do not apply any of the 
exclusion criteria (see Section 3.3.3) are eligible for participation and can be registered in the 
trial by the discretion of investigator.
6.2.2
Patient registration
Patient must be registered in the trial as soon as possible after the investigator confirmed the 
patient eligibility for the study treatment.  Procedures for the patient registration are listed as 
follows: 


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x
The investigator or clinical research coordinator will document the necessary details in a 
patient registration form and facsimile the form to the registration centre at
x
The registration centre will confirm all contents of patient registration form and judge 
whether the patient is eligible to participate in the trial and then facsimile the form 
describing the result of judgement to the trial site.
6.2.3
Treatment period
All assessments and evaluations must be performed before infusion of BI 836845 except for a 
part of vital signs, ECG measurements, and pharmacokinetic blood samplings (see 
Flow Chart).
The investigator confirms whether inclusion and exclusion criteria are still valid or not before 
study treatment on Visit 1 of Cycle 1.  For patients who are willing to continue the study 
treatment after completion of Cycle 1, written informed re-consent must be obtained before 
study treatment on Visit 1 of Cycle 2.
All planned visit dates are programmed from the start of Day 1 of Cycle 1. If a visit is 
missed, there will be no re-scheduling.  If a patient should attend the trial site between the 
“missed” and the next scheduled visit, the missed visit assessments should be performed. 
The current date and the reason for the delay must be recorded in the medical records. All 
subsequent visits should adhere to the scheduled visits for all cycles of treatment period.
The treatment period of the trial will continue for an indeterminate number of cycles until any 
one of discontinuation criteria (see Section 3.3.4.1) is met, and then the EOT visit must be
performed.  The end of treatment period will be the last day of study treatment.
6.2.3.1 Rollover part
At the time of all patients in the trial having sufficient data to answer the primary endpoint 
(see Section 5.2.1), patients continuing on study treatment will have the EOT assessments 
(except for blood collection for biomarker analyses) performed and then continue on study 
treatment into the rollover part with reduced clinical data collection.  For patients who are 
willing to continue the study treatment in the rollover part, written informed re-consent must 
be obtained before the initial study treatment in the rollover part. After initiation of the 
rollover part, the investigator should make efforts to keep administration of BI 836845 at 
intervals of 7 days.  However, weekly administration schedule can temporarily be 
accelerated, delayed or skipped due to administrative reasons at the discretion of the 
investigator. Clinical assessments and laboratory tests are not mandatory and appropriately 
performed as per the standard of care at the study sites or at the discretion of investigator, and 
only clinical relevant abnormalities are reported as adverse events according to 
Section 5.2.2.2. Results for the assessments and tests should be recorded in the source data 
only, additional documentation in the eCRF is not required. 


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6.2.4
End of Treatment
EOT visit must be performed within 5 days after discontinuation of study treatment.  If 
patient discontinuation of study treatment falls on a scheduled visit, EOT visit should be 
conducted instead of assessments at the scheduled visit.  In the rollover part, EOT visit will 
be performed on the same day or after discontinuation of study treatment. The investigator 
must confirm sufficient recovery from drug-related adverse events before patients will 
receive the next anti-cancer therapy between EOT visit and the first follow-up (FU1) visit. 
6.2.5 
Follow-up period
The FU1 visit must be performed 42 (a window of +7) days after the last administration of 
BI 836845.
Patients are also followed up at the second follow-up (FU2) on 28 (a window of ±4) days
after FU1 visit. This FU2 visit may be performed over the telephone if a visit at the trial site 
cannot be arranged. 
FU2 visits will be skipped for patients conducted the rollover part. 
6.3
END OF THE WHOLE TRIAL
The trial will be considered completed as soon as the last patient has completed follow-up 
period.  In case no MTD can be identified up to the highest dose tested in this trial, the 
sponsor will determine whether an expansion cohort will be conducted or not. 


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This trial follows a traditional 3 + 3 design with dose de-escalation in oncology phase I trials.
All planned analyses will be descriptive and no statistical model will be used in analyses. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory.  No formal statistical tests will be 
performed. 
7.3
PLANNED ANALYSES
All patients who received at least one dose of BI 836845 will be included in the analyses. 
7.3.1
Primary analyses 
The objective of this study is to identify the MTD (for definition of MTD, see
Section 4.1.3.3) of BI 836845.  In order to identify the MTD, the number of patients who are 
observed DLTs at each dose level will be presented.
7.3.2 
Secondary analyses 
7.3.3 
Safety analyses 
The following measures will indicate how well BI 836845 is tolerated: 
x
Adverse events of special interest


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x
Adverse events leading to dose reduction 
x
Adverse events leading to discontinuation of study treatment
x
The overall incidence and intensity of AEs according to Common Terminology Criteria, 
CTCAE version 4.03 (R10-4848) as well as relatedness of Adverse events to treatment
x
SAEs
x
Causes of death
x
Vital signs
x
Change from baseline for all laboratory tests
x
ECOG performance status
x
ECG
Frequency distributions, descriptive statistics and listings will be used to examine these 
variables.
Adverse event data from the first cycle will be presented separately.  All data collected during 
the study will be assigned to a study period (e.g. screening, on-treatment, follow-up etc.) and 
be presented by BI 836845 dose level.  Details will be provided in the TSAP.
7.3.4
Interim analyses
No interim analyses are planned. 
If considered necessary, as soon as the MTD is identified, an evaluation of the safety and 
efficacy aspects may be performed via a snapshot of the data base.  Results of this evaluation 
will be documented and stored. If applicable such an analysis will be defined in more detail 
in the TSAP.
7.3.5
Pharmacokinetic analyses 


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7.3.6 
Pharmacodynamic analyses 
Pharmacodynamic parameters, as described in Section 5.6, will be analysed using an 
explorative approach to determine whether given biomarkers can be used as potential signals 
for efficacy with BI 836845.
7.3.7 
Pharmacogenomic analyses 
The exploratory pharmacogenetic analysis will investigate the association between genetic 
factors and response or resistance. All statistical analysis performed will be considered 
hypothesis generating in scope. 
7.4
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data.
Missing baseline laboratory values will be imputed by the respective values from the 
screening visit.


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7.4.1 
Plasma concentration–time profiles
Concentration data identified with no sample available (NOS), no valid result (NOR), not 
analysed (NOA), below the limit of quantification (BLQ), and no peak detectable (NOP) will 
be ignored and not replaced by zero at any time point (applies also to the lag phase including 
the pre-dose value).  Descriptive statistics of concentrations at specific time points will be 
calculated only when at least 2/3 of the individuals have concentrations within the validated 
concentration range.  The overall sample size to decide whether the “2/3 rule” is fulfilled will 
be based on the total number of samples intended to be drawn for that time point (i.e. BLQ, 
NOR, NOS, NOA, NOP are included).
7.4.2
Pharmacokinetic assessment
7.5
RANDOMISATION
No randomisation will be performed.  Patients will be assigned into dose cohorts which are 
determined according to Section 4.1.3.4 by order of admission into the trial.


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7.6
DETERMINATION OF SAMPLE SIZE
The trial will be based on a traditional 3 + 3 design which is generally applied in oncology 
phase I trials to identify the MTD (see Section 4.1.3.3), where cohorts of 3 to 6 patients will 
be entered sequentially into escalating dose tiers.  Maximum 18 patients evaluable for the 
MTD of BI 836845 will be enrolled when no patient is replaced because of early 
discontinuation (see Section 3.3.5).  If the expansion cohort will be conducted, additional 
6 patients will be entered.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the International Conference on Harmonisation
(ICH) Harmonised Tripartite Guideline for GCP (ICH–GCP) and relevant Boehringer 
Ingelheim SOPs and the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997.  Standard medical care (prophylactic, diagnostic and 
therapeutic procedures) remains in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH–GCP and the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997). 
The rights of the investigator/trial site and of the sponsor with regard to publication of the 
results of this trial are described in the trial site’s contract. As a general rule, no trial results 
should be published prior to finalisation of the clinical trial report. 
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB 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 must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions.  The patient is 
given sufficient time to consider participation in the trial.  The investigator obtains written 
consent of the patient’s own free will with the informed consent form after confirming that he 
patient understands the contents.  The investigator must sign (or place a seal on) and date the 
informed consent form. If a trial collaborator has given a supplementary explanation, the trial 
collaborator also signs (or places a seal on) and dates the informed consent.


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The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law.  The level of 
disclosure must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by authorised 
monitors (CTL/CRA) or Clinical Quality Assurance auditors appointed by
 by appropriate IRB members, and by inspectors from 
regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs 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
eCRFs for individual patients will be provided by the sponsor via RDC/EDC.  For drug 
accountability, refer to Section 4.1.8. 
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the trial; also 
current medical records must be available.
For eCRFs, all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data/documents. eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical trial monitor, auditor 
and inspection by health authorities (e.g. Food and Drug Administration [FDA]). The CRA 
and auditor may review all eCRFs, and written informed consents. The accuracy of the data 
will be verified by reviewing the documents described in Section 8.3.1. 


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8.3.3 
Storage of records 
Storage period of records 
Trial site:
The trial site must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and the trial site’s contract with the sponsor. 
Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is “listed”, i.e. is a known side effect of the drug or not.  
Therefore, a unique reference document for the evaluation of listedness needs to be provided.  
For the BI 836845, this will be the current version of the Investigator’s Brochure. The 
current versions of these reference documents are to be provided in the ISF. No adverse 
events are classified as listed for matching placebo, study design, or invasive procedures. 
8.4.2
Expedited reporting to health authorities and IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IRBs, will be done according to local regulatory 
requirements. Further details regarding this reporting procedure are provided in the ISF. 
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below.  
Patient confidentiality will be ensured by using patient identification code numbers. 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB and the regulatory authorities. 


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8.6
COMPLETION OF TRIAL
When the trial is completed, the principal investigator should inform the head of the trial site 
of the completion in writing, and the head of the trial site should promptly inform the IRB 
and sponsor of the completion in writing. 
8.7
PROTOCOL VIOLATIONS
The investigator should document any deviation from the protocol regardless of their reasons.
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R01-0787 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982;5(6):649-655. 
R06-1414 
Thomas JD, Adams DB, Devries S, Ehler D, Greenberg N, Garcia M, et al.
Guidelines and recommendations for digital echocardiography. J Am Soc 
Echocardiogr 2005;18(3):287-297. 
R07-4212 
Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and 
neoplasia. Nat Rev Cancer 2004;4(7):505-518. 
R09-0262 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009;45(2):228-247. 
R10-4848 
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), 
revised June 2010, reprinted June 2010). Website: evs.nci.nih.gov/ftp1/ 
CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 2010. 
R10-5355 
Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in 
cancer growth and metastasis: overview and recent insights. Endocr Rev 
2007;28(1):20-47. 
R10-5694 
De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL. 
M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of 
heterozygosity. Nat Genet 1995;11(4):447-449. 
R10-5756 
Karamouzis MV, Papavassiliou AG. The IGF-1 network in lung carcinoma 
therapeutics. Trends Mol Med 2006;12(12):595-602.
R10-5757 
Gualberto A, Pollak M. Emerging role of insulin-like growth factor receptor 
inhibitors in oncology: early clinical trial results and future directions.
Oncogene 2009;28(34):3009-3021. 
R10-5758 
Weroha SJ, Haluska P. IGF-1 receptor inhibitors in clinical trials--early 
lessons. J Mammary Gland Biol Neoplasia 2008;13(4):471-483.
R10-5759 
Sachdev D, Yee D. Inhibitors of insulin-like growth factor signaling: A 
therapeutic approach for breast cancer. J Mammary Gland Biol Neoplasia 
2006;11(1):27-39. 
R10-5760 
Pollak M. Targeting insulin and insulin-like growth factor signalling in 
oncology. Curr Opin Pharmacol 2008;8(4):384-392.


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9.2
UNPUBLISHED REFERENCES
c01690707 
Investigator’s Brochure: Xentuzumab (BI 836845), Indication: Cancer. Project 
No. 1280.P1, 1280.P2, 1280.P3. 








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10.3
CLINICAL EVALUATION OF LIVER INJURY
10.3.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (adverse events of 
special interests), are to be further evaluated using the following procedures. 
10.3.2
Procedures
Repeat the following lab tests: ALT, AST, and bilirubin (total and direct) – within 48 to 
72 hours.  If ALT and/or AST  × ULN combined with an elevation of total 
bilirubin  × ULN are confirmed, results of the laboratory parameters described below must 
be made available to the investigator and to Boehringer Ingelheim as soon as possible.
In addition, 
x
obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF 
x
obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF; 
x
obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;
and report these via the eCRF (except for the rollover part). 
Clinical chemistry: 
alkaline phosphatase, albumin, PT or INR, CK, CK-0%FRHUXORSODVPLQĮ-1 antitrypsin, 
transferrin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology: 
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HBsAg, Anti-HBs, DNA), Hepatitis C (Anti- 
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti- 
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody 
<project dependent: Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), 
herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis 
(IgG, IgM)> 
Hormones, tumour marker: 
TSH
Haematology: 
Thrombocytes, eosinophils 


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x
Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahpeatic 
pathology, e.g. bile duct stones or neoplasm. 
x
Initiate close observation of subjects by repeat testing of ALT, AST, and total bilirubin 
(with fractionation by total and direct) at least weekly until the laboratory ALT and/or 
AST abnormalities stabilise or return to normal, then according to the protocol.  
Depending on further laboratory changes, additional parameters identified e.g. by reflex 
testing will be followed up based on medical judgement and GCP.


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11
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1 
Number of global amendment
1
Date of CTP revision
04 Jul 2019
BI Trial number
1280.15
BI Investigational Product
Xentuzumab (BI 836845)
Title of protocol
An open-label phase I dose escalation trial of 
weekly intravenous administrations of BI 836845
in Japanese patients with advanced solid tumours
To be implemented only after 
approval of the IRB
To be implemented 
immediately in order to 
eliminate hazard -  
IRB to be notified of change 
with request for approval
Can be implemented without 
IRB approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Throughout the Clinical Trial Protocol
Description of change
Changes by amendment of Clinical Trial 
Protocol
Rationale for change
Update version number, revision date etc.
Section to be changed
Synopsis
Section 1.2 – DRUG PROFILE
Description of change
Addition of ‘xentuzumab’
Rationale for change
Decide the generic name of BI 836845
Section to be changed
Synopsis
Section 3.1.1 – Administrative structure of the 
trial
Section 8.1 – STUDY APPROVAL, PATIENT 
INFORMATION, AND INFORMED 
CONSENT
Description of change
Changes of organisation and role names
Rationale for change
Re-organisation of sponsor


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Section to be changed
Synopsis – Methodology
FLOW CHART
FLOW CHART – ROLLOVER PART
Section 3 – DESCRIPTION OF DESIGN AND 
TRIAL POPULATION
Section 4 – TREATMENTS
Section 5 – VARIABLES AND THEIR 
ASSESSMENT
Section 6 – INVESTIGATIONAL PLAN
Table 10.1: 3 – Blood sampling scheme for Cycle 
4 onwards 
Appendix 10.3.2 – Procedures
Description of change
Addition of rollover part
Rationale for change
Add procedures regarding rollover part
Section to be changed
Section 1.4 – CLINICAL INFORMATION
Section 9.2 – UNPUBLISHED REFERENCES
Description of change
Change of description regarding Investigator’s 
Brochure and the reference
Rationale for change
Refer the latest version of Investigator’s 
Brochure
Section to be changed
Section 3.1 – OVERALL TRIAL DESIGN AND 
PLAN
Section 7.3.4 – Interim analyses
Description of change
Addition regarding clinical trial report and 
change of interim analysis plan
Rationale for change
Clarify the procedure
Section to be changed
Section 3.1.1 – Administrative structure of the 
trial
Section 4.1.3.1 – Initial dose and dose levels to 
be evaluated
Section 5.2.2.2 – Adverse event and serious 
adverse event reporting
Section 5.2.5 – Electrocardiogram 
Section 5.3.4 - Pharmacogenomic evaluation
Section 8.3 – RECORDS
Description of change
Optimisation of terminology
Rationale for change
Change systems using in this trial.  Adopt 
adequate terminologies


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11.2
GLOBAL AMENDMENT 2 
Number of global amendment
2
Date of CTP revision
29 Apr 2022
BI Trial number
1280.15
BI Investigational Product
Xentuzumab (BI 836845)
Title of protocol
An open-label phase I dose escalation trial of 
weekly intravenous administrations of BI 836845
in Japanese patients with advanced solid tumours
To be implemented only after 
approval of the IRB
To be implemented 
immediately in order to 
eliminate hazard -  
IRB to be notified of change 
with request for approval
Can be implemented without 
IRB approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Section 2.3 – BENEFIT–RISK ASSESSMENT
Description of change
Update of risk-benefit evaluation in consideration 
of topline results of 1280-0022 trial
Rationale for change
Clarify the reason for termination of BI 836845
clinical development and cessation of further 
BI 836845 manufacturing
Section to be changed
Section 3.3.4.3 – Discontinuation of the trial by 
the sponsor
Description of change
Update of information that significantly affect 
continuation of trial
Rationale for change
Clarify the sponsor’s decision
Section to be changed
Section 5.2.9 – Pregnancy testing
Description of change
Modification of information on methods and 
duration of contraception
Rationale for change
Refer to the latest subject information for 
updated appropriate methods and duration of 
contraception

SAP_001.pdf: 
ABCD 
Trial Statistical Analysis Plan  
c02246780-02 
BI Trial No.:
1280.15
Title:
An open-label phase I dose escalation trial of weekly intravenous 
administrations of BI 836845 in Japanese patients with advanced 
solid tumours 
Test Substance
Xentuzumab, BI 836845 
Responsible trial 
statistician:
Phone: 
, Fax: 
Date of statistical 
analysis plan:
10 DEC 2018 SIGNED
Version:
Revised
Page 1 of 30 
Proprietary confidential information
¤ 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1
TABLE OF CONTENTS
TITLE PAGE ...................................................................................................... 1
1
TABLE OF CONTENTS ...................................................................... 2
LIST OF TABLES .............................................................................................. 4
2
LIST OF ABBREVIATIONS ............................................................... 5
3
INTRODUCTION.................................................................................. 7
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY......... 8
4.1
ADDITIONS/NEW ANALYSES ........................................................................ 8
4.2
CHANGES ............................................................................................................ 8
4.3
CLARIFICATIONS ............................................................................................. 8
5
ENDPOINTS .......................................................................................... 9
5.1
PRIMARY ENDPOINT ...................................................................................... 9
5.2
SECONDARY ENDPOINTS .............................................................................. 9
5.2.1
Key secondary endpoints ................................................................................ 9
5.2.2
Other secondary endpoints ............................................................................. 9
6
GENERAL ANALYSIS DEFINITIONS...........................................15
6.1
TREATMENTS .................................................................................................. 15
6.2
IMPORTANT PROTOCOL DEVIATIONS ................................................... 15
6.3
PATIENTS SETS ANALYSED ........................................................................ 17


6.5
POOLING OF CENTRES ................................................................................ 18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ................................... 18
6.6.1
Adverse events ............................................................................................... 18
6.6.2
Laboratory values at baseline ...................................................................... 18
6.6.3
PK parameters ............................................................................................... 19
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS ................. 19
6.7.1
Baseline ........................................................................................................... 19
6.7.2
Time windows for every RECIST assessment ............................................ 19
7
PLANNED ANALYSES......................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........ 21
7.1.1
Disposition of patients ................................................................................... 21
7.1.2
Important protocol deviations ...................................................................... 21
7.1.3
Demographic and other baseline characteristics ........................................ 22
7.2
CONCOMITANT DISEASES AND MEDICATION .................................... 22
7.3
TREATMENT COMPLIANCE ....................................................................... 22
7.4
PRIMARY ENDPOINTS .................................................................................. 22
7.5
SECONDARY ENDPOINTS ............................................................................ 23
7.5.1
Key secondary endpoints .............................................................................. 23




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LIST OF TABLES
Table 6.2:1 
Important protocol deviations ......................................................................... 15
Table 6.7.2: 1 
Nominal time-points and windows for imaging ........................................ 19
Table 10: 1
History table .................................................................................................... 30


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2
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event 
AESI
Adverse event of Special Interest
ATC
Anatomical, Therapeutic, Chemical
AUC
Area under the curve 
BI
Boehringer Ingelheim
BMI
Body mass index 
BSA
Body surface area
CR
Complete response
CRF
Care report form
CT
Concomitant therapies
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol 
CTR
Clinical Trial Report
DBL
Database Lock
DLT
Dose limiting toxicity
ECG
Electrocardiogram
ENR
Enrolled set
EOT
End of treatment 
IGF
Insulin-like growth factor
iPDs 
Important protocol deviations 
LLT
Lowest Level Term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MQRMs 
Medical Quality Review Meetings 
MRI
Magnetic Resonance Imaging
MS
MTD set
MTD
Maximum tolerated dose
NE
Not evaluable 


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P25
25th percentile
P75
75th percentile
PD
Progressive disease
PK
Pharmacokinetics
PKS
Pharmacokinetics Set
PPS
Per Protocol Set
PR
Partial response
PT
Preferred term
RECIST
Response Evaluation Criteria In Solid Tumours 
REP
Residual effect period
RPM
Report planning meeting
SAE
Serious adverse event
SD
Stable disease
SOC
System organ class
SOP
Standard Operating Procedures 
TCM
Trial clinical monitor
TS
Treated set
TSAP
Trial statistical analysis plan
WHO DD
World Health Organisation – Drug Dictionary 


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3
INTRODUCTION
As per ICH E9, 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 (see in section “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, randomisation. This TSAP follows 
Boehringer Ingelheims (BI) internal reference (1).
In general, study or trial medication refers to Xentuzumab.
SAS Version 9.4 or later version will be used for all analyses unless otherwise specified.




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5
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is the maximum tolerated dose (MTD) of trial medication based on the 
occurrence of dose limiting toxicity (DLT) during the first treatment course. The planned 
treatment course consists of 21 days.
MTD:
MTD is defined as the highest dose level examined of trial medication, at which no more than 
1 out of 6 patients experienced a DLT during the MTD evaluation period. The MTD 
evaluation period is defined as the time from the first administration of Xentuzumab up to 
start of cycle 2. That means that the exact duration of this period will be derived for each 
patient. If the patient does not start cycle 2, a fixed duration of 21 days will be used. 
In case the MTD will not be reached until 1400 mg, it will be deemed as a sufficient 
tolerability in Japanese patients with advanced solid tumours at 1400 mg. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable. 
5.2.2
Other secondary endpoints
There are no secondary endpoints. 


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6
GENERALANALYSIS DEFINITIONS
6.1
TREATMENTS
Patients will be analysed according to the cohort initially assigned. All planned analyses will 
be presented by this cohort, unless specified otherwise. Handling of patients where cohort 
assignment has not been followed will be handled on a case-by-case basis, to be agreed at 
report planning meetings or DBL meeting (but prior to database lock). 
For safety summaries data recorded during the Residual Effect Period (REP) will be 
considered as on-treatment. For this trial, the length of the REP is 42 days. 
The actual study periods and treatment codes are defined in a document entitled “8-7-other-
sdtm-trial-arms-trial-elements”, which can be found in Data Management and Statistics 
(DMS) folder, Section 8, within BIRDS.
6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set (PPS) analysis will be performed for this study, hence, no patient will be 
excluded from the analyses. However patients with potentially important protocol deviations 
(iPDs) will be documented. The following list in Table 6.2: 1 of potentially IPDs will be 
used; note that this is a working list and may not be finalised until the final Report Planning 
Meeting (RPM) prior to database lock for the primary analysis. Potentially important protocol 
deviations will be handled according to BI standards (9). 
During the study conduct, protocol deviation should be monitored and guidance for 
improving / teaching the respective sites should be discussed during the study Medical 
Quality Review Meetings (MQRMs).
Table 6.2:1  
Important protocol deviations 
Category/
Code
Description
Requirements
Exclude
d from
A
[1] 
Entrance criteria not 
met
A1
Diagnosis of trial disease 
questionable 
Inclusion criteria IN1 not met
None
A2
Prohibited baseline 
condition, diagnosis or 
treatment
Inclusion criteria IN3 not met
or 
Exclusion criteria EX1, 3-12, EX14-
15 or EX17-19 
None
A3
Laboratory result 
indicating inadequate 
organ function at 
screening
Exclusion criteria EX2
None
Table 6.2:1 (continued) 
 
Important protocol deviations 


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Category/
Code
Description
Requirements
Exclude
d from
A4
Adequate archival 
tumour tissue not 
available
Exclusion criteria EX13
None
B
[1] 
Legal Criteria
B1
Informed consent not 
available / not done 
Informed consent date missing
or 
Inclusion criteria IN4 not met 
All
B2
Informed consent too late
Informed consent date was after 
Screening Visit date
None
B3
Age limit for patient 
inclusion not adhered to 
Inclusion criteria IN2 are not met or, 
Calculate age given the date of birth 
and date of informed consent: 
SDWLHQWVPXVWEH20 years old 
All
C
[2] 
Trial medication and 
randomisation 
C1
Time window deviation
for procedures performed 
at screening
Assessment at screening not within 
28 days prior to first treatment
None
C2
Trial medication not 
given according to 
protocol 
Dose reduction scheme not followed
description in section 4.1.3.6 in CTP. 
None
C3
Infusion time for the 
investigational treatment 
outside of CTP specific 
boundaries 
Check medical review of 
administration data.
Total infusion time (allowing for 
interruptions) < 60 minutes 
See the section 4.3 in CTP.
None
C4
Patient assignment not 
followed
Patients do not receive the initial 
treatment they were allocated to
None
Table 6.2:1 (continued) 
 
Important protocol deviations 


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Category/
Code
Description
Requirements
Exclude
d from
D
[2] 
Concomitant 
medication
D1
Prohibited treatment 
during trial conduct 
phase 
Indicated by medical review of 
concomitant therapy use during 
study treatment according to section 
4.2.2.1 in CTP. 
Discuss the list which is given by 
TCM during MQRM.
None
E
[2] 
Missing Data
E1
Imaging assessments not 
done according to CTP 
instructions
Imaging assessment should be 
performed at Screening and several 
time points thereafter (see table 
6.7.2: 1).
None
E2
Pregnancy test not done 
according to CTP 
instructions
Exclusion criteria EX16
or 
Pregnancy test missing.
None
F
[2]
Trial Specific protocol 
deviations
F1
Other protocol deviations
affecting patient rights or 
safety
Manual PVs can be collectively 
captured
None
[1] iPD will be derived automatically 
[2] iPD will be identified via individual review at MQRM/RPM/DBL.
6.3
PATIENTS SETS ANALYSED
The following analysis sets will be defined for this trial:
z
Enrolled set (ENR)
This patient set includes all patients with informed consent given. The enrolled set will be 
used for patient disposition tables. 
z
Treated set (TS)
This patient set includes all patients who are documented to have received and taken at least 
one dose of study medication during the treatment cycles (from day 1). 
The TS will be used for all planned safety and efficacy analyses. 
z
MTD Set (MS)


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The MTD set defines the set of patients that are fully evaluable for the MTD in the first 
treatment course. The MTD set will be used for some safety analyses, this is specified in the 
technical TSAP.
Patients in the TS who were replaced within the MTD period of the trial will be excluded 
from the determination of the MTD. Patients in the TS who entered in an expansion cohort 
will be also excluded from the determination of the MTD. Replacement of patients of the 
study is defined in Section 3.3.5 of the CTP. The final list of replaced patients is supplied by 
the Trial Clinical Monitor (TCM) no later than the last report planning meeting before the 
database lock for the safety analysis.
z
Pharmacokinetic set (PKS)
This patient set includes all patients in the treated set who have at least one valid drug plasma 
concentration available. The decision whether a concentration is considered valid or not will 
in general be made at the RPM before Database Lock (DBL). The PKS will be used for the 
PK analyses of the trial.
No per protocol population will be used for analyses.  
6.5
POOLING OF CENTRES
This section is not applicable because there are no inferential statistics, and therefore there is 
no statistical model in which centre/country can be included. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, missing data will not be imputed, unless required for the following analyses and 
definitions. Then the rules as described below apply.
Missing dates that affect the evaluation of endpoints specified in relevant sections of this 
TSAP will be imputed utilising a “worst case” approach, which will be applied on a case-by-
case basis (depending on the affected endpoint) and agreed to by the trial team members at 
the final RPM before database lock at the latest. The agreements are implemented in the 
technical TSAP.
6.6.1
Adverse events
Missing or incomplete AE dates are imputed according to BI standards (2).
6.6.2
Laboratory values at baseline
For missing laboratory data at Visit 1 (before the very first administration of study 
medication) data from preceding visits will be used if not obtained longer than 2 days before 
the very first treatment with study medication.


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6.6.3
PK parameters
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
6.7.1
Baseline
The last measurement observed prior to start of trial medication will be assigned to baseline. 
Note that for some trial procedures (for example body weight, vital signs, laboratory tests) 
this may be the value measured on the same day trial medication was started. In these cases it 
will be assumed that the measurements were taken prior to the intake of any study 
medication. For tumour assessment, baseline evaluations must be based on Magnetic 
Resonance Imaging (MRI) or Computed Tomography scans performed no more than 28 days 
prior to start of trial medication.
Study days and visits will be labelled according to the flow chart of the CTP. 
Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of any study medication. If this criterion is not fulfilled then no baseline will 
be derived . 
Laboratory values:
Baseline is defined as the latest time-point before the very first administration of any study 
medication. For laboratory values where not only the examination date but also time are 
recorded, examination time has to be taken into account when defining baseline. That is, a 
laboratory value on the same date as the first study drug administration is considered as 
baseline value if and only if the recording time was before or the same as the time of first 
study drug administration. 
If any of these times are missing and the date of laboratory value is equal to the date of first 
study drug administration, then the laboratory assessment will be considered as according to 
protocol, i.e. as prior to first study medication.
6.7.2
Time windows for every RECIST assessment
In order to identify whether consecutive imaging time-points are missing for a given patient, 
a nominal time point [6, 12, 18 weeks and every 9 weeks thereafter] will be assigned to each 
and every image. This is achieved by creating windows for every RECIST assessment. The 
windows are defined in Table 6.7.2: 1 below. 
Table 6.7.2: 1  
 
Nominal time-points and windows for imaging 
Nominal time-point [weeks 
from start of therapy]
Due date of scans [days]
Window [days]
6
43
1 to =< 64
12
85
65 to =< 106


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Table 6.7.2: 1(continued)  
Nominal time-points and windows for imaging 
Nominal time-point [weeks 
from start of therapy]
Due date of scans [days]
Window [days]
18
127
107 to =< 158
27
190
159 to =< 221
Every 9 weeks interval
*
*
*Due date of imaging = (nominal time point * 7) + 1. To calculate the lower bound of the 
window, use the middle point between the due date of the previous time point and the 
current due date+1. To calculate the upper bound of the window, use the middle point 
between the due date of the next time point and the current due date. 
If a patient does not have an image in one of the windows described above, he/she will be 
said to have 'missed an assessment' for that time-point. In case a patient has more than one 
assessment in one window, the assessment with the latest outcome will be used for the 
analysis unless a PD has been recorded earlier then PD will be used.


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7
PLANNED ANALYSES
The labelling and display format of statistical parameters will follow BI standards (10).
Descriptive statistics for continuous variables will generally contain N (number of patients in 
that patient set), Mean, Standard Deviation, Minimum (Min), P25 (25th percentile), Median, 
P75 (75th percentile), Maximum (Max). In general, means, SDs, medians, P25 and P75 will 
be presented to one more decimal place than the raw data. Minima and maxima will be 
presented to the same number of decimal places as 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 total. Percentages will be rounded to one decimal place.
In general a category “missing” will be displayed. Percentages will also generally be based 
on all patients in the respective patient set whether they have non-missing values or not. 
Sort order for general categorical variables: If categories correspond to the collected 
categories on the eCRF and the table shells do not explicitly specify the ordering, the “default 
ordering” defined by the eCRF is to be used in such cases. If categories are derived the 
ordering as specified in the table shell document should be used; in general ordinal data (e.g. 
categorised continuous data) are to be displayed in ascending order.
The denominator of the main categories is defined by the number of patients in the used 
patient set. The main categories define the denominators of the subcategories. Subcategories 
should be indented and “[N (%)]” to be displayed only for the main category. 
If a table includes only categorical data, “[N (%)]” is to be displayed in the column header.
Abbreviations (e.g., Wors.) or acronyms (e.g., PD) should not be displayed in tables and 
patients data listings without any explanation. They will be either spelled out in the table or 
explained in footnotes (whatever is more reasonable from the programming point of view).
If applicable, conversion from days to weeks, months and years will be as follows: 
z
Weeks = days ÷ 7
z
Months = 12 × days ÷ 365.25 
z
Years = days ÷ 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.1.1
Disposition of patients
For patient disposition the standard descriptive table from the EOT catalogue will be 
populated. 
7.1.2
Important protocol deviations 
A table and a listing of patients with important protocol deviations based on Table 6.2: 1 will 
be created in Section 15.1.3 and Appendices 16.2.3 and 16.1.13.1.3 respectively, of the 
clinical trial report (CTR). 


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7.1.3
Demographic and other baseline characteristics
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demographic data, oncological history and baseline conditions. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Concomitant diseases will 
be coded similarly as adverse events based on the most current Medical Dictionary for 
Regulatory Activities (MedDRA) version. Concomitant therapies will be coded according to 
World Health Organisation - Drug Dictionary (WHO-DD). Concomitant therapies (CT) will 
be classified according to the Anatomical, Therapeutic, Chemical (ATC) classification 
system. The third ATC level will be used to categorise CTs by therapy type. In situations 
where a medical product may be used for more than one equally important indication, there 
are often several classification alternatives. As appropriate, patients receiving CTs with more 
than one possible ATC level-three category will be counted more than once; footnotes will 
clarify this possible double counting in tables. 
Concomitant medications will be presented according to whether they are concomitant with 
the reception of study medication, or whether they were given prior to study medication. In 
case start and stop dates of the medications are completely missing, they are assigned as 
given prior to study medication. 
7.3
TREATMENT COMPLIANCE
Compliance was not analysised separately, but assessed in terms of exposure (including dose 
intensity, refer to Section 7.7 for further details on exposure analysis). 
7.4
PRIMARY ENDPOINTS
The primary endpoints are the MTD and the occurrence of DLT. The MTD is determined 
from the occurrences of DLTs during the MTD evaluation period (this period is defined in 
Section 5.1). An overall summary of the DLTs (see CTP Section 4.1.3.2 for definitions of 
DLT) which occurred during the MTD evaluation period and the on-treatment period will be 
provided for each dose cohort. 
Patients that were treated but replaced for the MTD evaluation (see CTP Section 3.3.5) will 
be excluded from the MTD determination. Replacement of patients will be determined on a 
case by case basis; exclusion of these patients from the MTD evaluation will be confirmed by 
the trial team at the report planning meeting prior to database lock.
A listing of patients with DLTs by initial treatment will be performed.
In case the MTD will not be reached until 1400 mg, it will be deemed as a sufficient 
tolerability in Japanese patients with advanced solid tumours at 1400 mg. 


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol. 
7.5.2
Other secondary endpoints
This section is not applicable as no secondary endpoint has been specified in the protocol. 
7.7
EXTENT OF EXPOSURE
The variables defined in Section 5.4.2 will be summarised descriptively for each dose cohort.
7.8
SAFETY ANALYSES
All safety analyses will be performed on the TS. Patients who were replaced within the first 
treatment cycle will be excluded from the determination of the MTD. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses will be based on the number 
of patients with AEs (not the number of AEs).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies: 
z
All AE attributes are identical (Lowest Level Term (LLT), Common Terminology 
Criteria for Adverse Events (CTCAE) grade, action taken with trial medication, therapy 


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required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest)
z
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
For further details on summarisation of AE data, please refer to (2) and (6).
Adverse events will be coded with the most recent version of MedDRA. The severity of AEs 
will be scaled according to CTCAE (CTCAE version 4.03 (11)).
The analyses of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events with an onset between first treatment 
administration until end of the REP will be assigned as ‘on treatment’. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’; these AEs will 
be displayed in listings only. Adverse events will be displayed by the initial dose of 
Xentuzumab administered on the first day of treatment with Xentuzumab. Adverse events 
will be displayed by the initial dose of study medication administered on the first day of 
treatment
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term. Separate tables will be provided for patients with drug-related adverse events, adverse 
events leading to dose reduction, adverse events leading to discontinuation, serious adverse 
events, adverse events leading to death, other significant adverse events, adverse events of 
special interest, and adverse events fulfilling the DLT definition
Sorting order:
In tables presenting System Organ Classes (SOCs) and Preferred Terms (PTs), SOCs will be 
sorted alphabetically and PTs (within SOC) by descending frequency. 
Reporting of CTCAE grades in tables: 
In tables showing AEs by worst CTCAE grade, AEs with missing CTCAE grade will only be
displayed under the category “All grades”, but no category “Mising grade” will be displayed. 
Therefore the categories “Grade 1” to “Grade 5” might not add up to the category “All 
grades”; a footnote will explain this handling.  
Displaying of CTCAE grades in AE tables (Section 15) will be “All grades”, “Grade 1”, 
“Grade 2”, “Grade 3”, “Grade 4”, and “Grade 5” separately. 
Listings of adverse events
Adverse events will be reported with start and end day as calculated from the first day of 
treatment with study medication.
Incidence and severity of adverse events
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and serious AEs (SAE) will be reported by severity according to CTCAE grades. 
Other significant adverse events


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Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
or permanent discontinuation of study medication. Their incidence will be reported by 
severity according to CTCAE grades. 
A listing of patients who developed ‘other significant’ AEs will be provided and a flag for 
serious and non-serious will be included.
AEs leading to dose reduction or permanent discontinuation will include: 
z
AEs leading to dose reduction of Xentuzumab 
z
AEs leading to permanent discontinuation of Xentuzumab 
AEs leading to death
AEs leading to death during the on-treatment period will be tabulated in a separate table. In 
this table no CTCAE grades will be shown. For fatal AEs without CTCAE garde 5 or missing 
grade, the grade will be imputed as CTCAE grade 5. Reported fatal AEs that occurred in the 
post-treatment period will be listed within the listing containing all post-treatment AEs.
Protocol-specified Adverse Events of Special Interest (AESI)
Protocol-specified AESIs are specified in the CTP Section 5.2.2.1. Their incidence will also 
be reported. 
7.8.2
Laboratory data 
7.8.2.1
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). The same on-treatment periods as considered for the analysis of adverse events 
will be applied for laboratory values except for that the baseline laboratory value will be 
included in the ‘on-treatmen’ period. Patients having at least one post-baseline laboratory 
value will be displayed in the descriptive analyses.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.03 (11). The 
following outputs will be presented:
z
Transitions of CTCAE grade from baseline to worst laboratory value, from worst to last 
laboratory value during the on-treatment phase, and from baseline to last laboratory 
value. 
Patients with missing CTCAE grade at baseline or no baseline value but post baseline values 
will be displayed in the category “Missing CTCAE grade at baseline”. Laboratory values 
without CTCAE grading will be compared to their reference ranges and frequency tables will 
be provided for the number of patients within and outside the refrence range at baseline and 
the last measurement on treatment.
Analysis of potentially clinically significant abnormal laboratory values, and handling of 
CTCAE grade -1 and -9 laboratory parameters, are described in the SOP for “Display and 
analysis of laboratory data” (8). 


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7.8.2.2
Laboratory values of special interest
Drug-induced liver injury (DILI)
Criteria for 'potential' DILI can be found in Section 5.2.2.1 of the CTP. 
Patients fulfilling these criteria will be followed up according to the procedures described in 
Section 10.3 of the CTP. 
Patients with missing laboratory values for liver enzymes will be excluded from these 
analyses but will be presented separately in a listing.
Tabulations of hepatic enzyme elevations and liver laboratory values (see Section 5.2.2.1 of 
the CTP), including flags of true DILI cases, are created in accordance with the Food and 
Drug Administration (FDA) DILI guidance (12).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Any findings for ECG will be reported as AE. Separate ECG analyses will not be performed 
in this trial.
7.8.5
Others
7.8.5.1
ECOG Performance Status changes 
A shift table of the worst (highest) and last ECOG performance status category recorded on 
treatment or during follow-up by baseline category will be produced 


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8
REFERENCES
1
001-MCG-160_RD-06: "Trial Statistical Analysis Plan - Template", current 
version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
4
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON.
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON.
6
001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
7
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.
8
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.
9
001-MCS-40-413: “Important Protocol Deviations”, current version; IDEA for 
CON.
10
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON.
11
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), revised 
June 2010, reprinted June 2010).  
12
Guidance for industry: drug-induced liver injury: premarketing clinical evaluation 
U.S. Departement of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation 
and Research (CBER), 2009. 
13
Shankar G et al. Assessment and reporting of the clinical immunogenicity of 
therapeutic proteins and peptides-harmonized terminology and tactical 
recommendations. AAPS J 16 (4), 658 - 673 2014 


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10
HISTORY TABLE
Table 10: 1 
History table 
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
26-Jun-17
None
This is the final TSAP without any 
modification
Revised
10-Dec-18
Section 
4.2
Section 
6.2 and 
7.1.2
Section 
7.1.2
Section 
7.9.1 
and 
section 
7.9.2
Section 
7.9.3
Added the description the CTR report 
timing.  
Terminology changed from “Protocol 
violation” to “Protocol deviation” 
followed latest SOP. 
Appendices section from 16.1.9.2.3 
to 16.1.13.1.3 changed followed 
latest SOP.
Provided more details on the 
biomarker analyses.
Deleted the dose proportionality PK 
analysis based on the PK colleagues 
discussion.