Conditions: Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 164
Healthy volunteers: no

Brief summary:
Phase Ib / II study to determine the Maximum Tolerated Dose and Recommended Phase II Dose, and to evaluate the safety and antitumour activity, of BI 836845 and everolimus in combination with exemestane in women with HR+/HER2- advanced breast cancer

Detailed description:

Arms:
arm 1: Subjects received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. arm 2: Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. Administration of xentuzumab was stopped after 28th October 2016, and participants in this group who remained in the trial could continue with everolimus 10 mg + exemestane 25 mg. arm 3: Subjects received a single dose of 750 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28- day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal. arm 4: Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Interventions: intervention 1: Everolimus intervention 2: Exemestane intervention 3: BI 836845
Intervention descriptions: intervention 1: 10mg dose intervention 2: Fixed dose at 25mg intervention 3: 1000 mg, recommended dose per Phase Ib part. Human monoclonal antibody. Dose escalation in Phase Ib. 2 dose levels (high or low) depending on the dose cohort explored

Protocol document:
Prot_000.pdf: 




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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836845
Protocol date:
Trial number:
Revision date:
30 March 2016
13 December 2013
1280.4
Main criteria
for inclusion:
Histologically-confirmed locally advanced or metastatic breast cancer not deemed 
amenable to curative surgery or curative radiation therapy 
Tumors are positive for estrogen-receptor (ER) and/or progesterone receptor (PgR); 
HER2 negative
Postmenopausal women
Disease refractory to non-steroidal aromatase inhibitors
Objective evidence of recurrence or progression on or after the last systemic therapy 
prior to the study entry
Patients must have a measurable lesion according to RECIST version 1.1 or bone 
lesion only: lytic or mixed (lytic + sclerotic) in the absence of measurable lesion
Test product(s):
BI 836845
dose:
Phase I: 750 mg weekly as starting dose; Phase II: RP2D as established in Phase I
mode of admin.:
Intravenous infusion over 60 minutes
Comparator products:
Exemestane plus
Everolimus
dose:
Exemestane: 25 mg per day
Everolimus: Phase I:10 mg per day as starting dose; Phase II: Arm 1: 10 mg per day, 
Arm 2: RP2D as established in Phase I
mode of admin.:
Oral
Duration of treatment: Continuous treatment until disease progression, intolerable AEs, consent withdrawal 
or non-compliance with the study protocol








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∀
Every 12 weeks after week 48 (e.g. during week 59-60 (406 – 420 days after start of BI 836845), during week 
71-72 (490 – 504 days after start of BI 836845), etc.)
In the event of an interruption/delay to treatment, the tumor assessment schedule should not be changed. 
Patients who discontinue the trial for any reason other than imaging based progressive disease should have a 
tumour assessment (RECIST 1.1) performed at EOTV. Except in case of discontinuation from treatment due 
to imaging based progression, tumor assessment at EOTV is not necessary if the previous evaluation was 
done within 4 weeks of EOTV
Unscheduled scan based on the investigator’s judgement is allowed and should also be documented in eCRF 
16. Everolimus should be dispensed through IRT. The prescription of exemestane should be filled by pharmacy. 
Patient’s screening, run-in, all drug dispensation visits and EOTV will be collected in the IRT system
17. Compliance check: on Day 1 of every course and at EOTV
18. For Course 2 only








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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
FLOW CHART ∀PHASE I PART...............................................................................5
FLOW CHART ∀PHASE II PART .............................................................................8
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 16
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................20
1.2.1 BI 836845 ...............................................................................................20
1.2.2 Everolimus.............................................................................................23
1.2.3 Exemestane............................................................................................24
2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONAL FOR PERFORMING THE TRIAL...........................................25
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33
3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................35
3.3.4
Removal of patients from therapy or assessments.............................38
3.3.4.1
Removal of individual patients................................................38
3.3.4.2
Discontinuation of the trial by the sponsor..............................38
3.3.5
Replacement of patients .......................................................................39
4.
TREATMENTS........................................................................................ 40
4.1
TREATMENTS TO BE ADMINISTERED....................................................40
4.1.1
Identity of BI investigational product and comparator products ....40
4.1.1.1
BI 836845 (investigational product)........................................40
4.1.1.2
Everolimus (Afinitor®) (investigational product)...................40
4.1.1.3
Exemestane (Aromasin®) (non-investigational product)........41


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4.1.2
Method of assigning patients to treatment groups ............................42
4.1.2.1
The Phase I part: ......................................................................42
4.1.2.2
The Phase II part:.....................................................................42
4.1.3
Selection of doses in the trial................................................................42
4.1.3.1 Run-in treatment with everolimus and exemestane in the Phase 
I part.........................................................................................42
4.1.3.2 Determination of MTD in the Phase I part ..............................43
4.1.3.3
Selection of phase II dosing schedule......................................46
4.1.4
Drug assignment and administration of doses for each patient .......46
4.1.4.1
Initial study drug assignment and administration....................47
4.1.4.1.1BI 836845.................................................................................47
4.1.4.1.2Everolimus...............................................................................47
4.1.4.1.3Exemestane ..............................................................................48
4.1.4.1.4Special instructions for the Run-in period and up to Course 1 
Day 8 of the Phase I part..........................................................48
4.1.4.2
Additional course of treatment in Phase I part.........................49
4.1.4.3
Temporary treatment interruption and dose reduction.............49
4.1.5
Blinding and procedures for unblinding ............................................51
4.1.5.1
Blinding....................................................................................51
4.1.5.2
Procedures for emergency unblinding .....................................51
4.1.6
Packaging, labelling, and re-supply ....................................................51
4.1.7
Storage conditions.................................................................................52
4.1.8
Drug accountability ..............................................................................52
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................53
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................53
4.2.1.1
Rescue medication ...................................................................53
4.2.1.2
Emergency procedures.............................................................53
4.2.1.3
Concomitant treatments ...........................................................53
4.2.2
Restrictions............................................................................................54
4.2.2.1
Restrictions regarding concomitant treatment .........................54
4.2.2.2
Restrictions on diet and life style.............................................56
4.3
TREATMENT COMPLIANCE.......................................................................56
4.3.1
BI 836845 ...............................................................................................57
4.3.2
Everolimus and exemestane.................................................................57
4.3.3
Compliance Assessment........................................................................57
4.4
MANAGEMENT OF EXPECTED ADVERSE EVENTS.............................58
4.4.1
Management of oral mucositis.............................................................58
4.4.1.1
Mouth care ...............................................................................58
4.4.1.2
Treatment of established mucositis..........................................59
4.4.2
Management and grading of infusion reactions.................................59




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6.
INVESTIGATIONAL PLAN.................................................................. 83
6.1
VISIT SCHEDULE............................................................................................83
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................84
6.2.1
Screening and run-in periods...............................................................84
6.2.1.1
Screening period ......................................................................84
6.2.1.2
Phase I part run-in period (from Day -7 to -1).........................84
6.2.2
Treatment periods.................................................................................84
6.2.2.1 Phase I part...............................................................................85
6.2.2.2 Phase II part .............................................................................86
6.2.3
End of trial and follow-up period........................................................87
6.2.3.1
End of treatment visit...............................................................87
6.2.3.2
Follow-up.................................................................................87
6.2.3.3
Observation period...................................................................88
6.2.3.4
End of Trial..............................................................................89
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 90
7.1
STATISTICAL DESIGN – MODEL ...............................................................90
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................90
7.3
PLANNED ANALYSES....................................................................................90
7.3.1
Primary analyses...................................................................................90
7.3.2
Secondary analyses ...............................................................................91
7.3.2.1 Other analyses ............................................................................91
7.3.3
Safety analyses.......................................................................................92
7.3.4
Interim analyses ....................................................................................92
7.4
HANDLING OF MISSING DATA ..................................................................94
7.5
RANDOMISATION ..........................................................................................95
7.6
DETERMINATION OF SAMPLE SIZE ........................................................95
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS ................................................................................................ 99
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................99
8.2
DATA QUALITY ASSURANCE ...................................................................100




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ABBREVIATIONS
aBC/mBC
ADA
AE
AESI
ALT (SGPT)
AST (SGOT)
Locally advanced/metastatic Breast Cancer
Anti-Drug Antibody
Adverse Event
Adverse Event of Special Interest
Alanine amino Transferase (Serum Glutamate Pyruvate Transaminase)
Aspartate amino Transferase (Serum Glutamic Oxaloacetic Transaminase)
BOLERO-2
Breast cancer trials of OraL EveROlimus-2
CI
Confidence Interval
CML
CR
Local Clinical Monitor 
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
DC
DILI
DLT
Clinical Trial Report
Disease Control (also called Clinical Benefit)
Drug-Induced Liver Injury
Dose Limiting Toxicity
DMC
Dlco
Data Monitoring Committee
Carbon Monoxide Diffusing Capacity 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EudraCT
ER+
EOTV
European Clinical Trials Database
Estrogen Receptor positive
End of Treatment Visit
FAS
FU
Full Analysis Set
Follow up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
HER2∀
HR+
Human Epidermal growth factor Receptor 2 negative
Hormone Receptor positive
IB
Investigator’s Brochure
IEC
IGF
IGF-1R
IGF-2R
INR
InsR
Independent Ethics Committee
Insuline-like Growth Factor
Insuline-like Growth Factor-1 Receptor
Insuline-like Growth Factor-2 Receptor
International Normalized Ratio
Insulin Receptor


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IRB
IRT
Institutional Review Board
Interactive Response Technologies
ISF
Investigator Site File
i.v.
Intravenous
IVRS
Interactive Voice Response System
IWRS
mAb
Interactive Web-based Response System
Monoclonal Antibody
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
mTOR
Maximum Tolerated Dose
mammalian Target Of Rapamycin
OPU
Operative Unit
p.o.
per os (oral)
PD
PD
PFS
P-gp
PI3K
PR
PTM
Pharmacodynamics
Progressive Disease
Progression Free Survival
P-glycoprotein
Phosphoinositide 3-kinase
Partial Response
Planned Time
q.d.
RECIST
RP2D
quaque die (once a day)
Response Evaluation Criteria in Solid Tumors
Recommended Phase II Dose
SAE
Serious Adverse Event
s.c.
SD
SNPs
Subcutaneous
Stable Disease
Single nucleotide polymorphisms
SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TMM
Team Member Medicine
TSAP
Trial Statistical Analysis Plan


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Breast cancer is the most common malignancy in women worldwide. It is estimated that more 
than 1.6 million new cases of breast cancer occurred globally among women in 2010 (R13-
2186). Even though death rates have fallen steadily since 1990, reflecting improvements in 
early detection and treatment, currently breast cancer is the second leading cause of cancer-
related death in women (R09-5656). This high death rate reflects the limited effectiveness of 
current therapeutic options, particularly in patients with advanced disease. 
Approximately 75% of primary breast cancers are positive for hormone receptor (HR+). 
These cancers express Estrogen Receptor (ER) and/ or Progestone Receptor (PgR). Therapies 
directed at endocrine receptors are important treatment option. For postmenopausal HR+ 
breast cancer, an aromatase inhibitor (AI), such as letrozole and anastrozole, is the 
recommended first-line therapy for management (P13-05504). Unfortunately, not all patients 
have a response to first-line endocrine therapy (primary or de novo resistance), and even 
patients who have a response will eventually relapse (acquired resistance). On disease 
progression, second-line treatment options include other classes of aromatase inhibitors 
(steroidal or nonsteroidal) and the estrogen-receptor (ER) antagonists fulvestrant and 
tamoxifen (R13-2054).
De novo and acquired resistance to endocrine therapy presents a major challenge in the 
management of HR+ breast cancer and is an area under intense investigation. The 
mammalian target of rapamycin (mTOR) pathway has been shown to play an important role 
in the resistance to endocrine therapy. Two recently published reports showed that a novel 
mTOR inhibitor everolimus combined with endocrine therapies were of benefit.  In hormone 
refractory, hormone receptor-positive, HER2-negative metastatic breast cancer patients,
tamoxifen plus everolimus resulted in increased clinical benefit compared to tamoxifen alone 
with improved time to progression (PFS 8.6 vs. 4.5 months) and overall survival (55% 
reduction in the risk of death associated with combination therapy, HR, 0.45; 95% CI, 0.24 to 
0.81; exploratory P=007) (R13-1976). In a similar patient population, the Phase III Breast 
Cancer Trial of Oral Everolimus 2 (BOLERO-2) (R12-5635) demonstrated that treatment 
with everolimus plus exemestane more than doubled median progression-free survival to 7.8 
months compared with 3.2 months for those treated with exemestane alone (hazard ratio, 
0.45; 95% confidence interval, 0.38 - 0.54; one-sided log rank P < .0001) by local 
investigator assessment (R12-5281). The overall response rate was also improved compared 
to exemestane alone (12.6 % vs. 1.7%) (R12-5281).  Based on the result of this trial, 
everolimus, as the first drug in the mTOR class, was approved by the regulatory agency for 
the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-
negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of 
treatment with letrozole or anastrozole (R12-5281).
The insulin-like growth factor (IGF) pathway holds crucial role in cell growth, differentiation 
and proliferation. The insulin-like growth factor family encompasses three ligands, IGF-1, 
IGF-2, insulin; their corresponding receptors IGF-1 receptor (IGF-1R), IGF-2 receptor (IGF-


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2R), Insulin-Receptor (InsR) (two isoforms: InsR-A and InsR-B); and six ligand-binding 
proteins, IGF-binding proteins (IGFBP1-6) and IGFBP degrading enzymes known as 
proteases (R13-2052, P13-05658). Activation of IGF-1R triggers a cascade of reactions 
involving two main signal transduction pathways: the Ras–Raf–mitogen-activated protein 
kinase (MAPK) network and the phosphatidylinositol 3-kinase (PI3K)–Akt–mTOR pathway. 
Certain transcription factors have been identified to be impaired by this IGF-mediated 
signaling process and involved in breast carcinogenesis (R13-1986, R13-1995, R13-1996).
Preclinical and clinical data indicated that aberrant regulation of the IGF system is attributed 
to the pathogenesis of breast cancer and also contributes to various stages of breast 
carcinogenesis. IGF-1R over-expression is common in breast cancer cell lines and fresh 
tumor biopsies (R13-2004, P13-05525, R13-2010), and IGF activity captured in a microarray 
signature has been associated with poor clinical outcome (P13-05658). Bidirectional crosstalk 
between the oestrogen and the IGF signalling pathways is well documented (R13-1983, R13-
1984) with activation of the latter mediating endocrine resistance (R13-2185). In ER+ breast 
cancer resistant to hormonal therapy, InsR-A isoform is the predominant insulin receptor, 
suggesting an important role for IGF-2 signaling (R13-1976). Therefore, the IGF signalling 
network represents a promising target in advanced breast cancer.
Currently there are three different strategies inhibiting IGF pathways including anti-receptor 
monoclonal antibodies (ganitumab, cixutumumab, and dalotuzumab), tyrosine kinase 
inhibitors (TKI, including dual IGF-1R and InsR tyrosine kinase inhibitors BMS-754807, 
KW2450, and linsitinib), and anti-IGF ligand antibodies (dusigitumab (MEDI-573,
 
) and BI 836845) (R13-1980). These agents are now being tested in the 
clinic either as monotherapy or in combination with cytotoxic agents and/or other 
molecularly targeted agents (P13-05658). 
The major advantage of neutralizing antibodies for both IGF-1 and IGF-2 is that the 
sequestration of the ligands ensures that receptor activation by IGF-1 or IGF-2 does not 
occur, and eliminates the possibility of activation of the InsR-A by IGF-2. Hence it offers a 
balanced approach with therapeutic potential in a variety of cancers, with few of the pitfalls 
of targeting the IGF-1R with monoclonal antibodies (mAbs). Currently, BI 836845 and 
dusigitumab are the only agents in development using this approach (R13-1980).
A potential mechanism of resistance to mTOR inhibitor therapy is the induction of AKT 
phosphorylation, which is frequently observed in both preclinical and clinical studies [R13-
3257, R08-5567, R11-4665, R11-4672]. Furthermore, up-regulation of AKT activity is 
dependent on Insulin-like growth factor (IGF)/Insulin like growth factor type 1 receptor 
(IGF-1R) signaling [R13-3257, R08-5567, R11-4665, R11-4672]. It has been shown in 
tumors that inhibition of mTOR with rapalogs releases a negative feedback loop on growth 
factor receptors, including the insulin-like growth factor-1 receptor/insulin receptor substrate 
(IRS)-1 complex, resulting in activation of IGF-1R signaling and ultimately phosphorylation 
of AKT (R08-5567, R11-4672), which in turn could potentially counteract the anti-tumor 
effects of mTOR inhibitors. The activation may be prevented if IGF signaling is blocked 
simultaneously (R13-2053). 


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In preclinical models, dual inhibition of both IGF-1R, with monoclonal antibodies or tyrosine 
kinase inhibitors, and mTOR, results in a superior anti-proliferative effect compared with 
inhibition of each target alone (R13-1987). In a Phase I trial using IGF-1R antibody
cixutumumab in combination with temsirolimus in a heavily treated metastatic breast cancer 
patients, no objective response were observed, but four patients experienced stable disease 
that lasted for at least 4 months (R13-2183). 
Another Phase I clinical study combining ridaforolimus (a rapalog) and dalotuzumab (an 
antibody targeted against IGF-1R) reported remarkable clinical activity in breast cancer 
(R13-2056). More specifically, of 23 breast cancer patients enrolled at the time of analysis, 5 
had efficacy signals (2 PRs, 1 SD for 9 months, and 2 partial metabolic responses (PMRs) on 
FDG-PET scan); all 5 patients were ER+, and 4 had high Ki67 breast tumors. This 
combination is now being explored in a larger, Phase II study restricted to women with HR-
positive metastatic breast cancer (R13-2047). 
Taken together, these results justify the evaluation of the IGF network as a therapeutic target 
in HR+ breast cancer, in combination with Everolimus.
1.2
DRUG PROFILE
1.2.1 
BI 836845
BI 836845 is a fully human monoclonal antibody of the IgG1 isotype that binds to human 
insulin-like growth factor-1 and insulin-like growth factor-2 and thereby neutralizes the 
growth-promoting activities of 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). The four polypeptide chains of the 
antibody molecule are linked together by disulfide bonds. Each heavy polypeptide chain 
contains one consensus sequence for N-linked glycosylation, which is occupied. There are 
two binding sites for IGF-1 and IGF-2 per antibody molecule. The antibody protein has a 
molecular mass of approximately 146 kDa.
BI 836845 binds with high affinity to IGF-1 and IGF-2, and potently neutralizes the 
proliferative and prosurvival cellular signaling triggered by both proteins. The mode of action 
of BI 836845 is different from IGF-1 receptor targeted mAbs. In particular, BI 836845 can 
inhibit IGF-2 stimulated Insulin Receptor-A activation, which is an additional proliferative 
and prosurvival pathway not blocked by IGF-1R targeted mAbs (U10-2830). In addition, by 
sparing InsR-B and its hybrid receptors, BI 836845 may achieve antitumor activity without 
perturbing glucose homeostasis. 
Preclinical study showed that BI 836845 treatment inhibited the rapamycin-induced feedback 
phosphorylation of AKT in PI3K-AKT-mTOR pathway. Similarly, rapamycin resulted in an 
increase in the IGF bioactivity (IGF-1R phosphorylation potential) of mouse serum, which 
could be inhibited by BI 836845 (P12-07179).


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In animal study, the Cynomolgus monkeys and rats were selected as relevant species for the 
investigation of the preclinical safety because the monkeys show a 100% sequence homology 
to human IGF-1 and IGF-2, and comparable binding affinities to BI 836845 were 
demonstrated in rats. For BI 836845, safety pharmacology (core battery) endpoints integrated 
in the Cynomolgus monkeys toxicity study demonstrated a favourable safety profile. There 
were no effects of treatment on neurological parameters, auditory response, respiratory rate, 
body temperature or cardiovascular function.
Repeat-dose toxicity studies with once weekly intravenous administration of BI 836845 for 
13 weeks in Cynomolgus monkeys and for 13 or 26 weeks in rats revealed 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 neutralization 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 of 
no toxicological relevance.
Glomerulopathy (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. On the other hand, a higher 
incidence and severity of interstitial structures called ‘persistent granulosa cell nests 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, even 
though fully pharmacologically active doses were achieved in both species in terms of the 
reduction of IGF-1R phosphorylation potential (IGF bioactivity) in the plasma. Similar to 
rats, exposure to BI 836845 induced a weak increase in blood glucose levels up to upper limit 
of normal, fructosamines and HbA1c in male Cynomolgus monkeys given 30 or 100 mg/kg 
(equivalent to 10 to 32 mg/kg human equivalent dose - HED). 
Based on the studies summarized above, the preclinical safety profile of BI 836845 is 
considered to be favorable for the intended oncological indications (U10-2830). 
Two Phase I studies with BI 836845 monotherapy given weekly or every three weeks are 
conducted in patients with advanced solid tumors.  These studies are intended to determine 
the safety, maximum tolerated dose and/ or relevant biological dose, pharmacokinetics (PK) 
and PK/pharmacodynamic (PD) correlation. Preliminary interim data from these trials 
indicate that maximum plasma concentrations of BI 836845 were observed at the end of the 


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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 (approx. two times the plasma volume) and the total plasma 
clearance was about 0.5 mL/min. The incidence of anti-drug antibodies (ADA) was approx. 
19% in 1280.1 and 30% in 1280.2. Overall, the ADA-response was weak, dose-independent 
and in many cases transient and had no impact on PK or PD.
No deviations from dose-proportional pharmacokinetics have been observed in the dose 
range tested (10-1050 mg qw in 1280.1 and 10-3600 mg q3w in 1280.2). Steady state plasma 
concentrations of BI 836845 were achieved after 5-7 weeks. Repeated weekly dosing resulted 
in about 1.5 fold accumulation of BI 836845 plasma concentration at steady state, while only 
limited accumulation was observed after repeated infusions every three weeks. 
It is known that human IgGs like BI 836845 are mainly cleared by catabolism. This 
mechanism of clearance is not shared or overlapping with the clearance mechanism for small 
molecules. Thus, BI 836845 is not predicted to directly affect the hepatic, renal, or biliary 
elimination of small molecules. Furthermore, BI 836845 is not targeting cytokines, and mAbs 
targeting upstream IGFs have not been related to modulation of CYP450 isozymes or drug 
transporters (P13-02270). Hence, the potential of BI 836845 to alter the pharmacokinetics of 
co-medication is considered low. 
BI 836845 has been formulated for i.v. infusion and will be provided as a liquid formulation. 
The appropriate dose of BI 836845 should be diluted in physiological sodium chloride 
solution (0.9%) prior to intravenous administration. 
As of July 10, 2013, 48 and 33 patients have been dosed in 1280.1 and 1280.2 trial using 
weekly and every three-week schedule, respectively. Among these two trials, only one dose 
limiting toxicity (DLT), a pulmonary hemorrhage, was observed at 450 mg (in the trial using 
weekly schedule), which was considered drug-related by the investigator. Consequently, 3 
additional patients were dosed at this level for a total of 6 patients, no additional DLT was 
observed. Four subjects in study 1280.2 discontinued treatment due to non drug-related AEs. 
A CTCAE grade 3 hyponatraemia (syndrome of inappropriate antidiuretic hormone secretion 
- SIADH) occurred in a single patient in the 3600 mg q3w cohort. As there is no connection 
to the mechanism of action of BI 836845, an alternative explanation may have been an 
underlying paraneoplastic syndrome. However, consequently, investigators should carefully 
monitor electrolytes and excretion under treatment with BI 836845.
Dose escalation to 1800 mg weekly or 3600 mg q3w did not identify a maximum-tolerated 
dose (MTD).
Based on toxicity studies the side effects expected with BI 836845 are possibly abnormal 
liver function tests and changes in haematological parameters (reduced white and red blood 
cells). However, abnormal liver function tests as well as anaemia and decreased white blood 
cells were only infrequently observed in the 81 patients treated thus far in Phase I and 
generally of low grade (grade 1 and 2).


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Infusion reactions have not been observed. Metabolic AEs involving perturbed glucose 
homeostasis, among the most common toxicities documented for IGF-1R-targeting mAbs and 
small molecule TKIs, were observed at low frequencies: Two out of 81 subjects reported 
transient hyperglycemia; 1 patient (Grade 2) in 1280.1 and 1 patient (Grade 3) in 1280.2.
Of note, two confirmed partial responses (PR) have been reported in the weekly schedule 
trial; firstly, in a 62-year old male with a recurrent nasopharyngeal carcinoma (NPC) and 
multiple lung metastases after concurrent chemoradiotherapy; secondly, in a 19-year old 
woman with a peripheral primitive neuroectodermal tumor (pPNET). In addition, twelve 
(25.0%) and four (12.1%) patients with confirmed stable diseases were reported in study 
1280.1 and 1280.2, respectively.
Full details of the clinical pharmacology, toxicology, clinical pharmacokinetics and safety 
data can be found in the current Investigator Brochure for BI 836845 (U10-2830).
1.2.2
Everolimus
Everolimus (RAD001, Afinitor®, 
) is the 40-O-(2-hydroxyethyl) derivative of 
sirolimus; it inhibits mTOR by binding with high affinity to its intracellular receptor FKBP12, 
resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus 
inhibits mTOR kinase activity. 
Everolimus has been developed as both an immunosuppressant for the treatment of transplant 
organ rejection and as an anticancer agent (R13-2184). A phase 1 study conducted in solid 
tumor patients identified mucositis and fatigue as dose-limiting toxicities when everolimus 
was administered as a single agent using a weekly schedule. Everolimus was rapidly 
absorbed with a Tmax of 0.5-2.5 h, exposure was dose proportional over the therapeutic dose 
range (2.5 – 25 mg), with steady-state concentrations achieved within 7 days or less 
following once-daily dosing (R08-5716, R13-0654, R13-0655). Its terminal half-life is 30 h 
(range, 26–38 h). Metabolism of everolimus occurred primarily in the gut and liver by 
cytochrome P450 3A4, 3A5 and 2C8, with the majority of drug (approximately 98%) 
excreted in the bile in the form of metabolites (R08-5716).
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the 
multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a 
mixed inhibitor of CYP2D6 (R12-5281).
Everolimus is approved for various conditions: advanced hormone receptor-positive, HER2-
negative breast cancer, advanced neuroendocrine tumors of pancreatic origin, advanced renal 
cell carcinoma, renal angiomyolipoma with tuberous sclerosis complex and subependymal 
giant cell astrocytoma with tuberous sclerosis complex. Additionally, biologic activity has 
been seen in a variety of tumors, including gastric cancer, hepatocellular carcinoma and 
lymphoma; worthy of mention, phase III trials are under way, in the aforementioned 
malignancies [website clinicaltrials.gov]. The approved treatment dose of everolimus in 
advanced HR+ BC is 10 mg daily (please refer to the most current drug precribing 
information for update).


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1.2.3
Exemestane
Exemestane is an irreversible, steroidal aromatase inactivator.  Exemestane structure is 
related to androstenedione, a natural substrate of the aromatase enzyme. Exemestane binds 
irreversibly to the active site of the enzyme and causes its inactivation. Exemestane inhibition 
of aromatase results in deep suppression of circulating estrogen concentrations in 
postmenopausal women, which is frequently below the detection limits of standard assays, 
but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Unlike 
tamoxifen, exemestane has no partial estrogen agonist activity (R13-0738).
Following oral administration to healthy postmenopausal women, exemestane is rapidly 
absorbed with a mean Tmax of 1.2 hours. After maximum plasma concentration is reached, 
levels decline polyexponentially with a mean terminal half-life of about 24 hours. The 
pharmacokinetics of exemestane is dose proportional after single (10 to 200 mg) or repeated 
oral doses (0.5 to 50 mg). Its steady-state was achieved within 7 days following once-daily 
dosing (R13-0766). Exemestane is extensively distributed and is cleared from the systemic 
circulation primarily by metabolism. Studies using human liver preparations indicate that 
CYP 3A4 is the principal isoenzyme involved in the oxidation of exemestane. It does not 
inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. 
Exemestane plasma levels increased after a high-fat breakfast. Exemestane is mainly excreted 
from urine and feces (R13-0738).
Exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral 
density and increased risk of fracture, which do not appear to persist at follow-up, with 
subsequent return to pretreatment values. Compared with tamoxifen, there is a reduced 
incidence of endometrial changes, thromboembolic events, and hot flashes. Limited evidence 
shows nonadherence in 23%–32% of patients. Evidence is growing in support of exemestane 
in all clinical settings. It is generally more efficacious and has a better safety profile than 
tamoxifen (R13-0738). How it compares with the nonsteroidal aromatase inhibitors remains 
to be established (R13-1990). 
Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal 
women whose disease has progressed following tamoxifen or anti-oestrogen therapy.  The 
approved treatment dose of exemestane is 25 mg taken once daily after a meal (please refer to 
the most current drug precribing information for update).






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As of 16 Apr 2014, the ten most common treatment-emergent AEs regardless of relatedness 
are shown below:
#
1280.1 (weekly schedule): decreased appetite, anemia, back pain, weight decreased, 
dizziness, fatigue, cough, dyspnea, abdominal distension, and ALT increased.
#
1280.2 (3-weekly schedule): abdominal pain, diarrhea, nausea, vomiting, fatigue, 
decreased appetite, constipation, hypokalemia, back pain, and dyspnea.
No listed AEs are established so far. Since there is currently no relationship with dose and 
with IGF-mediated mechanisms, AEs which are truly drug-related and those that are possibly 
a reflection of the underlying cancer or concomitant illnesses cannot be differentiated at this 
point in time.
Although BI 836845 is a fully humanised antibody given intravenously, there may be a 
potential for infusion-related reactions and immune responses to occur. Such infusion 
reactions will be graded and treated following standard of care or local guidance. Out of 81
patients who received BI 836845; no infusion reaction has been observed (U10-2830). The
immune responses to BI 836845 mAb will be assessed through anti-drug antibody in the 
study.
The class-effect AEs of everolimus include: epithelia-cutaneous events (stomatitis and skin 
rash), metabolic abnormalities (hyperglycemia and hyperlipidemia), immunosuppression 
(infection), and non-infectious pneumonitis. The toxicity profile of BI 836845 and 
everolimus plus exemestane appears not overlapping. However, some caution is warranted 
when co-targeting both systems. mTOR inhibitors disrupt negative intracellular feedback 
loops and enhance IGF/insulin signaling and subsequent PI3K/AKT activation (R11-4670), 
which in turn may aggravate everolimus-related adverse events (especially mucositis and 
metabolic disturbance including hyperglycemia). Therefore, it is conceivable that BI 836845 
may increase the efficacy as well as the side effects of everolimus, depending on whether 
resistance to mTOR inhibition is restricted to the tumor - or also occurs in normal tissue, for 
example the mucosae (stomatitis). Evidence of support may be seen from a phase II study of 
single agent temsirolimus in patients with metastatic breast cancer (R13-1971), in which 16% 
of patients experienced grade 2 stomatitis. In contrast, in a similar patient population using a 
combination of cixutumumab (a monclonal antibody targeting IGF-1R) and temsirolimus, 
36% of patients experienced grade 2 or higher stomatitis (R13-1991). The possibility of 
enhanced class-effect AEs of everolimus by adding BI 836845 could be considered from the 
underlying mechanisms of those class effects. The stomatitis lesions of everolimus are similar 
to aphthous or herpetic ulcers and are different to chemotherapy-induced mucositis. mTOR 
inhibitor-induced stomatitis is believed to be caused by a T cell mediated inflammatory 
reaction. Non-infectious pneumonitis is a non-malignant inflammatory infiltration of the 
lungs that is associated with the use of rapamycin derivatives. The immunosuppressive 
properties of mTOR inhibitors may predispose patients to localized and systemic infections. 
So far, the clinical AE pattern of BI 836845 is less likely to be associated with 
immunosuppression, immune cells disturbance, or inflammation.
Early, proactive, and effective management of stomatitis is mandated in this study (see 
Section 4.4 for guideline). Fasting serum glucose level and lipid profiles will be assessed 


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monthly throughout the study for metabolic related adverse events; endocrinologist or 
specialist care access is required in case of grade 3 or higher event including hyperglycemia. 
Furthermore, patients with grade 2 or higher hyperglycemia will be excluded at the study 
entry; prolonged systemic corticosteroid treatment will also be prohibited during the study.
Weight loss should be monitored closely. Nutritional consultation may be recommended 
early and nutrition support including tube feeding or total parenteral nutrition should be 
provided if indicated.
Although rare, a potential for drug-induced liver injury 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. 
A steering committee will oversee the conduct of the trial. A Data Monitoring Committee 
(DMC, internally at the sponsor) will be appointed to periodically review and monitor the 
data from Phase II part of the trial.
In conclusion, given the life-threatening situation of the advanced/metastastic breast cancer, 
potential benefits expected from BI 836845 in combination with everolimus and exemestane 
treatment is anticipated to outweigh its risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This clinical trial will involve two components: a dose finding Phase I part followed by a 
two-arm, open-label, randomized Phase II part. As the steady state of everolimus and 
exemestane is reached in about 7 days (R08-5716, R13-0654, R13-0655), to assess the 
pharmacokinetic and biomarker effect, a run-in treatment with exemestane and everolimus
for 7 days prior to commencing the combination therapy with BI 836845 in the Phase I part is 
mandated. In addition, given the elimination half-life of all study drugs, the (first) follow-up 
visit is scheduled 42 days after last dose of study drug administration in order to assess the 
PK, biomarker and immunogenicity of BI 836845 when study drugs have been eliminated 
from the body.
Patients are included in the study once the informed consent is signed. The screening period 
will be up to 4 weeks (28 days) during which time the eligibility will be confirmed. The 
eligibility criteria will be reconfirmed prior to the first administration of study medications, 
eligible patients will be treated continuously with the study regimen in the absence of disease 
progression, intolerable adverse events, or other reason necessitating withdrawal (refer to 
Section 3.3.4). The treatment will be administered as courses of 28 days. Continued treatment 
beyond disease progression will not be allowed in the study.
Tumor response and progression will be assessed using RECIST 1.1 (R09-0262). Assessment 
at the investigator site will be used to make decisions on eligibility and continuation of 
treatment.
Phase I part:
Initially a “3+3” Phase I dose finding study will be performed to determine the Maximum 
Tolerated Dose (MTD), Recommended Phase II dose (RP2D) and pharmacokinetics of 
BI 836845, everolimus and exemestane in women with HR+/HER2∀advanced breast cancer. 
It is estimated that approximately 18 patients at RP2D are needed to evaluate 
pharmacokinetics and a potential impact of BI 836845 on the pharmacokinetics of 
exemestane and everolimus. Once the RP2D is determined in approximately 12 evaluable 
patients, the Phase II part of the trial will commence. Meanwhile, 6 additional patients will 
continue to be enrolled at RP2D in the phase I part to evaluate pharmacokinetics and a 
potential impact of BI 836845 on the pharmacokinetics of exemestane and everolimus. 
After screening, eligible patients will start the run-in with everolimus and exemestane for 
seven consecutive days prior to commencing the combination therapy of everolimus and 
exemestane with BI 836845. Patients participating in the Phase I part will be concluded after 
the completion of the follow-up visit.  
The diagram below depicts the stages of a patient’s participation in the Phase I part of the
protocol.






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recruitment issues, data quality, etc.). A steering committee charter will be prepared to 
specify the objectives of the committee.
A BI internal data monitoring committee (DMC) will be appointed to periodically assess the 
Phase II data, including the aggregated data at the treatment level to ensure overall safety and 
integrity of the trial. Moreover, the DMC will meet at two additional pre-specified timepoints 
to have a look at efficacy data with emphasis on the primary endpoint. More details on the 
evaluations and the DMC responsibilities can be found in Section 7.3.4 as well as in the 
DMC charter.
Inclusion of patients in the Phase II trial will continue during the scheduled meetings of the 
DMC. Decisions on trial termination, amendment or cessation of patient recruitment, based 
on safety or outcome findings will be made after recommendations from the DMC have been 
assessed by the trial team and steering committee.
BI will appoint CROs and independent service providers for special services such as storage 
and potential central analysis of tumour images, central laboratory services for biomarker 
testing and part of bioanalytical testing, biosample collection and logistics, ECG, and 
Interactive Response Technologies (IRT) for randomisation and trial medication logistics.
The analysis of biomarker and PK will be performed by BI or a CRO appointed by BI.
On-site monitoring will be performed by BI or Contract Research Organisations (CRO) 
appointed by BI.
All trial relevant documentation will be stored in the clinical trial master file (CTMF) at BI. 
In addition each site will have an Investigator Site File (ISF) containing all trial documents 
relevant for the site.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Phase I part
The ‘3+3’ up-and-down design is a classic dose-finding design for Phase I clinical studies in 
oncology, requiring no control group. As no data on the optimal dose for the BI 836845/ 
everolimus/exemestane combination therapy exist so far, the study will first determine the 
MTD and RP2D of the triple drug regimen prior to further exploring its anti-tumor activity in 
the Phase II part.
Phase II part
Due to the inherent differences between the two treatment arms, i.e. continuous oral treatment 
with intravenous infusion in the BI 836845 containing arm versus continuous oral treatment 
only in the control arm, the trial will be open-label.  Since the only way to conduct this as a 
blinded trial would have been the addition of an i.v. placebo to the control arm, which is not 
ethically acceptable in an exploratory Phase II setting. 


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However, steps to minimize potential bias are in place for this open-label clinical trial. These 
include the use of a central randomisation method and the blinding of the trial team to 
treatment level aggregated data until database lock.
3.3
SELECTION OF TRIAL POPULATION
Phase I part
It is estimated that a total of about 21 to 48 evaluable patients will be necessary to determine 
the MTD, the Recommended Phase II Dose and pharmacokinetics of BI 836845, everolimus 
and exemestane. 
The Phase I part of the trial will be conducted in about six to twelve centers in Europe. If 
needed, centers from other region such as Asia may also participate. Each center is expected 
to enroll about one to three patients. If center(s) are unable to recruit patients, additional 
centers may be opened and underperforming centers may be closed.
Phase II part
In the Phase II part, approximately 150 patients will be randomized at approximately 45 
study sites globally. The rate of randomization will vary by study site, but is expected to be 
approximately 3 to 4 patients per site. Additional country may be added if necessary.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Enrollment is competitive. Investigators will be notified when the appropriate number of 
patients has been screened and screening is complete, thereafter additional patients will not 
be allowed to recruit for this study. Patients who have signed an informed consent and are 
eligible prior to notification of the termination of recruitment will be allowed to continue in 
the study.
3.3.1
Main diagnosis for study entry
3.3.2
Inclusion criteria
1. Histologically-confirmed locally advanced (aBC) or metastatic breast cancer (mBC) 
not deemed amenable to curative surgery or curative radiation therapy
2. Tumors are positive for estrogen-receptor (ER) and/or progesterone receptor (PgR). 
Tumors must be negative for HER2 per local lab testing. ER, PgR and HER2 status 
previously assessed by local lab is acceptable
3. Must have adequate archival tumor tissue from surgery or biopsy (refer to 
Section 5.3.3 and Section 5.6.3.3 for details). If multiple surgeries/biopsies are 
available for individual patient, the most recent and/or the most appropriate tissue 
material is requested  


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4. Postmenopausal female patients aged ≥18 years old. Postmenopausal status is defined 
either by:
a. Age ≥ 55 years and one year or more of amenorrhea
b. Age < 55 years and one year or more of amenorrhea, in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression, and FSH and
estradiol within postmenopausal ranges as per insititution standard/normal 
practice. 
c. Surgical menopause with bilateral oophorectomy
5. Objective evidence of recurrence or progressive disease on or after the last line of 
systemic therapy for breast cancer prior to study entry
6. The patient is disease refractory to non-steroidal aromatase inhibitor (letrozole and/or 
anastrozole): defined as recurrence during or within 12 months after the end of 
adjuvant treatment or progression during or within 1 month after the end of aromatase 
inhibitor treatment for locally advanced or metastatic disease
Note: Letrozole or anastrozole do not have to be the most recent treatment. Prior 
anticancer therapy, e.g. tamoxifen, fulvestrant are allowed
7. Patients must have 
a. Measurable lesion according to RECIST version 1.1 (R09-0262) or
b. Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable 
lesion as defined above
Both, 7a and 7b above must fulfil the condition described in Section 5.1.2 for irradiated 
tumors.
8. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score ≤ 2. 
Refer to APPENDIX 10.2
9. Life expectancy of ≥ 6 months in the opinion of the investigator
10. Fasting plasma glucose < 8.9 mmol/L (< 160 mg/dL) and HbA1c < 8.0% 
11. Adequate organ function, defined as all of the following:
a) Absolute neutrophil count (ANC) ≥ 1500/mm3
b) Platelet count ≥100,000/mm3
c) International Normalized Ratio (INR) ≤ 2.0
d) Serum creatinine ≤ 1.5 times ULN. 
e) Total Bilirubin  ≤ 1.5 times upper limit of institutional normal (patients with 
Gilbert syndrome total bilirubin must be < 4 times institutional upper limit of 
normal)


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f)
Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤ three 
times the upper limit of institutional normal (ULN) (if related to liver metastases ≤ 
five times ULN)
g) Fasting triglycerides ≤300 mg/dL or 3.42 mmol/L
h) Hemoglobin (Hgb) ≥ 9.0 g/dL
12. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry 
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
13. Written informed consent that is consistent with ICH-GCP guidelines and local 
regulations
Optional fresh biopsy substudy for the Phase II part:
Inclusion criteria for the biopsy substudy are identical to the main study of the phase II part 
except for the following two inclusion criteria:
#
Fresh tumor biopsy should be taken when deemed safe and feasible by the 
investigator and upon informed consent by the patient. Bone lesion is not 
recommended for biopsy
#
Patients eligible to undergo tumor biopsy should have normal coagulation parameters 
(INR and PTT within normal range)
3.3.3
Exclusion criteria
Phase I part:
1. Previous treatment with agents targeting on IGF pathway, phosphoinositide 3-kinase 
(PI3K) signaling pathway, protein kinase B (AKT), or mammalian target of 
rapamycin (mTOR) pathways (sirolimus, temsirolimus, etc.)
2. Prior treatment with exemestane (except adjuvant exemestane stopped > 12 months 
prior to start of study treatment as long as the patient did not recur during or within 12 
months after the end of adjuvant exemestane)
3. Known hypersensitivity to monoclonal antibody, mTOR inhibitors (e.g. sirolimus), or 
to the excipients of any study drugs
4. Ovarian suppression by ovarian radiation or treatment with a luteinizing hormone-
releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate)
5. Less than one week after receiving immunization with attenuated live vaccines prior 
to study treatment


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6. Radiotherapy within 4 weeks prior to the start of study treatment, except in case of 
localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture 
which can then be completed within two weeks prior to study treatment   
7. Chemotherapy, biological therapy (other than bevacizumab), immunotherapy or 
investigational agents within 5 half-life of the drug or within two weeks prior to the 
start of study treatment, whichever is longer; bevacizumab treatment within 4 weeks 
prior to start of study treatment (this criterion concerns anti-cancer therapy only)
8. Hormonal treatment for breast cancer within 2 weeks prior to start of study treatment  
9. Major surgery in the judgement of the investigator within 4 weeks before starting 
study treatment or scheduled for surgery during the projected course of the study
10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids 
use except in cases outlined below:
a. Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways 
diseases), eye drops or local injections (e.g. intra-articular) are allowed
b. Patients on stable low dose of corticosteroids for at least two weeks before 
study entry are allowed
11. Chronic hepatitis B infection (defined as presence of HBsAg and/ or HBV- DNA), 
chronic hepatitis C infection (defined as presence of anti-HCV Ab and/or HCV-RNA) 
and/or known HIV carrier
12. QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the 
investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the 
mean of the 3 ECGs taken at screening (see Section 5.2.4)
13. Disease that is considered by the investigator to be rapidly progressing or life 
threatening such as extensive symptomatic visceral disease including hepatic 
involvement and pulmonary lymphangitic spread of tumor (subjects who are intended 
for urgent chemotherapy) 
14. History or current presence of brain or other CNS metastases
15. Bilateral diffuse lymphangitic carcinomatosis (in lung)
16. Hypokalemia of Grade >1
17. History of another primary malignancy within 5 years, with the exception of 
adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell 
carcinoma or non-melanomatous skin cancer
18. Family history of long QT syndrome


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19. Any concomitant serious illness or organ system dysfunction which in the opinion of 
the investigator would either compromise patient safety or interfere with the 
evaluation of the safety and anti-tumor activity of the test drug(s) such as:
a) History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure, New York Heart Association 
(NYHA, refer to Appendix 10.1) functional classification of 3 or 4, unstable angina 
or poorly controlled arrhythmia, including any type of atril fibriliation. Myocardial 
infarction within 6 month prior to the study entry
b) Impairment of gastrointestinal function or who have gastrointestinal disease that 
may significantly alter the absorption of study drugs (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) , or any GI 
disorders of Grade > 1
c) Active skin, mucosa or ocular disorders of Grade > 1
d) Significant symptomatic deterioration of lung function. If clinically indicated, 
pulmonary function tests including measures of predicted lung volumes, DLco, O 2
saturation at rest on room air should be considered to exclude restrictive pulmonary 
disease, pneumonitis or pulmonary infiltrates
20. Patients being treated with drugs recognized as being strong or moderate CYP3A4 
and/or P-glycoprotein (PgP) inhibitors and/or strong CYP3A4 inducers within 2 
weeks (or use of amiodarone within 6 months) prior to study entry. Refer to Section 
10.3
21. Patients unwilling or unable to comply with study and follow-up procedures in the 
opinion of the investigator
22. Patients received more than two lines of chemotherapy for locally advanced or 
metastatic breast cancer
Note: A chemotherapy line in advanced/metastatic disease is an anticancer regimen(s) 
that contains at least 1 cytotoxic chemotherapy agent and given for 21 days or longer. 
If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease 
progression and lasted less than 21 days, then this regimen does not count as a "prior 
line of chemotherapy". Locally advanced / metastatic disease is to be understood as 
not amenable for curative therapy/surgery. Therefore chemotherapy agents in the
adjuvant/neoadjuvant setting should not be considered here.
Phase II Part:
Exclusion criteria for the Phase II part are identical to the Phase I part except t hat exclusion 
criteria number 22 of the Phase I part is replaced with the following exclusion criteria:
#
Patients received more than one line of chemotherapy for locally advanced or 
metastatic breast cancer


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient has to be withdrawn from study therapy in case any of the following applies:
1. The patient withdraws consent from study treatment
2. Documented progressive disease
3. The patient is no longer able to receive any of the study treatments (e.g. adverse 
events, 
concomitant 
diagnoses, 
surgery, 
concomitant 
medications
or 
administrative reasons)
4. An increase in QT/QTc to >500 ms or of >60 ms over baseline
5. Significant deviation from the protocol or eligibility criteria. The decision to 
continue or withdraw treatment will be made after discussion between the sponsor 
and the investigator
6. Further dose reductions considered necessary but not allowed according to the 
protocol (for exceptions, refer to Section 4.1.4.3)
A patient has to be considered to have completed the trial and any further study assessment 
(except the observation period for collection of vital status and further therapies) in case any 
of the following applies:
1. Documented progressive disease (refer to Section 5.1.2)
2. Start of new anti-cancer treatment
3. Withdrawal of consent
If possible, a patient who discontinues treatment for reasons other than the above criteria 
should continue to be followed up based on the tumor assessment schedule.
All patients who are included into the trial (i.e. having given informed consent) will have 
their data entered into the trial database. This includes patients who are considered screen
failures i.e. do not commence study drug treatment.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial, 


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3. Violation of GCP, the CTP, or the contract by a trial site or investigator, 
disturbing the appropriate conduct of the trial,
4. Decision to terminate the trial by the sponsor.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
premature trial termination (except in case of the third reason).
3.3.5
Replacement of patients
Phase I part:
Replacement of entered patients is only applicable in phase I part before the determination of 
MTD.
Patients will be replaced for the assessment of Dose Limiting Toxicity in cases of:
1) Patient’s withdrawal during the first cycle of treatment for reasons other than DLT, 
e.g. patient no longer wishes to participate, or lost to follow up during first cycle
2) Patients who do not experience DLT but miss ≥ one BI 836845 administration or ≥ 6
doses of everolimus in first treatment course
3) Patients who miss one complete cycle at any time beyond the first cycle of treatment 
may be replaced after discussion between the sponsor and the investigator
4) Patients who are non-evaluable with respect to DLT
5) Patients who miss more than one dose of everolimus or exemestane during the run-in 
period may be replaced after discussion between the sponsor and the investigator.
Patients that have been replaced might continue treatment in the trial should criteria in 
Section 4.1.4.2 apply; however these patients will not be considered for the evaluation of 
DLT.
Phase II part:
Patients who withdraw from the trial after randomisation/entering active treatment phase will 
not be replaced.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will receive BI 836845 plus everolimus and exemestane triple-drug combination or 
everolimus plus exemestane doublet therapy. The manufacturers for each of the products are 
listed in Section 4.1.1. 
4.1.1
Identity of BI investigational product and comparator products
4.1.1.1
BI 836845 (investigational product)
Substance:
BI 836845 human monoclonal antibody
Pharmaceutical form:
Liquid formulation
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml of BI 836845 supplied in 20 ml vials (200 mg/vial)
Weekly dose
1000 mg, 750 mg (starting dose)
Posology:
Once weekly administrated through one hour intravenous infusion. 
Infusion duration may be extended to over one hour and up to a 
maximum of three hours in cases of grade ≥ 2 infusion reactions
Route of administration: Intravenous infusion. Appropriate dose of BI 836845 will be 
diluted in isotonic sodium chloride solution (0.9%)
Duration of use:
Continuous weekly dosing (days 1, 8, 15 and 22 in a 28-day 
course) in the absence of disease progression, intolerable AEs or 
other reason necessitating withdrawal
Detailed preparation and handling of BI 836845, including information on infusion 
equipment and infusion procedure, will be described in ISF.
4.1.1.2
Everolimus (Afinitor®) (investigational product)
Everolimus is a registered commercially available drug and will be provided by the sponsor. 
However, if the recommended phase II dose of Everolimus is on label, e.g. 10 mg daily, for 
countries starting the trial with the phase II part, and if local regulation permits, Everolimus 
will be considered non-investigational product and hence, will be supplied by a pharmacy. 
For countries starting the trial with the phase I part, Everolimus will be supplied by the 
sponsor throughout the trial.
Pharmaceutical form:
Tablets


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Source:
 
(for EU countries) 
Unit strength:
2.5 mg and 5 mg
Daily dose:
Phase I part: Starting dose 10 mg continous daily at Cohort 1a. If 
necessary, dose deescalation will occur as outlined in Section 4.1.3
until determination of MTD and RP2D. In Phase II part, starting
dose will be 10 mg in arm 1 and RP2D in arm 2 as outlined in 
Section 3.1.1
Duration of use:
Continuous dosing in the absence of disease progression, 
intolerable AEs or other reason necessitating withdrawal
Route of administration: Oral (swallowed)
Posology:
       Once daily after a meal
Additional information:    Drug should be administered according to the summary of product 
characteristics for EU or the prescribing information for respective 
country
4.1.1.3
Exemestane (Aromasin®) (non-investigational product)
Exemestane is a registered commercially available drug; the generic version of exemestane is 
now available. Exemestane will not be provided by the sponsor.  Instead, it will be provided 
by a pharmacy.
Pharmaceutical form:
Tablets
Source:
 
or other companies with therapeutic equivalents
Unit strength:
25 mg
Daily dose
25 mg
Duration of use:
Continuous dosing in the absence of disease progression, 
intolerable AEs or other reason necessitating withdrawal
Route of administration: Oral (swallowed)
Posology:
       Once daily after a meal
Additional information:    Drug should be administered according to the summary of product 
characteristics for EU or the prescribing information for respective 
country. From the start of run-in period through Course 1 Day 8 of 


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phase I part, exemestane from the same manufacture must be used 
for PK evaluation
4.1.2
Method of assigning patients to treatment groups
4.1.2.1
The Phase I part:
Treatment slots are assigned by the BI Clinical Monitor (CM) in close communication 
(email/phone/fax) with the recruiting sites and IRT system and will be assigned on a 
competitive basis. After the BI Clinical Monitor has been notified by a site about a potential 
patient, the slot will be reserved to this site for a reasonable period of time until patient signs 
ICF. If more than one site notifies potential patients and there are no slots for all proposed 
candidates, BI Clinical Monitor will allocate the slot prioritizing by planned calendar, 
balanced number of patients per site and other parameters as needed.
Patients that meet the eligibility criteria and who have given their written informed consent 
will be entered into the study.
Before entering patients at the next dose level it will be ensured that all patients at an ongoing 
cohort have completed the first course. Prior to inclusion of a new patient, the investigator 
should confirm the respective dose with the BI clinical monitor. 
4.1.2.2
The Phase II part:
Patients that meet the eligibility criteria and who have given their written informed consent
will be randomized in a 1:1 ratio to everolimus plus exemestane (Arm 1) or BI 836845 plus 
everolimus and exemestane (Arm 2) treatment regimen.
Randomisation will be carried out centrally using Interactive Response Technologies (IRT, 
also called IVRS/IWRS).  The company that provides the IRT will receive the randomisation 
list from 
 or a CRO appointed by the 
sponsor. The BI standard validated random number generating system will be used to 
generate the randomisation schedules which will be verified by an independent statistician 
who is not involved in the study. The access to the randomisation code will be supervised by 
the 
; persons directly involved in the conduct and analysis of the 
trial will have no access to the randomisation schedule.
4.1.3
Selection of doses in the trial
4.1.3.1 Run-in treatment with everolimus and exemestane in the Phase I part
Prior to commencing the combination therapy with BI 836845 in the Phase I part, patients 
will receive treatment with exemestane 25 mg and everolimus for 7 days (from Day -7 to -1). 
The treatment dose of everolimus will depend on the treatment cohort the patient has been 
assigned to (e.g. 5 mg/d, 7.5 mg/d or 10 mg/d). 


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4.1.3.2
Determination of MTD in the Phase I part
In this study, the dose of exemestane is 25 mg daily continuous based on the label. The 
starting dose of everolimus is 10 mg daily, which is the approved dose for the study 
population (please refer to the latest version of SPC or PI).
In a Phase I study of everolimus plus ganitumab in patients with advanced solid tumors, the 
RP2D of everolimus is 10 mg daily (R13-2441). The approval of 10 mg daily dose of 
everolimus in breast cancer patient population is based on BOLERO-2 study in which, 50% 
patients reported grade 3 or 4 AEs (R12-5281) with 67% patients had dose reduction or 
treatment interruption (R13-1647).  The first dose reduction in BOLERO-2 is 50% or 5 mg 
daily dose. The mean dose intensity of everolimus is 7.1 mg/day and 7.9 mg/day for patients 
at least 65 years old and those below 65 years old, respectively. All of these implied that 
everolimus can be tolerated at different dose levels. As the toxicity profile of everolimus 
could be augmented by the inhibition of IGF pathway, several dose levels of everolimus 
might be tested in case the occurrence of DLT is related to everolimus.
Based on biological effects observed in two dose finding studies using monotherapy of BI 
836845 (please refer to the current version of the Investigator's Brochure, U10-2830), a dose 
level of 750 mg with weekly dose schedule are selected as the starting dose for this study. 
BI 836845 is to be administrated weekly without a loading dose. The plan is to start with 
everolimus 10 mg daily in combination with escalating/de-escalation dose tiers of BI 836845 
until determination of MTD and RP2D (refer to Sections 5.2.6 and 5.2.7 for definition). Intra-
patient dose escalation is not permitted. If 10 mg everolimus dose is not tolerated, cohort with 
lower dose level of everolimus will be started.
Cohorts of 3 patients are to be entered sequentially into escalating/deescalating dosage tiers 
of BI 836845/everolimus/exemestane and observed until the end of the first course for the 
occurrence of a DLT. If no DLT is observed, the dose will be escalated in the next cohort and 
three more patients will be treated at the next higher dose; if one patient experiences DLT, 
then three additional patients will be treated at the same dose; if two or more patients have 
DLT, then the MTD has been exceeded and the dose will be deescalated or the trial may be 
terminated. To further approximate the MTD, the dose may be re-escalated, as long as it 
remains lower than the dose which exceeded the MTD.
Starting doses are outlined in Table 4.1.3.2: 1 / Cohort 1a. The dose of BI 836845 for the 
successive cohort is to be increased directly to that of Cohort 1b unless two or more patients 
out of six with DLTs are observed, in which case, if the DLT is mainly related to BI 836845, 
the dose level of Cohort 1a will be determined as MTD; if the DLT occurred in Cohort 1b is 
mainly related to everolimus, the Cohort -1b should be followed. If one or none DLT 
occurred at Cohort 1b out of six evaluable patients, the dose level of Cohort 1b will be 
determined the MTD. Cohort -1b could be the MTD, or be followed by Cohort -1a or Cohort 
-2b, depending on the number of DLT observed and the relatedness of DLT to the study 
drugs. 


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On the other hand, if two or more DLT is observed at Cohort 1a, Cohort -1a may be followed, 
subsequently followed by Cohort -1b, Cohort -2b or Cohort -2a depending on the DLT 
observed. If two or more DLTs are observed at Cohort -2a, the trial may be terminated.
Examples of dose escalation/deescalation plan are illustrated in Figure 4.1.3.2: 1 and 4.1.3.2: 
2. During dose finding stage, safety profile as well as DLT will be discussed with the 
investigators and the steering committee. The decision on the next dose level or 
determination of MTD and RP2D will be documented. 
Table 4.1.3.2: 1
Concomitant dosing schedule schemes of the Phase I part
Cohort
BI 836845
(mg)
Everolimus
(mg)
Exemestane
(mg)
Cohort -2a
750
5
25
Cohort -2b
1000
5
25
Cohort -1a
750
7.5
25
Cohort -1b
1000
7.5
25
*Cohort 1a
750
10
25
Cohort 1b
1000
10
25
*-Starting dose level
Additional patients can be enrolled at MTD/RP2D if required for safety and/or PK analysis. 
If the RP2D is different from the MTD, a total of 18 patients should be treated at the RP2D of 
the phase I part. 
Above dose levels may be modified and/or additional dose levels/administration regimens 
may be added based on safety profile and other emerging data upon discussion and agreement 
between the sponsor and investigators. 
Examples of dose decision tree are illustrated as following:


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Figure 4.1.3.2: 1
Dose decision tree example one


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Figure 4.1.3.2: 2
Dose decision tree example two
Refer to Sections 5.2.6 and 5.2.7 for definition of DLT, MTD and RP2D.
4.1.3.3
Selection of phase II dosing schedule
The decision on dose escalation/deescalation, MTD and RP2D will be determined in 
discussion with steering committee comprised of at least BI Trial Clinical Monitor, BI project 
physician (TMM) and Coordinating Investigator and taking into account patient safety. This 
decision will be documented.
4.1.4
Drug assignment and administration of doses for each patient
The treatment medication assignment for BI 836845 and everolimus, if supplied by BI, will 
be managed through IRT system. However, if everolimus is used on label in the phase II part, 
it will be prescribed by the investigator and supplied by a pharmacy in some countries; under 
this circumstance, everolimus will not be managed through IRT system.  Exemestane will not 
be supplied by the sponsor throughout the study; therefore, it will not be managed through 
IRT system.


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In addition, patient’s screening, run-in, randomization, all drug dispensation visits and EOTV 
will be collected in the IRT system.
4.1.4.1
Initial study drug assignment and administration
General information that applies in this study regardless of IRT is described in below sections 
of individual study drug. The medication kit as well as the treatment will be assigned with the 
support from IRT. The detailed information regarding handling of medication number will be 
described in ISF.
Before entering patients at the next dose level of the phase I part, it will be ensured that all 
patients at the current ongoing dose level have completed at least one course of treatment.
4.1.4.1.1 BI 836845
Patients will start treatment with their assigned dose tier (see Section 4.1.3) or RP2D of 
BI 836845 from course 1 day 1. BI 836845 will be administered at the investigator site 
intravenously over one hour with a constant infusion rate on the treatment day as specified in 
the Flow Chart. If scheduled infusion of BI 836845 is not performed within the time window, 
this treatment will be skipped and will not be made up. Subsequent visits should follow the 
original visit date schedule. Mannitol is used in the formulation of BI 836845, so an infusion 
duration of less than one hour must be avoided. The infusion time may be extended to over 
one hour and up to a maximum of three hours in cases of CTCAE grade ≥ 2 infusion 
reactions (see Section 4.4.2 for grading and management of infusion reactions). Further 
information on infusion equipment and procedure is described in the ISF. In case of a delay 
or an interruption of infusion, the reason and the exact time of deviation must be recorded in 
the eCRF. The accuracy of this information is crucial for the proper evaluation and appraisal 
of the pharmacokinetics and other data.
At days of PK sampling during the Phase I and II part, everolimus and exemestane 
should be administrated within 5 minutes after start of BI 836845 infusion.
Detailed information of dispensation, preparation, and handling of BI 836845 will be 
described in ISF.
4.1.4.1.2 Everolimus
Everolimus should be taken orally once daily after a meal at the same time every day. The 
blisters for everolimus tablets should be opened only at the time of administration as drug is 
both hygroscopic and light-sensitive. All blisters will conform to local regulatory 
requirements. The tablets should not be crushed or chewed. Everolimus should be swallowed 
whole with a large glass of water. 
At days of PK sampling, patients should NOT take study medication at home prior to 
their visits to the study site.


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Missed doses of everolimus can be made up if taken within 6 hours of the regularly scheduled 
time. Otherwise, the dose should be skipped and patients should take the next scheduled dose 
at the usual time. Patients must not take 2 doses to make up for the missed dose. Missed 
doses of everolimus should be recorded in the eCRF throughout the study.
Everolimus will be prescribed by the investigator. If everolimus is supplied by the sponsor, it
will be dispensed at visits described in Flow Chart either by the investigator, site staff or 
affiliated pharmacy through IRT.  Otherwise, the prescription of everolimus should be filled 
by pharmacy. During the study, patients may be administered a combination of different dose 
strengths of everolimus to reach the expected dose level as outlined per protocol.  For 
example, 10 mg everolimus can be given with two tablets of 5 mg or one tablet of 5 mg plus 
two tablets of 2.5 mg.
4.1.4.1.3 Exemestane
The recommended treatment dose for exemestane is one 25 mg tablet once daily after a meal. 
Complete guidelines for management and administration of exemestane can be found in EU 
Summary of Product Characteristics or the prescribing information of respective country.
At days of PK sampling, patients should NOT take study medication at home prior to 
their visits to the study center.
Missed doses of exemestane can be made up if taken within 6 hours of the regularly 
scheduled time. Otherwise, the dose should be skipped and patients should take the next 
scheduled dose at the usual time. Patients must not take 2 doses to make up for the missed 
dose. Missed doses of exemestane should be recorded in the eCRF throughout the study.
There will be no investigational supply of exemestane. Exemestane will be prescribed by the 
investigator at visits described in Flow Chart and filled by pharmacy.
4.1.4.1.4 Special instructions for the Run-in period and up to Course 1 Day 8 of the Phase I 
part
During the study period critical for DDI analysis (Run-in period and up to Course 1 Day 8 of 
the Phase I part), the timing of drug administration and food intake are specified in the 
following:
Patients should be advised to take everolimus and exemestane at approximately the same 
clock time in the morning after breakfast when taking study drugs at home. 
At days of PK sampling critical for DDI analysis (on Day -1 of Run-in and C1D1, C1D2 of 
the Phase I part), patients need to come fasted to the study site and should not take 
study medication at home prior to their visits. Breakfast should be taken at approximately 
the same clock time on these days. The content and amount of the breakfast must be as close 
as possible on Day -1 of Run-in and C1D1, i.e. containing the same ingredients in a very 
similar amounts.


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The breakfast and drug administration should be timed according to the following schedule:
1. Patients start breakfast 30 min prior to start of infusion AND/OR 35 min prior to 
administration of everolimus and exemestane. Patients should complete their 
breakfast within 25 min
2. The pre-treatment sample should be taken 5 min prior to BI 836845 infusion 
AND/OR 10 min prior to administration of everolimus and exemestane.
3. 5 min after start of infusion AND/OR 35 min after start of breakfast, everolimus and 
exemestane are administered.
Information on drug and food intake during the Run-in and up to C1D8 should be recorded 
on the diary card and the eCRF.
Sites should be encouraged to schedule PK visits in the early morning to accommodate 
consistent dosing schedules.
4.1.4.2
Additional course of treatment in Phase I part
The dose of BI 836845, everolimus and exemestane assigned upon entry to this trial will be 
used on all the scheduled administrations described in the Flow Chart unless the patient 
experienced DLT or treatment related adverse events which require dose modification. 
Patients demonstrating a clinical benefit (i.e., with either an objective tumor response or the 
absence of disease progression) with the trial drug, and who have recovered from any 
clinically relevant drug-related AE, are eligible for further treatment courses as per the Flow 
Chart, until any of the conditions in Section 3.3.4.1 is met.
4.1.4.3
Temporary treatment interruption and dose reduction 
DLT or those AEs requiring dose adjustment as indicated on the label, should be managed by 
treatment interruptions and subsequent dose reductions of the presumed causal study drug(s) 
according to the schedule described in Table 4.1.4.3: 1. Please also refer to Section 4.4 for 
additional recommendations. In Phase I, both BI 836845 and everolimus must be paused 
when DLT occurs during the first treatment course.
To prevent the development of more severe adverse events, treatment related stomatitis, non-
infectious pneumonitis and metabolic events should be closely monitored and managed early 
as described in Section 4.4.
The treatment should be paused until patient has recovered from the drug-related toxicity to 
grade ≤1 or baseline. Baseline is defined as the CTCAE grade at the start of treatment. For 
patients who develop DLT, treatment may be resumed at reduced dose according to dose 
reduction scheme of the patient’s starting dosage. If a patient has not recovered to Grade ≤1 
or baseline within 28 days, study treatment must be permanently discontinued. In the event 


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that the patient is deriving obvious clinical benefit according to the investigator’s judgement, 
further treatment with study drug(s) will be decided in agreement between the sponsor and 
the investigator.
Dose reductions will apply to individual patients only. Doses of BI 836845 and/or everolimus 
can be reduced independent of each other.  Once the treatment dose is reduced for a particular 
patient, it should not be increased back to the previous dose. 
Table 4.1.4.3: 1
Dose reduction scheme
Dose 
level
BI 836845
BI 836845
Everolimus 
dose (1)
Everolimus 
dose(2)
Everolimus 
dose (3)
0 = starting dose
1000 mg
750 mg
10 mg daily
7.5 mg daily
5 mg daily
-1 dose level
750 mg
500 mg
5 mg daily
5 mg daily
2.5 mg daily
-2 dose level
500 mg
Off-drug
2.5 mg 
daily
2.5 mg daily
2.5 mg every 
other day
Stomatitis, non-infectious pneumonitis, and metabolic events including hyperglycemia and 
dyslipidemia are common side-effects of everolimus listed on drug label. Please refer to the 
current everolimus prescribing information for dose adjustment recommendations (except for 
the Course 1 of the Phase I part where DLT occurs, in which both drugs need to be 
interrupted until AE recovery, refer to section 5.2.6). When these AEs occur and are 
considered related to study treatment, first dose modification is recommended to be made to 
everolimus preferentially.
No dose reduction is allowed below 500 mg for BI 836845 or 2.5 mg every other day for 
everolimus. 
Alternative dose modification scheme can only be considered after discussion and agreement 
between the investigator and the BI clinical monitor.
Management of everolimus related adverse reaction and dose adjustment should be based on 
the European SPC or current prescribing information for everolimus of respective country or 
institutional standard, except for the Course 1 of the phase I part, for which, protocol should 
be followed in case of DLT. 
Patients who need to reduce the dose of the same drug for more than two times should be 
discontinued from that drug treatment. Exception to this in patients who derive obvious 
clinical benefit according to the investigator’s judgement could be considered upon 
discussion with BI’s Clinical Monitor.
During temporary treatment interruption of BI 836845, the scheduled drug infusion will be 
missed and will not be administered retrospectively. 


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In the event of any unrelated AEs or related non-DLT AEs, the study drug(s) may be 
interrupted for up to 28 days, but no dose reduction should occur unless indicated in the 
current drug label/SPC of everolimus or exemestane. Otherwise, the decision to continue with 
the study treatment will be made by the BI Clinical Monitor in agreement with the 
investigator.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label study. Blinding is not applicable. However, to reduce bias, the BI trial 
team will be blinded for the aggregated phase II part data at the treatment level until the trial 
database lock for the primary readout.
The prespecified looks by the DMC (see section 7.3.4) will not lead to an unblinding of the 
trial team in order to prevent potential introduction of operational bias. A logistics plan 
prepared and approved in accordance with BI’s specific procedures will detail procedures 
used to ensure that all members of the trial team remain blinded. All subsequent actions 
requested by the DMC will be performed by an independent team as defined in the DMC 
charter. The logistics plan will also contain a detailed list of functions that need to be 
unblinded to perform this analysis.
4.1.5.2
Procedures for emergency unblinding
This is an open-label study. Procedures for emergency unblinding are not applicable.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
For details of drug supply, refer to Section 4.1.1.
Boxes and vials of BI 836845 and boxes of everolimus (if supplied by BI) will be labelled 
according to local regulations and will include the following as a minimum:
#
The study number (1280.4)
#
Product name
#
Contents of the bottle/carton box
#
Strength
#
Batch number
#
Use-by date
#
Storage information
#
Instructions for use
#
Sponsor name and address
#
A statement indicating that the medication is for clinical trial use only
#
A caution statement


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Examples of the labels will be filed in the ISF.
The BI 836845 and Everolimus (if provided by BI) drug supply will be managed through 
Interactive Response Technologies (IRT) by the study sites and BI personnel. Refer to the 
ISF for details of packaging and the description of the label as well as the process for 
resupply of study drug.
4.1.7
Storage conditions
BI 836845 and everolimus (for those provided by the sponsor) must be kept in a secure, 
limited access storage area under the storage conditions defined on the drug label. 
Temperature logs must be maintained to assure that drug supplies are stored at the correct 
temperature.  If the storage conditions are found to be outside the specified range, 
immediately contact the local clinical monitor as provided in the list of contacts.
Investigational drug supply of BI 836845 and everolimus must be stored in the original 
packaging. 
4.1.8
Drug accountability
The investigator or the pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:
#
Approval of the study protocol by the IRB / ethics committee, 
#
Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,
#
Approval/notification of the regulatory authority, e.g. competent authority,
#
Availability of the curriculum vitae of the principal investigator,
#
Availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol,
#
If applicable, availability of the proof of a medical licence for the principal 
investigator.
The investigator or pharmacist must maintain records of the product’s delivery to the trial 
site, the inventory at the site, the use by each patient, and the return to the sponsor or 
alternative disposition of unused products. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the medication kit numbers assigned to the investigational products and trial patients.  The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational product(s) received from the sponsor. The investigator / 
pharmacist / investigational drug storage manager must verify that all unused or partially 
used drug supplies have been returned by the clinical trial patient.


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Any opened vials of BI 836845 should be discarded after use following local regulations and 
local hospital practices.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
4.2.1.1
Rescue medication
Rescue medications to reverse the effects of BI 836845, everolimus, and exemestane are not 
available. Side effects of these treatments should be treated symptomatically with treatment 
interruption and dose reduction when needed. There is no specific antidote to overdosage of 
everolimus or exemestane. 
4.2.1.2
Emergency procedures
There are no special emergency procedures to be followed.
Precaution should be taken to avoid extravasation of BI 836845. 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 reinitiated according to 
local practice.
4.2.1.3
Concomitant treatments
Symptomatic treatments of tumor-associated symptoms are allowed. Concomitant 
medications or therapy to provide adequate supportive care may be given as clinically 
necessary. 
After study enrollment, palliative radiotherapy may be given for analgesic purposes, lytic 
lesions at risk of fracture or for other reasons (e.g. bronchial obstruction, skin lesions), 
provided that the total dose delivered is in a palliative range to non-target lesion according to 
institutional standards. Information on palliative radiotherapy will be captured in e-CRF. It is 
at the investigator’s discretion to withhold the study treatment during palliative 
radiotherapy. The investigators should assess the signs/symptoms carefully to exclude the 
progressive disease prior to the administration of the palliative radiotherapy.
The acute use of bisphosphonates for symptomatic treatment of bone metastases is permitted 
during the study, but chronic use for the prevention of bone metastases is prohibited (see 
Section 4.2.2.1). Bisphosphonate therapy for the treatment of osteoporosis, at the doses 
indicated under prescribing information, is permitted during the study. If bisphosphonate 
therapy is initiated after enrollment, the reason for its use must be clearly documented clearly 
documented in the eCRF.
All medications (other than study drug), including anaesthetic agents, vitamins, 
homeopathic/herbal remedies, nutritional supplements, and significant non-drug therapies 
(including physical therapy and blood transfusions) starting or changing after the patient 


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signed informed consent must be listed on the concomitant medication page of eCRF 
including trade name, start and end dates, indication for use etc. as specified in the Flow 
Chart. Subsequent anti-cancer therapy received after discontinuation of the study treatment 
must also be recorded in the eCRF for patients participating in the Phase II part of the study.
If patients receive parenteral nutrition during the trial, the components need not be specified 
in detail. It should just be indicated as “parenteral nutrition”. If a patient requires anesthesia, 
it will be sufficient to indicate “anesthesia” without specifying details.
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with BI 836845 and/or everolimus around one week prior to the surgery, and to restart 
treatment after complete wound healing. If the patient can’t recover within 28 days since 
stopping study medication, she should be removed from the study. Exception to this in 
patients who derive obvious clinical benefit according to the investigator’s judgement could 
be agreed upon discussion with BI’s Clinical Monitor.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
For everolimus: Everolimus is a substrate of CYP3A4, and also a substrate and moderate 
inhibitor of PgP. Systemic concomitant strong CYP3A4 inhibitors and PgP inhibitors should 
not be used with everolimus. (refer to Appendix 3 for a list of examples). 
Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot 
be avoided (refer to Appendix 3 for a list of examples). If patients require co-administration 
of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg daily or 2.5 mg daily may be 
considered. Due to between subject variability the recommended dose adjustments may not 
be optimal in all individuals, therefore close monitoring of side effects is recommended. If 
the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days 
(average elimination time for most commonly used moderate inhibitors) before the 
everolimus dose is returned to the dose used prior to initiation of the co-administration.
Avoid the use of concomitant potent CYP3A4 inducers (e.g. rifampicin, phenytoin, 
carbamazepine, phenobarbital, dexamethasone or St. John’s wort). If patients require co-
administration of a potent CYP3A4 inducer, an everolimus dose increase from 10 mg daily 
up to 20 mg daily should be considered using 5 mg increments or less applied on Day 4 and 8 
following start of the inducer. If treatment with the inducer is discontinued, consider a 
washout period of at least 3 to 5 days (reasonable time for significant enzyme de -induction), 
before the everolimus dose is returned to the dose used prior to initiation of the co -
administration.
St.John’s Wort may decrease everolimus exposure unpredictably and therefore should be 
avoided.
For exemestane: Exemestane is a substrate of CYP3A4. Pharmacokinetic study showed that 
co-medications that induce CYP3A4 (e.g.,
rifampicin, phenytoin, carbamazepine, 


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phenobarbital, dexamethasone or St. John’s wort) may significantly decrease exposure to 
exemestane. 
Since the clinical relevance of this interaction has not been evaluated, the co-administration 
of drugs, known to induce CYP3A4 may reduce the efficacy of exemestane.
Exemestane does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 
2D6, 2E1, and 3A4. Nevertheless, exemestane should be used cautiously with drugs that are 
metabolised via CYP3A4 and have a narrow therapeutic window.
In order to effectively assess the pharmacokinetics of exemestane, everolimus and BI 836845 
and to investigate potential alterations of pharmacokinetics during co-administration, strong 
and moderate CYP3A4 inhibitors/inducers and/or strong and moderate P-gp inhibitors 
are prohibited during the run-in period and the first treatment course at the Phase I 
part (refer to Appendix 3 for a list of examples). Switching to a different class of drug that is 
not a strong or moderate CYP3A4 inhibitor/inducer and/or strong or moderate P-gp inhibitor 
at least 14 days prior to the run-in period is permitted.
Starting from Day 1 of Course 2 of the Phase I part and Day 1 of Course 1 of the Phase II 
part, follow the respective drug package insert/SPC when considering concomitant treatment 
with CYP3A4/PgP inhibitors/inducers.
Antiplatelet medications (e.g. acetylsalicylic acid) should be discontinued 7 days prior to 
tumor biopsy. Anticoagulant medications should be discontinued prior to tumor biopsy. 
Warfarin should generally be discontinued at least 5 days prior to tumor biopsy. In all 
patients, the risk of discontinuing antiplatelet and/or anticoagulant medications must be 
weighed against the (potential) risk of bleeding during/after biopsy. These medications may 
be restarted after tumor biopsy at the discretion of the investigators.
In addition, the following concomitant treatments are not allowed during the study:
1) Chronic concomitant bisphosphonate therapy for the prevention of bone metastases
(the use of any other agent for the prevention of bone metastasis is not allowed during 
the study). 
2) Investigational or commercial anticancer treatment and/or standard chemo-, 
immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy 
other than exemestane 
3) Growth hormones or growth hormone inhibitors
4) Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (e.g. 
raloxifene) 
5) Prolonged systemic corticosteroid treatment, except for topical applications (e.g. 
rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections 


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(e.g. intraarticular) should not be given. A short duration (<2 weeks) of systemic 
corticosteroids is allowed (e.g. chronic obstructive pulmonary disease, anti-emetic)
6) Hematopoietic growth factors (e.g. erythropoietins, G-CSF and GM-CSF) are not to 
be administered prophylactically. Use of these should be reserved to cases of severe 
neutropenia and anemia as per the labelling of these agents
7) The use of concomitant medications that prolong the QT/QTc interval (refer to 
website crediblemeds.org for the list of medications) should be avoided, except in 
those cases where treatment is necessary after a risk-benefit evaluation by the 
investigator and provided that the drug in question cannot be substituted by any other 
agent.
It is to be noted that
1) Everolimus may affect the response to vaccinations making it less effective. Live 
vaccines should be avoided while a patient is treated with everolimus.
2) Lipid-lowering drugs may be given in case of hyperlipidemia according to local best 
clinical practice. 
3) Antihyperglycemic drugs may be given in case of hyperglycemia according to local 
best clinical practice. 
Otherwise, the use of other concomitant medication/therapy deemed necessary for the care of 
the patient is allowed. 
4.2.2.2
Restrictions on diet and life style
Patients should avoid grapefruit and grapefruit juice while treated on everolimus. Patients 
also have to show up in fasting condition at the site when blood draw for safety lab is 
required.
Everolimus and exemestane tablets should be administered with a large glass of water (~ 240 
mL). Patients should be advised not to eat within 2 hours after drug administration and not to 
drink within 1 hour after drug intake.
For specific instructions on food and drug intake during the Run-in period and up to C1D8 of 
the phase I part for DDI analysis, refer to section 4.1.4.1.4.
4.3
TREATMENT COMPLIANCE
The study medications will be given in accordance with the protocol and the instructions of a 
site investigator. The investigator should instruct the patient to take the study drugs exactly as 
prescribed to promote compliance.


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4.3.1
BI 836845
BI 836845 will be administered as a single infusion under supervision of the investigator or 
dedicated study personnel. In the event that the full dose of BI 836845 is not administered to 
the patient, it must be documented and explained.
A maximum of three BI 836845 infusions may be skipped for the recovery from AEs. 
Missing BI 836845 treatment for any other reasons is considered non-compliant.  
4.3.2
Everolimus and exemestane
Patients should be given appropriate number of everolimus and exemestane tablets to be self-
administered. During the run-in phase and up to the Visit 3 (Day 8±1) in first treatment 
course of the Phase I part, the patient will be requested to record each dose of medication in a 
diary.  The medication diary will be returned to clinic staff at the end of run -in phase and at 
Visit 3 of the first treatment course.
Patients will be asked to bring the remaining investigational oral medication everolimus on 
Day 1 of each treatment course to the investigator site. Compliance of investigational 
everolimus will be assessed by the investigator and/or study personnel using pill counts and 
information provided by the patient or caregiver. This information and discrepancies between 
the number of tablets remaining and the calculated number of tablets the patients should have 
taken must be documented and explained. The compliance of exemestane and non-
investigational everolimus (if applicable) will be assessed following the local regulation and 
practice, using either patient diary, pill counts, information provided by the patient or 
caregiver or the combination of any of them. If a patient is eligible for further treatment, 
medications of everolimus and exemestane must be made available. 
During the run-in phase, everolimus and exemestane must be taken daily without skipping 
any dose. If doses of everolimus or exemestane are missed during run-in period, treatment 
with BI 836845 may commence and the reason for not taking everolimus and exemestane as 
per protocol requirement must be documented in the eCRF (refer to section 3.3.4.1). During 
the treatment phase, a maximum of 25% of the planned doses per four-week period may be 
missed 
for 
reasons 
other 
than 
recovering 
from
AEs;
patients 
who 
miss 
everolimus/exemestane treatment more frequently are considered non-compliant.  
4.3.3
Compliance Assessment
Patients who do not attend a minimum of 75% of scheduled study visits, unless due to 
exceptional circumstances, should be discussed with BI clinical monitor and be evaluated for 
compliance.
The investigator and/or the sponsor can withdraw a patient from the study in the event of 
serious and persistent non-compliance which jeopardizes the patient’s safety or render study 
results. 


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4.4
MANAGEMENT OF EXPECTED ADVERSE EVENTS
The following recommendation should be followed unless institutional guidelines can be 
implemented based on the investigator’s judgement. The EU Summary of product 
characteristics or prescribing information of respective country for everolimus and 
exemestane should also be referred to when managing drug related adverse events.
In everolimus SPC, non-infectious pneumonitis, infections, hypersensitivity reactions, 
concomitant use of angiotensin-converting enzyme inhibitors, oral ulceration, renal failure 
events, and some lab tests and monitoring are described under “Special warnings and 
precautions for use”. For updated information regarding warning and precautions of 
everolimus and exemestane, please refer to the most current version.
4.4.1
Management of oral mucositis
4.4.1.1
Mouth care
#
Routine and systematic oral hygiene is extremely important to reduce the incidence 
and severity of the side effects of cancer treatment.
#
Correct oral hygiene should be maintained with daily brushing of the teeth, tongue 
and gums, performed after meals and before going to bed, using a non-irritant 
toothpaste, a soft toothbrush and dental floss to clean between the teeth. This should 
be followed by rinsing the mouth with a mouthwash.
#
Mouthwashes eliminate food particles that can accumulate and favour bacterial 
growth. The preferred solutions are normal saline, sodium bicarbonate, or a mixture of 
the two, to be used after each meal and before going to bed; solutions containing 
alcohol should be avoided as they dehydrate the mucosa. If the mucosa is ulcerated, 
do not use hydrogen peroxide solution as this will interfere with the formation of 
granulation tissue and healing of the ulcer. Do not use products that contain alcohol, 
glycerine or lemon, or toothpastes with an abrasive action.
#
Dental prostheses should be cleaned and brushed in the same way as the mouth, and at 
night should be left in 1% sodium hypochlorite solution (if they contain no metal) or 
in a solution of povidone iodine.
#
The lips must be maintained in a perfect state of hydration using lip balms (cocoa 
butter), methylcellulose solutions, moisturising cream or olive oil. Avoid using 
petroleum jelly or glycerine because of their dehydrating effects on the lip tissue.
#
Chlorhexidine is an antiseptic with a broad antimicrobial spectrum. It has a 
bacteriostatic action and is particularly active against gram-positive micro-organisms; 
it is sporostatic and fungistatic (activity against candida). It has a rapid effect and, in 
addition, presents considerable persistence and residual adherence. Due to its cationic 
nature, it has the property of binding to the oral mucosa. It has been used in the form 
of 15 ml of 0.12% chlorhexidine mouthwash 2-3 times a day.


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#
Avoid foods that trigger pain: acids, spicy and hot foods. Attempt to eat a soft diet and 
increase the intake of cold and nutritious fluids.
#
Avoid irritants such as alcohol and tobacco 
4.4.1.2
Treatment of established mucositis
#
Lidocaine is an amide-type local anaesthetic that is widely used both topically and 
parenterally. In the management of mucositis, it can be useful for the treatment of pain. 
It is administered locally in the form of a gel or solution. Apply 1% lidocaine viscous to 
ulcers before each meal.
#
Nystatin is an antifungal (fungistatic) agent with a broad spectrum. Nystatin suspension 
has been studied as prophylaxis against candida in patients on treatment with 
antineoplastic and/or immunosuppressant drugs. Apply after the main meals if there are 
signs of candidal superinfection of mucositis.
Corticosteroids, in the case of mucositis, reduce the inflammatory reaction that occurs in this 
condition, probably by inhibiting the production of leukotrienes and prostaglandins. 
#
Triamcinolone acetonide 0.1% in orabase qsp 30 g or
#
Hydrocortisone 1% in orobase qsp 50 g
Applications are performed 2-3 times a day with the recommendation not to eat or drink for 
30 minutes after the application to facilitate its adherence to the mucosa. 
In case of no improvement of mucositis, additional therapy may be added:
#
Fluconazol oral 100 mg daily in case of no improvement with topical antifun gal 
treatment with nystatin. 
Please note that fluconazole is a moderate inhibitor of CYP3A4, which may potentially 
have an impact on metabolism of everolimus and exemestane. 
#
Systemic antiherpetic therapy (ie Famvir 750 mg/d for 7 days otherwise Aciclov ir oral 
or iv.) at investigator’s discretion.
4.4.2
Management and grading of infusion reactions
The BI 836845 infusion should always be administered under close supervision of a 
medically qualified staff member with immediate availability of appropriate resuscitation 
facilities.
Infusion reactions may occur during infusion with BI 836845 and include pyrexia, chills, 
rigors, dyspnoea, urticaria, bronchospasm, hypotension and hypertension. A one hour 
observation period is recommended following each infusion. If there is no infusion 
reaction during the first treatment course, the observation period following BI 836845 


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infusion may be adjusted at the discretion of the investigators. Mild to moderate infusion 
reactions may be managed with a slower infusion rate and prophylactic antihistamines for 
subsequent dosing. Severe reactions require immediate and permanent discontinuation of 
infusion. The hypersensitivity reactions will be graded according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
(R10-4848).
Table 4.4.2: 1
Infusion reaction management
Infusion Reaction Grade
Management
CTCAE Grade 1 or 2
In the event of a CTCAE grade 1 infusion reaction, the infusion 
rate should be reduced by 50%. 
Grade 2 infusion reaction may require symptomatic treatment 
(e.g., antihistamines, NSAIDs, steroids, narcotics, IV fluids) 
with infusion interruption. Once the event has resolved, the 
infusion may be restarted at the reduced rate.
CTCAE Grade 3
For patients experiencing CTCAE grade 3 infusion reaction, 
infusion should be interrupted immediately and patients should 
receive aggressive symptomatic treatment.
Only after all the symptoms have disappeared, the infusion may 
be re-started if it is within 3 hours since the infusion start. The 
infusion rate should be reduced by half if it is restarted.
CTCAE Grade 4
Patients experiencing CTCAE grade 4 such as anaphylaxis 
during an infusion should have infusion immediately stopped 
and receive appropriate treatment including use of resuscitation 
medications and equipment that must be available. Such 
patients should NOT receive any further BI 836845 treatment.
The infusion duration may be extended to over one hour and up to a maximum of three hours, 
see Section 4.1.4.
The infusion reactions should be treated symptomatically as judged clinically relevant by the 
investigator. For symptomatic treatment of infusion reactions: hydrocortisone, antihistamines 
such as chlorphenamine accompanied by an antipyretic/analgesic and/or a bronchodilator is 
recommended.
4.4.3
Management of hyperglycemia and hyperlipidemia
In case of hyperglycaemia and hyperlipedemia, treatment should follow institutional
standard, prescribing information for everolimus and/or guideline (R13-1975). Monitoring of 
fasting serum glucose is recommended prior to the start of everolimus therapy and 
periodically thereafter. Optimal glycemic control should be achieved before starting trial 
therapy. After commencing the study medication, in patients with diabetes, fingerstick 
glucose values should be monitored daily. If fasting glucose values above 200 mg/dL occur, 
the investigator should evaluate the need to intensify antihyperglycemic therapy potentially in 


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collaboration with the treating physician responsible for the treatment of the diabetic 
condition or a specialist. For hyperglycemia occurs to patients without history of diabetes or 
hyperglycemia, oral anti-diabetics, such as metformin 1 g to 2.5 g/d with less hypoglycemic 
risk, may be started if necessary.
In case of grade 3 or higher hyperglycemic event, the patient should have immediate access 
to consultation with an endocrinologist or specialist. When the study drug is discontinued, the 
need for further antidiabetic treatment has to be evaluated depending on the blood glucose 
levels of the patient.
4.4.4
Management of non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Fatal cases of non-
infectious pneumonitis (including interstitial lung disease) have occurred. The investigator 
should monitor patients for clinical symptoms or radiological changes. For dose reduction, 
interruption or discontinuation of everolimus in the management of non-infectious 
pneumonitits, refer to everolimus SPC or prescribing information of respective country. 
4.4.5
Management of viral hepatitis
Everolimus has immunosuppressive properties and may predispose patients to viral infection 
including reactivation of hepatitis virus.  Please follow the current label of everolimus and 
local guidance should treatment for viral hepatitis is needed.
Prior to study treatment, patients must be screened for hepatitis risk factors and any past and 
current illnesses of hepatitis B and hepatitis C. Refer to Flow Chart for lab screening of 
Hepatitis B and C. Patients with baseline positive HBV-DNA or positive HbsAg, positive 
HCV-RNA or positive anti-HCV Ab are not eligible for the study.
4.4.6
Management of infection (related to everolimus)
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoan infections, including infections with opportunistic pathogens. 
Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) have 
been reported in patients who received everolimus and should be ruled out in the differential 
diagnosis of non-infectious pneumonitis. Prophylaxis for PJP/PCP should be considered 
when concomitant use of corticosteroids (e.g. for treatment of non-infectious pneumonitis) or 
other immunosuppressive agents are required.
Please follow the most current everolimus SPC or local prescribing information for updated 
recommendations of management.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
5.1.1.1
Primary endpoint
Phase II part: Progression-free survival (PFS). 
PFS is defined as the duration of time from the date of randomization until the date of 
the first objective tumor progression according to RECIST 1.1 or death due to any 
cause, whichever occurs earlier. If a patient has not had an event, PFS will be 
censored at the date of last adequate tumor assessment.
5.1.1.2 Secondary endpoints
Phase II part:
1. Time to progression (TTP), defined as the duration of time from the date of 
randomization until the date of the first objective tumor progression according to 
RECIST 1.1.
2. Objective response (OR), defined as best overall response of complete response (CR) 
or partial response (PR) (CR + PR), where best overall response is determined 
according to RECIST 1.1 from date of randomisation until the earliest of disease 
progression, death or last evaluable tumor assessment before start of subsequent anti-
cancer therapy.
3. Time to objective response, defined as the time from randomisation until first 
documented CR or PR.
4. Duration of objective response, defined as the time from first documented CR or PR 
until the earliest of disease progression or death among patients with OR.
5. Disease control (DC), defined as best overall response of complete response (CR) or 
partial response (PR), or stable disease (SD) ≥24 weeks, or Non-CR/Non-PD for ≥24 
weeks, where best overall response is defined according to RECIST 1.1 from date of 
randomisation until the earliest of disease progression, death or last evaluable tumor 
assessment before start of subsequent anti-cancer therapy.
6. Duration of disease control, defined as the time from randomisation until the earliest 
of disease progression or death, among patients with disease control.


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5.1.2
Assessment of efficacy
5.1.2.1
Tumor response
Response and progression will be evaluated in this study using Response Evaluation Criteria 
in Solid Tumors (RECIST) guideline (version 1.1) (R09-0262).  Tumor response will be 
assessed by local investigator’s review.
For the Phase II part of the study, image acquisition will be performed as described in the 
Imaging Guideline (wich will be filed in the ISF). Images will be collected and s tored at a 
central facility assigned by the sponsor. The sponsor retains the option to perform an 
independent blinded central review of the study images at a later time.
See APPENDIX 10.4, RECIST 1.1 (R09-0262) for details on lesion measurements and 
response assessment.
Every effort should be made to objectively evaluate tumor response for all patients who enter 
into the trial, including those who discontinue prematurely. 
RECIST 1.1 will be followed in this study for tumor assessment. Tumor assessments should
include scans of the chest, abdomen and pelvis. If clinically indicated, imaging of any other 
known or suspected sites of disease (e.g. breast, neck, brain etc) should be performed using 
an appropriate method (CT/MRI, etc.). Assessment will be performed at screening and then 
every 8 weeks after the first dose of BI 836845 (Phase I) or after randomization (Phase II) 
until week 48 and every 12 weeks thereafter. After screening, for each scheduled tumor 
assessment -7 days and -14 days windows are allowed, respectively before and after week 48. 
Tumor assessment does not need to be repeated at the screening visit if there are valid results 
available from assessments which were performed as part of routine clinical practice within 
28 days prior to start of treatment. For the phase II part, these need to also meet the 
requirements in the Imaging Guideline. Patients who discontinue the trial for any reason other 
than imaging based progressive disease should have a tumour assessment (RECIST 1.1)
performed at EOTV before starting new anti cancer therapies (exception to this are patients 
who have already had tumor assessment within 28 days of EOT visit)
In case of skin lesions, these should be measured with calliper and photographic 
documentation should be performed. However, skin lesion should not be considered as target 
lesion in this study. 
A bone scan should be performed at screening. If the patient has known bone metastases or if 
bone metastases are detected at screening, correlative imaging (X-ray or CT scan with bone 
windows or MRI) of the respective lesion(s) must be done at screening and subsequent 
imaging time points. Post screening bone scans should also be performed if clinically 
indicated. Abnormalities suggestive of progression of existing lesions or new lesions must be 
confirmed by X-ray, CT scan or MRI. Additional tumor assessments performed prior to 
starting new anticancer therapy/disease progression must also be documented in eCRF.


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If a patient presented with both irradiated and non-irradiated bone lesions, only the non-
irradiated lesions should be followed for tumor assessments unless progression is 
documented after the radiation.
Follow-up tumor assessments must utilize the same CT/MRI method and acquisition 
technique as were used for screening assessments to ensure comparability. CT and MRI scan 
with contrast media should be used except for patients who are allergic/ sensitive to the 
radiographic contrast media. A chest X-ray or skeletal X-ray which clearly demonstrates a
new metastatic lesion may be used to document progression in lieu of CT/MRI/bone scan.  
For patients with only bone lesions at baseline, the evaluation of response will be based 
solely on non-target lesion responses of RECIST 1.1. Specifically, in the absence of new 
lesions, the overall response at each assessment will be one of the following: Complete 
Response, Non-CR/Non-PD, Not Evaluable (not assessable, insufficient data) or Progressive 
Disease. Non-CR/Non-PD would include all assessments not qualifying for Complete 
Response, Progressive Disease or Not Evaluable. In the presence of any new lesion, the 
overall lesion response will be Progressive Disease. 
In the event of a delay, interruption or discontinuation of treatment, tumor assessment should 
continue to follow the original schedule. For patients who prematurely discontinue study 
medication including those discontinued with only clinical disease progression but without 
radiographic PD, tumor assessments should continue to be performed every 8 or 12 weeks as 
if the patient remained on study drug until criteria for end of follow-up period are met (refer 
to section 6.2.3 for details).
5.1.2.2
Assessment of disease progression
Disease progression will be based on the local investigator’s tumor assessment. 
For patients with measurable disease at baseline, progression will be determined according to 
the RECIST 1.1 (R09-0262).
In the absence of measurable disease at baseline, patients with bone lesions, lytic or mixed 
(lytic + sclerotic), will be allowed to enter the study and the following will be considered 
disease progression among these patients:
#
The appearance of one or more new lytic lesions in bone
#
The appearance of one or more new lesions outside of bone
#
Unequivocal progression of existing bone lesions
Pathologic fracture, new compression fracture, or complications of bone metastases will not 
be considered as evidence of disease progression, unless one of the above-mentioned criteria 
is fulfilled.


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5.2
SAFETY
5.2.1
Endpoints of safety
For the phase I part, the primary endpoints are DLT and MTD.
MTD is defined as the highest dose level examined of BI 836845 in combination of 
everolimus and exemestane, at which no more than 1 out of 6 MTD evaluable patients 
experienced a dose limiting toxicity during the MTD evaluation period.
The number of MTD evaluable patients per dose level with dose limiting toxicities during the 
MTD evaluation period will be used for the determination of the maximum tolerated dose.
Safety of BI 836845 when administered together with everolimus and exemestane will be 
evaluated by intensity and incidence of AEs, graded according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 dated 14 
June 2010 (R10-4848). 
Other assessments of safety include:
#
The incidence and intensity of AEs, as well as seriousness and relatedness of adverse 
events to treatment
#
AE leading to dosage reduction or discontinuation
#
Change from baseline in laboratory values
#
Other safety-related assessments involving ECG parameters and ECOG score will be 
described with respect to possible changes compared to baseline values. Further 
details on the analysis of ECG data will be specified in the TSAP.
5.2.2
Assessment of adverse events
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs) and includes periodic physical examinations, measurement of 
vital signs, assessment of performance status, monitoring of laboratory tests (i.e. 
haematology, chemistry, coagulation, urine analysis, HBV and HCV) and assessment of 
cardiac function with periodic ECGs as outlined in the Flow Chart and Section 6.2.
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) 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.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE 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.
The following hospitalizations are not considered to be serious adverse events (SAEs) 
because there is no “adverse event” (i.e., there is no untoward medical occurrence) associated 
with the hospitalization:
#
Hospitalizations for respite care 
#
Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
#
Hospitalization for administration of study drug or PK assessment
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the eCRF.
Causal relationship of adverse event
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
Exemption to (S)AE Reporting
Disease Progression is a trial endpoint for analysis of efficacy and as such is exempted from 
reporting as an (S)AE. Progression of the subject's underlying malignancy will be recorded 
on the appropriate pages of the (e)CRF as part of efficacy data collection only and will not be 
reported on the SAE Form. It will therefore not be entered in the safety database (ARISg) and 


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hence not get expeditiously reported. Death due to disease progression is also to be recorded 
on the appropriate (e)CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy, the event must be reported as an SAE on 
the SAE Form and on the (e)CRF.
Examples of exempted events of PD may be:
• Progression of underlying malignancy (Progressive disease [PD]): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 
• Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)
• Clinical symptoms and/or signs of progression (without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be determined 
to be due to the progression of the underlying malignancy and does meet the expected 
pattern of progression for the disease under study. 
Exempted events are to be monitored by the study Data Monitoring Committee at the
intervals defined in the DMC charter for the phase II part of the trial. 
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the investigator.
Protocol-specified adverse events of special interest (AESI)
The following are considered as protocol-specified adverse events of special interest:
#
Hepatic injury is defined by the following alterations of hepatic laboratory parameters:
o
For patients with normal liver function (ALT, AST, and bilirubin within normal 
limits) at baseline, an elevation of AST and/or ALT ≥3 fold ULN combined 
with an elevation of total bilirubin ≥2 fold ULN measured in the same blood 
draw sample, and/or marked peak aminotransferase (ALT, and/or AST) 
elevations ≥10 fold ULN.
o
For patients with abnormal liver function tests at baseline (AST and/or ALT >ULN), 
an elevation of transaminase ≥(baseline + 4x ULN) combined with an elevation of 
total bilirubin ≥2 fold ULN measured in the same blood draw sample, with the 
exclusion of the causes due to underlying diseases.  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.


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to Appendix 10.6 of this clinical trial 
protocol and the "DILI checklist" provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Although rare, drug-induced liver injury is under constant surveillance by sponsors and 
regulators and is considered a protocol-specified adverse event of special interest. Timely 
detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory 
parameters to distinguish an effect of the underlying malignancy on liver function from other 
causes are important for patient safety.  
#
DLT occurs in the phase I part. Please refer to Section 5.2.6 for definition of DLTs.
#
Cases of pneumonitis (including interstitial lung disease, non-infectious pneumonitis and 
other analogous terms) occurring at any cycle in both phases.
These are considered as protocol-specified adverse events of special interest and have to be 
reported in an expedited manner similar to SAEs, even if they do not meet any of the 
seriousness criteria – for details please see Section 5.2.2.2.
If the investigator determines any protocol-specific adverse events of special interest are 
related to study drug, the administration of the study drug must be managed according to 
Section 4.1.4 of the protocol.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
i.e., from signing the informed consent onwards through the follow up visit will be collected, 
documented and reported to the sponsor by the investigator on the appropriate eCRFs / SAE 
reporting forms. Reporting will be done according to the specific definitions and instructions 
detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. 
The terminal half-life of BI 836845 is the longest one compared to that of everolimus and 
exemestane, the residual effect period (REP) for the study, after elimination of BI 836845, is 
therefore defined as 42 days in this study. All adverse events from the date of signing of 
informed consent until the last follow-up visit must be reported. All AEs, including those 
persisting at the end of follow-up visit, must be followed up until resolved or until 
sufficiently characterised.
Once the patient completed the follow-up, the investigator does not need to actively monitor 
patients for adverse events. However, if s/he becomes aware of a SAE(s) that occurred after 


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the patient has completed the follow-up, the event should be reported to the sponsor if 
considered relevant. Deaths (unless considered drug-related or trial related) will not be 
reported as SAE when occurring after the follow-up period.
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 AEs as defined in 
Section 5.2.2.1.
Table 5.2.2.2: 1
AE/SAE reporting requirements
Time period
Reporting requirements
From signing of informed consent until last 
follow up visit
Report all AEs and SAEs regardless of 
relatedness or whether the trial drug was 
administered. This includes all deaths.
Observation 
period 
(after 
the 
patient 
completed 
last 
follow-up 
and 
when 
progression occurred or when new anti-
cancer therapy started)
The investigator may report SAE if s/he 
becomes aware of and considers relevant.
Death should not be reported as a SAE 
except when it is considered related to trial 
treatment or trial design (because death is an 
outcome endpoint and will be followed up 
separately).
If not stipulated differently in the ISF, the investigator must report the following events via 
telephone/fax or, if available in the trial, by RDC using the SAE form immediately (within 
24 hours) to the sponsor: SAEs and non-serious AEs occurring at the same time as an SAE 
and/or which are medically related to the SAE(s), and protocol-specified adverse events of 
special interest. 
BI has set up a list of AEs 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 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the 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-system.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by 
the investigator.


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The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File) or by using the 
electronic submission process. 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 interest becomes available. 
Pregnancy
Patients are women of non-childbearing potential. Therefore pregnancy is not expected to 
occur in this study.
5.2.3
Assessment of safety laboratory parameters
Blood samples, including fasting serum samples (fasting state for at least 8 hours) and the 
fasting lipid profile, will be collected up to one day prior to the scheduled time points as 
specified in the Flow Chart and analysed in a laboratory facility at (or close to) the 
investigational site. Safety laboratory examinations include hematology, coagulation, 
biochemistry and urine examination. See Table 5.2.3: 1 for details. In case of abnormal 
findings such as neutropenia or thrombocytopenia, further test may be done if clinically 
indicated at the discretion of the investigator. All analyses are to be performed by the local 
clinical laboratory.  Unscheduled safety laboratory examinations will be documented in the 
eCRF along with the results. 
Safety laboratory assessment may be performed according to local practice but must include 
at least all of the following parameters:
Table 5.2.3: 1 Clinical laboratory tests
Category
Parameters 
Hematology
Red blood cell count (RBC), haemoglobin, haematocrit, platelet count,
white blood cell count (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Coagulation
International Normalized Ratio (INR), activated Partial Thromboplastin 
Time (aPTT)
Chemistry
Blood urea or blood urea nitrogen (BUN), creatinine, alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), bilirubin (total and direct), albumin, creatine 
phosphokinase (CPK); in case of pathological CPK further evaluation (e.g 
by determination of isoenzymes, troponin assays, ECG exam) should be 
performed as clinically indicated


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Table 5.2.3: 1 Clinical laboratory tests (Cont’d)
Category
Parameters 
Electrolytes
Sodium, potassium, calcium, magnesium, phosphorous
Lipid profile (fasting)
Total cholesterol, triglycerides, LDL, HDL
Other (fasting)
Glucose and HbA1C
Urinalysis
pH, protein, glucose, erythrocytes, leucocytes, ketones and 
nitrite will be analyzed by dipstick (semi-quantitative 
measurements: -, +, ++, +++); in case of pathological finding 
further evaluation should be performed and results documented
5.2.4
Electrocardiogram
Triplicate 12-lead ECGs (3 ECGs taken approximately 2-3 minutes apart) will be performed 
in all patients in both phases as specified in the Flow Chart. 
The ECG timepoints for the phase I part is defined as the following:
#
Screening
#
Day 1, Day 8, Day 15 of Course 1; Day 1, Day 15 of Courses 2 and 3; and Day 1 of 
Courses  6, 9, 12, etc. at pre-dose (-60 min. to -5 min. of administration of BI 836845) 
and immediately after the end of infusion 
#
EOTV
#
Follow-up Visit
The ECG timepoints for the phase II part is defined as the following:
#
Screening
#
Day 1, Day 8, Day 15 of Course 1; Day 1 of Course 2; and Day 1 of Courses  3, 6, 9, 
12, etc. at pre-dose (-60 min. to -5 min. of administration of BI 836845 and/or 
everolimus + exemestane), and immediately after the end of infusion (for patients 
receiving BI 836845) OR one hour after the administration of everolimus + 
exemestane (for patients not receiving BI 836845)
#
EOTV
#
First Follow-up Visit


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The ECGs will be digitally recorded using dedicated equipment provided by a CRO. In 
addition, a centralised evaluation of all recorded 12-lead ECGs will be performed by a CRO 
in a blinded fashion. It is not mandatory to wait for central evaluation of ECGs to take 
clinical decisions, but in case of values close to 470ms at screening visit, it’s strongly 
recommended to ask for central lab report to confirm eligibility for patients’ safety. The ECG 
recordings must also be analyzed and checked for abnormality by the investigator. Any ECG 
finding that meets AE criteria should be reported. Positive findings on QT prolongation must 
be followed up sufficiently as deemed by the investigator. Additional ECGs should be done 
whenever the investigator deems necessary.
After the primary analysis of the study, a decision can be made by the sponsor and 
communicated by the trial clinical monitor to stop the triplicate ECG monitoring and central 
evaluation if necessary. Thereafter the ECG will be evaluated locally by the investigator 
using site equipment if clinically indicated.
5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination
A full physical exam must include cardiopulmonary examination, examination of the regional 
lymph nodes, and examination of the abdomen and an assessment of the mental and 
neurological status. Additional symptoms which have not been reported during a previous 
examination must be clarified. Wherever possible the same investigator should perform this 
examination.
5.2.5.2
Vital signs, height and weight
Vital sign measurements (blood pressure [systolic blood pressure, diastolic blood pressure], 
pulse rate, temperature and measurement of height (at screening) and body weight and the 
evaluation of the ECOG performance status will be performed at the times specified in the 
Flow Chart and Schedule of Procedures/Assessments (Section 6.2).  Blood pressure and pulse 
will be measured after the patient has been recumbent or seated for 5 minutes.
5.2.6
Dose limiting toxicity (DLT)
The primary endpoints of the Phase I part are occurrence of Dose Limiting Toxicity (DLT)
and determination of MTD. 
A dose limiting toxicity (DLT) in this study is defined as an adverse event or laboratory 
abnormality which 1) is considered related to study drug and 2) meets any of the following 
criteria:
#
CTCAE Grade 3 hyperglycemia lasting > 48 hours
#
CTCAE grade 4 hyperglycemia
#
CTCAE Grade ≥ 3 stomatitis (oral mucositis) despite appropriate supportive care
#
CTCAE Grade ≥3 thrombocytopenia lasting  ≥ 7 days or thrombocytopenia associated 
with active bleeding or requiring platelet transfusion
#
CTCAE Grade ≥4 decreased platelet count


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#
CTCAE grade ≥ 3 febrile neutropenia and/or documented infection with ANC <1.0x109/L
#
CTCAE Grade 4 decreased neutrophil count lasting ≥ 7 days
#
AST or ALT > 5x ULN (for baseline AST/ALT ≤ ULN) or > (baseline value + 4x ULN) 
(for baseline AST/ALT > ULN)
#
CTCAE grade ≥ 3 diarrhea, nausea, or vomiting despite adequate supportive care
#
CTCAE Grade ≥ 3 skin rash despite adequate supportive care measures 
#
CTCAE Grade ≥ 3 fatigue/asthenia lasting for more than seven days
#
Grades 3 to 4 hyperlipidemia (total cholesterol > 400 mg/dL or triglycerides > 500 
mg/dL) not improving despite appropriate treatment for 4 weeks
#
Any AE necessitating a 2-week treatment interruption
#
All other toxicities of CTCAE Grade ≥3 (except alopecia, allergic reaction, infusion 
reaction and those mentioned above)
#
Any other study drug related toxicity considered significant enough to be qualified as 
DLT in the opinion of the investigators (e.g. AE which not defined as DLT but requires 
dose reduction according to everolimus label), and confirmed by the safety review with 
the BI clinical monitor and BI project physician (TMM), will be reported as a DLT
For the purposes of dose finding, only DLT events that occur during the first treatment period 
of 28 days will be considered. Decisions regarding dose escalation/de-escalation steps will be 
made only after discussion between the sponsor and the clinical investigators, and in 
consideration of all the available safety information. Available data of DLTs occurring after 
first treatment course and all unusual/unexpected AE at any time during treatment will be 
considered for the purpose of recommending the dose for phase II part.
All DLT events must be reported immediately to the sponsor and documented in the eCRF. 
5.2.7
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)
The MTD is defined as:
The highest dose level of combination of BI 836845, everolimus, and exemestane, at which 
no more than 1 out of 6 patients experience a drug related DLT during the first course of 
treatment. DLTs occurring after the start of the second treatment course will be analyzed 
separately. DLT will only be investigated in the phase I part of the study.
For the definition of DLT and determination of MTD refer to Sections 5.2.6 and 4.1.3.2.
The MTD or a lower dose level will be chosen as the recommended phase II dose (RP2D) 
based on the totality of the safety data available by the time that 12 evaluable patients have 
finished course 1 of treatment at the MTD (or tentative RP2D if MTD not reached); at the 
earliest. The discussion and agreement on dose selection between the investigator and the 
sponsor will be documented and communicated to all participating sites. 
5.2.8
HBV and HCV testing
The HBV and HCV testing at screening must include HBV-DNA and/or HBsAg, anti-HCV 








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4.
Previous anticancer treatments: previous surgery, hormonotherapy, chemo-, targeted, 
or radiation therapy will be reported including setting (neoadjuvant vs. adjuvant vs.
therapeutic), start and end dates (month and year may be sufficient), the therapy 
protocol with the number of courses (chemotherapy), total radiation dose and 
radiation field (radiotherapy), the best response obtained (complete response, partial 
response, stable disease/ non-CR/non-PD, progressive disease, unknown) and reason 
for treatment discontinuation
5.4
APPROPRIATENESS OF MEASUREMENTS
All clinical assessments are standard measurements commonly used in studies of advanced 
solid tumors. Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 are used 
for assessment of the change in tumor burden. These criteria are well established and well 
received by the regulatory authorities and scientific community. 
The US NCI CTCAE is used in the assessment of adverse events in cancer patients. In the 
present study CTCAE version 4.03 will be used.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients must provide written informed consent (ICF) before any study related screening 
procedures can be performed.  A diagram of the stages of a patient’s participation in this trial 
is included in Section 3.1, and allowable time windows for visits are included in the Flow 
Chart.
Investigational drugs BI 836845 and everolimus will be dispensed at each visit according to 
the Flow Chart. Patients will receive a new medication kit number through the IRT system on 
each occasion for medications supplied by the sponsor. Exemestane and non-investigational 
everolimus (if applicable) should be prescribed by the investigator and supplied by pharmacy 
at study visits according to Flow Chart.
All screening assessment including tumor assessments must be completed within 28 days of 
start of run-in/C1V1. However, upon clinical assessment, if a patient presents with clinical 
symptoms of progressive disease, the investigator may use clinical judgement to determine 
whether to have the patient undergo another scan prior to starting treatment. Tumor 
assessments required for study participation which are completed as part of Standard of Care 
before the patient sign the ICF can be used for the screening assessments if they are
completed within the allowed timeframe.
All patients are to adhere to the visit schedule as specified in the Flow Chart. In the event of 
any study drug interruption or delay of treatment, the tumor assessment schedule should not 
be changed.
Blood samples for pharmacokinetics, biomarkers and immunogenicity will be collected from 
all patients in the Phase I part. In the Phase II part, tissue and blood samples will be collected 
for biomarkers from both treatment arms; blood samples for PK and immunogenicity testing 
will be collected from the patients on arm 2 only (BI 836845 + everolimus + exemestane). 
For specific PK, biomarker and immunogenicity sampling schedule refer to Appendix 10.5, 
Tables 10.5.1: 1 to 10.5.2: 2. Actual clock time for study drug administration and for each 
blood draw needs to be documented in the eCRF.
On visit days when PK sampling is scheduled, everolimus and exemestane should be 
administered during the clinical visit. On visit days when safety lab is scheduled, patients 
should show up in fasting condition, the blood draw can be done up to one day prior to the 
scheduled date.
Adverse events and concomitant medication must be collected starting from Day -7 of run-in 
until the (last) follow-up visit. 


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in periods
6.2.1.1
Screening period
Refer to the Flow Chart for procedure details. Please review Section 3.3.2 and 3.3.3 for 
eligibility criteria. 
Patients who failed screening may repeat the screening after discussion between investigator 
and sponsor providing that reasons for screening failure were reversible and have resolved.
All screening assessments including tumor imaging scan and ECG must be completed within 
28 days of start of run-in/C1V1. 
The provision of tumor tissue is mandatory. An archival tumor tissue must be collected prior 
to the start of study treatment
 Please refer to Appendix 10.7 for 
details.
6.2.1.2
Phase I part run-in period (from Day -7 to -1).
Refer to the Flow Chart and Appendix 10.5 Table 10.5.1: 1 for details. Prior to starting of 
triple-drug combination therapy with BI 836845, everolimus and exemestane, patients will 
receive continuous daily everolimus and exemestane doublet therapy for a 7-day run-in 
period. Everolimus and exemestane should be dispensed/filled on Day -7 of run-in. 
On Day -7 of run-in, prior to the administration of everolimus and exemestane, blood samples 
for biomarkers will be collected.
On Day -1 of the run-in period, patients must come fasted to the study site and must not take 
everolimus or exemestane until they have been instructed to do so at the clinic visit (refer to 
4.1.4.1.2 and 4.2.2.2 for details). PK samples must be collected before (-0.05h) and after the 
administration of everolimus and exemestane at 1:15h, 2h, 4h, 7h.
Patients must show up at fasting condition for a safety lab blood draw.
6.2.2
Treatment periods
Every treatment course is 28 days. All subsequent visit dates should be calculated based on 
Course 1 Visit 1 date. If a visit is missed there will be no re-scheduling; if a patient should 
attend the study site between the “missed” and the next scheduled visit, then the missed visit 
assessments should be performed except for BI 836845 infusion (if applicable), in which 
case, the infusion should be skipped on the delayed visit. The current date and the reason for 
the delay must be noted in the medical records. 
One or more visits can be skipped in case of treatment interruption. However, in the event of 
any study drug interruption or delay of treatment, the tumor assessment schedule will not be 
changed. 


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In this trial, patients may be hospitalized for the day of BI 836845 treatment and PK sampling 
at the discretion of the investigator; patients may be discharged if tolerated the treatment well 
and no safety concerns are present as judged by the investigator.
6.2.2.1 Phase I part
Refer to the Flow Chart and Appendix 10.5 Tables 10.5.1: 1 – 10.5.1: 2 for details.
Course 1, Visit 1 (Day 1 of 1st treatment course)
All procedures must be completed on Day 1 of Course 1. Compliance regarding everolimus 
and exemestane intake during the run-in period will be assessed. Sufficient everolimus and 
exemestane should be made available for the patient. Patients should come fasted to the study
site and should not take everolimus and exemestane until they have been instructed to do so 
at the clinic visit (refer to 4.1.4.1.2 and 4.2.2.2 for details). Blood samples for PK, biomarkers 
and immunogenicity will be collected before (-0.05h) and 1:15h, 2h, 4h, 7h after the 
administration of BI 836845, everolimus and exemestane. ECG will be collected prior to 
trough PK sampling and BI 836845 infusion, and immediately after BI 836845 infusion.
Course 1, Visit 2 (Day 2 of 1st treatment course, consecutive to course 1 Day 1 visit)
Patients should come fasted to the study site and should not take everolimus and exemestane 
until they have been instructed to do so at the clinic visit (refer to 4.1.4.1.2 and 4.2.2.2 for 
details). On Course 1 Day 2, prior to the administration of everolimus and exemestane, one 
trough PK as well as biomarker blood samples must be collected 24h after the first 
administration of BI 836845, everolimus and exemestane on Course 1 Day 1.
Course 1, Visit 3 (8 ±1 days after start of BI 836845)
Blood samples for safety lab, PK and biomarker must be collected. PK and biomarker 
samples must be collected before and after drug administration of BI 836845, everolimus and 
exemestane. ECG will be collected prior to trough PK sampling and BI 836845 infusion, and 
immediately after BI 836845 infusion.
Course 1, Visit 4 (15 ±1 days after start of BI 836845)
Blood samples for safety lab, PK and biomarker must be collected. PK and biomarker 
samples must be collected before and after drug administration of BI 836845, everolimus and 
exemestane. ECG will be collected prior to trough PK sampling and BI 836845 infusion, and 
immediately after BI 836845 infusion.
Course 1, Visit 5 (22 ±1 days after start of BI 836845)
Blood samples for PK and biomarker must be collected before and after drug administration 
of BI 836845, everolimus and exemestane.


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Course 2 (Day 1, 8, 15, 22 ±2 days) and all subsequent visits
Refer to Flow Chart and Appendix 10.5 Tables 10.5.1: 1 – 10.5.1: 2 for details.
6.2.2.2 Phase II part
Refer to the Flow Chart and Appendix 10.5 Tables 10.5.2: 1 – 10.5.2: 2 for details including 
timing on ECG, PK and drug administration.
If extremely necessary, for arm 2 patients receiving BI 836845 infussion at a subsequent visit, 
the transaction with the IVRS/IWRS system can be done up to one day before the actual visit 
date. Please refer to BI 836845 Preparation Storage and Administration instructions for more 
information about BI 836845 stability and storage conditions once diluted in the infusion bag
Course 1, Visit 1 (Day 1 of 1st treatment course)
All procedures must be completed on Day 1 of Course 1. However, the randomization may 
take place up to 3 days prior to the C1V1 if site procedures require advance randomization to 
accommodate the logistics of dispensing study medication to patients. Sites that use this 
option must include a copy of the policy or a documented justification in the ISF and submit 
a copy to the sponsor. The patient must take the first oral dose of study medications and 
receive BI 836845 infusion (if randomized to BI 836845 containing arm), while she is still at 
the investigative site, and to record this in the site source document. Sufficient drugs 
(everolimus and exemestane) should be made available for the patient. Blood samples for 
biomarkers (for all patients), immunogenicity and PK (for arm 2 patients only) will be 
collected before (-0.05h) and after (form arm 2 patients only) the administration of 
everolimus and exemestane with or without BI 836845. ECG will be collected from all 
patients, prior to trough PK sampling and administration of any study drug, and immediately 
after the end of BI 836845 infusion (for patients receiving BI 836845) OR one hour af ter the 
administration of everolimus + exemestane (for patients not receiving BI 836845).
Course 1, Visit 2 (8 ±2 Day after C1V1)
BI 836845 should be administrated with PK blood samples taken before and after the infusion 
for patients on arm 2 only. ECG, vital signs, adverse events and concomitant medication will 
be collected from all patients.
Course 1, Visit 3 (15 ±2 Days after C1V1)
Blood samples for biomarkers, PK and immunogenicity (for patients on arm 2 only) will be 
collected before (-0.05h) the administration of BI 836845 and/or everolimus plus exemestane. 
Furthermore, for patients having a biopsy, in addition to fresh tumor biopsy, blood samples 
for biomarkers (for all patients) and PK (for arm 2 patients only) should also be collected 
before the biopsy tumor sample is obtained (but not earlier than one hour before the biopsy). 
ECG will be collected from all patients, prior to trough PK sampling and administration of 
any study drug, and immediately after the end of BI 836845 infusion (for patients re ceiving 


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BI 836845) OR one hour after the administration of everolimus + exemestane (for patients 
not receiving BI 836845).
Course 1, Visit 4 (22 ± 2 Days after C1V1)
BI 836845 should be administrated for patients on arm 2. Vital signs, adverse events and 
concomitant medication should be collected from all patients.
Course 2 (Day 1, 8, 15, 22 ±2 Days) and all subsequent visits
Refer to Flow Chart and Appendix 10.5 Tables 10.5.1: 1 – 10.5.1: 2 for details.
For patients on arm 1 (everolimus + exemestane) of the Phase II part, the study visits on 
Visits 2 and 4 of Courses 3 through 6, and on Visits 2, 3, 4 from Course 7 onwards can be 
conducted via phone for the collection of adverse events and concomitant medication.
6.2.3
End of trial and follow-up period
6.2.3.1
End of treatment visit
End of Treatment Visit (0-7 days after permanent discontinuation of study drugs)
Refer to the Flow Chart for details. The patient must return all study drugs, and the site must 
document the reason for permanent discontinuation of study medication. 
If permanent 
discontinuation of study drug occurs during a scheduled visit, examinations as defined for 
EOTV should be performed instead of the examinations for the scheduled visit. 
Blood samples for soluble biomarkers (for all patients), PK and immunogenicity (for patients 
on BI 836845 regimen) must be obtained.
In patients who are experiencing disease progression at EOTV of the phase II part, a fresh 
tumor biopsy should be performed from those with appropriate informed consent.
6.2.3.2
Follow-up
This follow-up period is aimed for collection of additional AE and PD information. Refer to 
the Flow Chart and Appendix 10.5 for details.
Blood samples for soluble biomarkers, PK and immunogenicity (for patients on BI 836845 
regimen) must be obtained at FU1.
Phase I part
All patients should have a follow-up visit 42 days (+7days) after the permanent 
discontinuation of study drugs.


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Phase II part
Follow-up 1 (42 +7 days after permanent discontinuation of study drug)
Every patient should complete the first follow-up visit. Refer to the Flow Chart for details.
Additional follow-up visits 
Additional follow-up visits should be performed at scheduled tumor assessment according to 
the Flow chart.
The follow-up period for every Phase II patient will end at the earliest of the following 
events:
•
Disease progression
•
Start of a new anti-cancer therapy
•
Lost to follow-up
•
Withdrawal of consent
•
Death
6.2.3.3
Observation period
Phase I part
There is no observation period in the phase I part.
Phase II part
All patients will be followed-up for Overall Survival every 90 days after the last follow-up 
visit (as specified in Section 6.2.2.2) until death or completion of the whole trial (as specified 
in Section 6.2.3.4) whichever occurs earlier. During this period only information on patient 
vital status and subsequent anti-cancer treatment(s) will be collected.  The investigator may 
report SAE if s/he becomes aware of it.
The following information should be collected from patient's notes or by telephone contact (a 
formal visit is not required). The investigator/site staff should make at least three tries to 
obtain the information if a phone contact is conducted.
#
Date of contact and method of contact
#
Further anticancer  treatment
#
Death
#
Lost to follow-up
#
Withdrawal of consent
A snapshot of observation period data may be requested at any time. Following the primary 
analysis, the collection of observation period data may be reduced in frequency or stopped as 
appropriate, as decided and communicated by the Trial Clinical Monitor.


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6.2.3.4
End of Trial
Phase I part
The end of the phase I part of the trial will be when the last patient has completed the 
follow-up visit.
Phase II part
The end of the phase II part of the trial will be when the last patient has completed the 
first follow-up visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
Only descriptive and exploratory analyses are planned and no formal statistical testing is 
planned.
7.2
NULL AND ALTERNATIVE HYPOTHESES
As an exploratory Phase II trial, inferences about the efficacy of BI 836845 in combination 
with exemestane and everolimus will be based on the magnitude of the observed difference in 
PFS and other efficacy endpoints, e.g. objective response, overall survival, rather than a 
formal hypothesis testing. 
7.3
PLANNED ANALYSES
During the Phase I part, cohorts of patients treated with BI 836845 in combination with 
exemestane and everolimus will be evaluated continuously based on the totality of the safety 
data available in order to determine the recommended phase II dose. 
Efficacy analysis will include all randomised patients in the Phase II part. For the Phase I
dose finding stage, PFS and objective tumor response will be summarized descriptively by
cohort. No comparison will be done between cohorts.
Safety analysis will be summarized separately for patients treated in the Phase I and Phase II 
part of the trial. The safety profile of the Phase II part will be compared in a descriptive 
manner between the experimental and the control arm.
7.3.1
Primary analyses
The primary analysis of PFS will be conducted and reported when approximately 90 patients 
(out of 150 randomized patients) have progressed or died. However, it may be performed 
with fewer events within approximately 30 months after the first patient is randomized in the 
Phase II part. Any additional information collected after the data cut-off for the primary 
analysis will be reported in a revised clinical trial report.
The stratified Cox proportional hazards model will be applied to derive the estimate and 
confidence interval of the hazard ratio between the two treatment arms, stratified by visceral 
involvement (yes vs. no). Median PFS and PFS rate at certain time points, e.g. 2, 4, 6 months 
after randomization will be calculated from Kaplan-Meier curves with 95% confidence 
interval using the Greenwood variance estimate. Nominal p-value of a two-sided log-rank test 
on PFS will also be provided.
Response and disease progression is assessed according to RECIST 1.1. Refer to 
Section 5.1.1.2 for PFS definition. Clinical deterioration without image-based progression 




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7.3.3
Safety analyses
DLTs will be tabulated for each dose cohort in the Phase I part. The tabulation will be done 
in two ways:
• DLTs with onset in the first treatment course, and
• All DLTs regardless of treatment course at onset
The definition of DLT and determination of MTD are defined in Section 4.1.3 and 
Section 5.2.6 respectively.
Adverse events will be graded according to CTCAE, Version 4.03 (R10-4848). Key safety 
measures will include:
#
The overall incidence and intensity of AEs, as well as seriousness and relatedness of 
adverse events to treatment
#
Events leading to dosage reduction
#
Events leading to permanent treatment discontinuation
Other safety-relevant assessments including those involving ECG, and ECOG score, will be 
described with respect to possible changes compared to baseline values. Further details on the 
analysis of ECG data will be specified in the statistical analysis plan.
The safety profile will be summarized after the determination of RP2D.  
7.3.4
Interim analyses
No formal interim analysis is planned during this trial. 
A continuous monitoring of safety data of the Phase II part will be done by a DMC to ensure 
a benefit risk assessment at any time. During regular meetings, the committee may examine 
the efficacy data in order to completely assess the benefit risk of BI 836845 in combination 
with exemestane and everolimus.
Additionally to the continuous monitoring, the DMC will examine the efficacy data at two 
pre-specified time-points, after 30 and 45 PFS events are observed according to investigator’s 
assessment. The objective of these meetings is to facilitate further drug substance 
development and project planning based upon evaluation of the primary endpoint.
In case some pre-specified thresholds are met, the DMC can give the recommendation to start 
the preparation of a phase III trial or to start discussion of results with authorities, depending 
on the strength of this signal. All details of the methodology as well as the thresholds used for 
the signal detection will be described in an appendix to the DMC charter. This appendix will 
be kept confidential. Only a limited number of persons from BI, who are independent from 
the trial and project team, will have access to this appendix to avoid the potential introduction 
of operational bias. The people will be named in the DMC charter.


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The trial or project team will remain blinded and will not be involved in any operation 
requested by the DMC. An independent team will be designated to perform any actions the 
DMC deems necessary. The composition of this team will be pre-specified and documented 
in an interim analysis logistics plan, which will also describe how data protection will be 
ensured and define which functions and individuals will have access to the unblinded results. 
Anyone included in the aforementioned groups will sign a confidentiality agreement for these 
tasks, and is not allowed to discuss any unblinded results with people who are not authorized 
to know about them.
Regardless of whether the efficacy signal is observed and the above actions initiated, the trial 
will continue until its final analysis. 






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The phase II part of the study is intended to provide evidence that will allow informed 
decision making in terms of the next stages of development. It is therefore sized such that, if 
the true effect of BI 836845 in combination with exemestane and everolimus relative to 
exemestane and everolimus alone had a hazard ratio of 0.72 (median PFS 10.8 months of 
triple combination vs. 7.8 months exemestane and everolimus alone), the probability of 
observing a small hazard ratio is sufficiently large. If the true hazard ratio is 1, the probability 
of observing a small hazard ratio is small enough.
Table 7.6: 2 summarizes different numbers of PFS events and associated probabilities for 
observing hazard ratio less than some thresholds under different assumptions of true hazard 
ratio value. With 90 PFS events, if the true HR is 0.72, the chance of observing a treatment 
effect with HR of ≤ 0.8 is 69%, while the chance of observing a treatment effect with HR of 
≤ 0.9 is 86%. With 90 PFS events, if the true HR is 1.0, the chance of observing a treatment 
effect with HR of ≤ 0.8 is 14%, while the chance of observing a treatment effect with HR of 
≤ 0.9 is 31%. In this phase II exploratory study, the sample size is calculated to make an 
informed decision instead of confirmatory hypothesis testing.
If the PFS events are to be increased from 90 to 100, the probability of observing a treatment 
effect with HR of ≤ 0.85 is increased by 2% (from 78% to 80%) if true HR is 0.72. The same 
probability is increased by 1% (from 61% to 62%) if true HR is 0.8. Increasing the sample 
size will benefit more if the true HR is smaller. However, the probability of 7 8% when true 
HR is 0.72 is considered high enough for 90 PFS events in this exploratory setting.


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Table 7.6: 2
Number of PFS events and corresponding probability of making 
observing HR below thresholds
Probability1 observing HR of ≤
PFS 
Events
True HR
0.8
0.85
0.9
1.0
80
0.72
68%
77%
84%
93%
90
69%
78%
86%
94%
100
70%
80%
87%
95%
Probability1 observing HR of ≤
PFS 
Events
True HR
0.8
0.85
0.9
1.0
80
0.80
50%
61%
70%
84%
90
50%
61%
71%
86%
100
50%
62%
72%
87%
Probability1 observing HR of ≤
PFS 
Events
True HR
0.7
0.8
0.85
0.9
80
1.0
6%
16%
23%
32%
90
5%
14%
22%
31%
100
4%
13%
21%
30%
1 Calculated based on the approximate normal distribution of the estimated 
log HR.
Ninety PFS events is considered sufficient in this phase II trial to show positive efficacy 
signal if the experimental treatment is superior to the control.
Assuming constant recruitment rate of 12.5 patients per month for a period of A months, the 
percentage of observed PFS events relative to sample size is a function of study duration T:
%
&
%
&
∋
(
)
∗
+
,
−−
.
/
00
1
2
∀
∀
3
−−
.
/
00
1
2
∀
∀
∀
∀
∀
∀
∀
∀
2
1
2
2
1
1
1
1
2
1
4
4
4
4
4
4
A
e
e
A
e
e
T
A
T
T
A
T
,
where λ1=0.064 and λ2=0.089 are the parameters of exponential distribution assuming median 
PFS 10.8 months for BI 836845 in combination with exemestane and everolimus and 7.8 
months for exemestane and everolimus alone. Assuming  rates of permanently censored 
patients between 20 to 30%, the study duration of observing 90 PFS events is estimated to be 
between 24.9 and 32.5 months (Table 7.6: 3). Permanently censored patients are those 
patients that leave the trial without having a PFS event. For the duration of a trial that is event 
driven it is a concern if patients leave the study without such an event before the primary 
evaluation, as it will take longer until the primary analysis can be performed. 
Therefore, the primary analysis is targeted when 90 PFS events are observed or 30 months 
after first patient was randomized in the phase II part.


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According to these considerations, a total of 150 patients will be randomised in the Phase II 
part of the trial.
Table 7.6: 3
Study duration until targeted number of PFS events for different rates
of permanently censored patients
Patients 
randomised
Accrual period 
[months]
Rate of 
permanently 
censored 
patients
Number of PFS 
events expected at 
primary readout
Expected trial duration 
to reach expected 
number of PFS events1
[months]
150
12
20%
90
24.9
150
12
25%
90
27.9
150
12
30%
90
32.5
1Assuming a true HR of 0.72 (median PFS 10.8 vs 7.8 months) and a recruitment rate of 
12.5 patients per month


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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 ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
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.
The rights of the investigator and of the sponsor with regard to publication of the results of
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
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 Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient -
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
If a patient has withdrawn consent to continue trial medication and trial procedures, the 
informed consent form must specifically indicate that the patient has given permission to 
collect informatin on his/her vital status and further treatment for those who participated in 
the Phase II part of the study.
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 (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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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/IECs or by regulatory authorities. The quality assurance
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. For drug accountability, refer to Section 4.1.8.
Coding of the data obtained will be done by using the medical dictionary for regulatory 
activities (MedDRA) and the world health organisation drug dictionary (WHO-DD).
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 / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/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. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents
described in Section 8.3.1.
8.3.3
Storage of records
Trial sites:
The trial sites must retain the source documents and essential documents for a period defined 
by GCP regulations or other Guidelines as applicable per country (i.e.
European Commission Directive, Japanese GCP regulation and FDA Guidelines). 


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Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs. When it is 
no longer necessary for the trial site to retain the source documents and essential documents, 
the sponsor must notify the trial site.
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 BI 836845, this is the current version of the Investigator’s Brochure (U10-2830). For 
everolimus and exemestane, this is the latest version of EU SPC. The current versions of 
these reference documents are to be provided in the ISF. No AEs are classified as listed for 
study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
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 / IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient out, unless specified differently in Section 6.2.3 of the CTP) 
or early termination of the trial. The sponsor needs to notify the IEC and CA within 90 days 
of regular completion of the trial and within 15 days in case of early termination in 
accordance with Directive 2001/20/EC. In case of early termination, a detailed written 
explanation of the reasons for the termination needs to be given. A summary of the trial 
results (tabulated summary of the CTR) needs to be provided to the IEC and CA within 1 
year of the end of the trial.


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9.
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9.1
PUBLISHED REFERENCES
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Murtaza M, Dawson SJ, Tsui DWY, Gale D, Forshew T, Piskorz AM, 
Parkinson C, Chin SF, Kingsbury Z, Wong ASC, Marass F, Humphray S,
Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N. Non-
invasive analysis of acquired resistance to cancer therapy by sequencing of 
plasma DNA. Nature 497, 108 - 112 (2013)
R15-0261
Bidard et al. Clinical validity of circulating tumour cells in patients with 
metastatic breast cancer: a pooled analysis of individual patient data. Lancet 
Oncol. 15, 406 (2014).
P12-07179 
Adam PJ, Friedbichler K, Hofmann MH, Bogenrieder T, Borges E, Adolf GR. 
BI 836845, a fully human IGF ligand neutralizing antibody, to improve the 
efficacy of rapamycin by blocking rapamycin-induced AKT activation. 48th 
Ann Mtg of the American Society of Clinical Oncology (ASCO), Chicago, 1 -
5 Jun 2012 (Poster) 2012
P13-02270
Zhou H, Mascelli MA. Mechanisms of monoclonal antibody-drug interactions.
Annu Rev Pharmacol Toxicol. 2011; 51: 359-72
P13-05504
NCCN Clinical Practice Guidelines in Oncology: breast cancer (V.2.2013). 
website nccn.org; National Comprehensive Cancer Network 2013
P13-05525
Yang Y, Yee D. Targeting insulin and insulin-like growth factor signaling in 
breast cancer. J Mammary Gland Biol Neoplasia 17 (3/4), 251 - 261 (2012)
P13-05658
Zardavas, D, Basalga J and Piccart M. Emerging targeted agents in metastatic 
breast cancer. Nat Rev Clin Oncol. 2013 Apr;10(4):191-210.
9.2
UNPUBLISHED REFERENCES
U10-2830 
 
Investigator’s Brochure: BI 836845, Indication: Oncology 1280.P1, Version 
2.0, 04-May-2012.


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10.
APPENDICES
10.1
NYHA CLASSIFICATION OF HEART FAILURE
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, or dyspnea 
(shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or 
dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, 
but less than ordinary activity causes fatigue, palpitation, or 
dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical 
activity is undertaken, discomfort is increased.
10.2
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
* As published in Am. J. Clin. R01-0787


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10.3
LIST OF CYP3A4 INHIBITORS, INDUCERS AND LIST OF INHIBITORS 
OF P-GLYCOPROTEIN
10.3.1
Examples of CYP 3A4 inhibitors and inducers
CYP3A4 Inhibitors
CYP3A4 Inducers
Strong inhibitors:
atazanavir, boceprevir,
ciclosporin,
clarithromycin,
conivaptan, darunavir,
grapefruit juice*,
indinavir, itraconazole,
ketoconazole,
lopinavir/ritonavir,
mibefradil, nefazodone,
nelfinavir, osaconazole,
posaconazole,
ritonavir, saquinavir,
telaprevir,
telithromycin,
voriconazole
Moderate inhibitors:
amprenavir, aprepitant,
atazanavir,
ciprofloxacin,
crizotinib,
darunavir,
diltiazem,
erythromycin,
fluconazole,
fosamprenavir,
grapefruit juice*,
imatinib, ritonavir,
verapamil
* The effect of grapefruit
juice varies widely and is
preparation-dependent.
Strong inducers:
carbamazepine, phenytoin,
rifampin/rifampicin,
rifabutin, rifapentine,
phenobarbital,
St. John’s wort**
** The effect of St. John’s wort
varies widely and is
preparation-dependent.
Moderate inducers:
bosentan, corticosteroids
(e.g. dexamethasone,
prednisone, prednisolone),
phenobarbital, efavirenz,
etravirine, modafinil,
nafcillin, nevirapine


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As the information may evolve, it is important for the investigator to assess such status on 
concomitant therapies and contact BI clinical monitor in case of questions.
10.3.2
List of inhibitors of P-glycoprotein (MDR1) 
Pgp Inhibitors
Amiodarone
Azithromycin
Captopril
Carvedilol
Ciclosporin
Clarithromycin 
Conivaptan
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quercitin
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
As the information may evolve, it is important for the investigator to assess the status of each 
concomittant therapies. In case of questions, please contact BI clinical monitor.


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10.4
TUMOR RESPONSE ASSESSMENT ACCORDING TO RECIST 1.1
Response criteria for target lesions
1.   Complete Response 
(CR):
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have a reduction in 
short axis to <10mm)
2.   Partial Response (PR):
At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum diameters
3.   Progression (PD):
At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of a least 5mm (note: the 
appearance of one or more new lesions is also considered 
progression).
4.   Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as references the smallest 
sum diameters while on study
Response criteria for non-target lesions
1.   Complete Response 
(CR):
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-
pathological in size (<10mm short axis)
2.   Non-CR/ Non-PD:
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits
3.   Progression (PD):
Unequivocal progression of existing non-target lesions (Note: 
the appearance of one or more new lesions is also considered 
progression)
Timepoint response for patients with measurable disease at baseline
Target lesions
Non-Target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Timepoint response for patients with non-measurable disease at baseline


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Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/ Non-PD
No
Non-CR/ Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
RECIST 1.1 is as published in Eur. J. Cancer R09-0262


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10.6
CLINICAL EVALUATION OF LIVER INJURY
10.6.1
Introduction
Alterations of liver parameters, as described in Section 5.2.2.1 (Protocol-Specified Adverse 
events of special interest), are to be further evaluated using the following procedures:
10.6.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible.
If the alert is confirmed on initial sample, or it is not possible to repeat testing using intial 
sample, the following must be completed:
1)
Evaluate patient within 48 hours and
2)
Perform the following laboratory tests: 
1.
Repeat of AST, ALT, bilirubin (with fractionation to total and direct) 
2.
Haptoglobin
3.
Complete blood count and cell morphology
4.
Reticulocyte count
5.
Creatine Kinase (CK)
6.
Lactate dehydrogenase (LDH)
7.
Alkaline Phosphatase
The results of these laboratory tests must be reported to BI as soon as possible.
If the initial alert values (ie AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging  
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or 
neoplasm) must be completed within 48 hours. 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process. In 
the event the etiology of the abnormal liver tests results is not identified based on the imaging 
(e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be 
completed.  Details of the “DILI checklist” are provided in the ISF.  The following 
assessments need to be performed in order to complete the “DILI checklist” and results will 
be reported via the eCRF:


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#
obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;
#
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;
#
obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;
#
complete the following laboratory tests as detailed in the DILI checklist provided in the 
ISF:
–
Clinical chemistry
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK, CK-MB, 
coeruloplasmin*, α-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, Epstein Barr Virus (VCA IgG, VCA IgM), 
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella (IgG, 
IgM)*, parvovirus (IgG, IgM)*
–
Hormones, tumor marker
Thyroid-stimulating hormone(TSH)*
–
Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g. immunocompromised patients)
 Long term follow-up
–
Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin 
(with fractionation to total and direct) at least weekly until the laboratory ALT and or 
AST abnormalities stabilize 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 Good Clinical 
Practices (GCP).
and report these via the eCRF.




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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
07 May 2015
EudraCT number
2013-001110-15
BI Trial number
1280.4
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II Randomized Study of BI 836845 in 
Combination with Exemestane and Everolimus Versus 
Exemestane and Everolimus Alone in Women with Locally 
Advanced or Metastatic Breast Cancer 
To be implemented only after
approval of the IRB/IEC/Competent 
Authorities
To be implemented immediately in 
order to eliminate hazard –
IRB / IEC / Competent Authority to 
be notified of change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve logistical 
or administrative aspects only
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
The sentence:
“Patients must have a measurable lesion according to 
RECIST version 1.1 or bone lesion only: lytic or mixed 
(lytic + sclerotic) in the absence of measurable lesion”
Has been updated to 
“Patients must have a measurable lesion according to 
RECIST version 1.1 or bone lesion: lytic or mixed (lytic + 
sclerotic) in the absence of measurable lesion”
Rationale for change
Clarification
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Criteria for efficacy section has been updated by replacing 
“6m” by “24w”
Rationale for change
Accuracy
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Criteria for efficacy section has been updated by replacing 
“Clinical benefit” by “Disease control”
Rationale for change
Terminology update
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
cfDNA tests and CTC tests have been added in the criteria 
for efficacy section.
Rationale for change
Additional tests.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Objectives for Phase I part. A “coma” has been replaced






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Number of global amendment
1
Rationale for change
Clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
Criterion 2 has been updated from:
“Prior treatment with exemestane”
To
“Prior treatment with exemestane (except adjuvant 
exemestane stopped > 12 months prior to start of study 
treatment as long as patient did not recur during or within 
12 months after the end of adjuvant exemestane)”
Rationale for change
Consistency with clinical practice. 
Section to be changed
3.3.3 Exclusion criteria
Description of change
On criterion 6, “run-in treatment” has been updated to “the 
start of study treatment”
Rationale for change
A synonym expression is preferred because fits better in the 
Phase II part of the trial, where treatment starts at C1V1 
because there’s no run-in period.
Section to be changed
3.3.3 Exclusion criteria
Description of change
On criterion 7, the sentence “(This criterion concerns anti-
cancer therapy only)” has been added.
Rationale for change
Clarification
Section to be changed
3.3.4 Removal of patients from therapy or assessments
Description of change
The sentence “The sponsor may remove patients from the 
study after completion of the primary efficacy analysis and 
the patient has access to BI 836845 through an expanded-
access program, named patient use program, or 
compassionate use protocol.” has been deleted.
Rationale for change
The procedure is not applicable in this trial 
Section to be changed
4.1.2 Method of assigning patients to treatment groups
Description of change
The sentence “If more than one site notifies potential 
patients and there are no slots for all proposed candidates, 
BI Clinical Monitor will allocate the slot prioritizing by 
planned calendar, balanced number of patients per site and 
other parameters as needed.” has been added.
AND
The sentence “for a maximum of seven calendar days. If the 
informed consent form (ICF) has not been signed by the 
potential patient within this time window, the slot will be 
opened up again for all recruiting sites.” has been updated 
to
“for a reasonable period of time until patient signs IC”
Rationale for change
Better describe the actual procedure to assign available slots 
to the sites participating in the Phase Ib part of the trial.
Section to be changed
4.1.4.3 Temporary treatment interruption and dose 
reduction
Description of change
“No dose reduction is allowed below 500 mg for BI 836845 
or 2.5 mg for everolimus.” 
Has been corrected to:
“No dose reduction is allowed below 500 mg for BI 836845 
or 2.5 mg every other day for everolimus.”
Rationale for change
Correction made for consistency throughout the protocol.
Section to be changed
4.2.1.3 Concomitant treatments
Description of change
The following paragraph has been moved from section 
4.2.2.1 Restrictions to this section:


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Number of global amendment
1
“The acute use of bisphosphonates for symptomatic 
treatment of bone metastases is permitted during the study, 
but chronic use for the prevention of bone metastases is 
prohibited (see Section 4.2.2.1). Bisphosphonate therapy for 
the treatment of osteoporosis, at the doses indicated under 
prescribing information, is permitted during the study. If 
bisphosphonate therapy is initiated after enrollment, the 
reason for its use must be clearly documented clearly 
documented in the eCRF.”
Rationale for change
For consistency, since the use of bisphosphonates is allowed 
in certain conditions it should be included in the 
concomitant treatments section 
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
The paragraphs:
“For everolimus: Everolimus is a substrate of CYP3A4, and 
also a substrate and moderate inhibitor of PgP. Concomitant 
strong CYP3A4 inhibitors should not be used with 
everolimus. 
Exercise caution when everolimus is used in combination 
with moderate CYP3A4 and/or strong and moderate PgP 
inhibitors. If alternative treatment cannot be administered, 
reduce the dose of everolimus.
Consider a dose increase of everolimus when co-
administered with strong CYP3A4 inducers if alternative 
treatment cannot be administered. St.John’s Wort may 
decrease everolimus exposure unpredictably and therefore 
should be avoided.
For exemestane: Exemestane is a substrate of CYP3A4. 
Pharmacokinetic study showed that co-medications that 
induce 
CYP3A4 
(e.g., 
rifampicin, 
phenytoin, 
carbamazepine, phenobarbital, or St. John’s wort) may 
significantly decrease exposure to exemestane. Hence, dose 
modification is recommended for patients who are also 
receiving a potent CYP 3A4 inducer.”
Has been updated to:
“For everolimus: Everolimus is a substrate of CYP3A4, and 
also a substrate and moderate inhibitor of PgP. Systemic 
concomitant strong CYP3A4 inhibitors and PgP inhibitors 
should not be used with everolimus. (refer to Appendix 3
for a list of examples). 
Use caution when co-administration of moderate CYP3A4 
inhibitors or PgP inhibitors cannot be avoided (refer to 
Appendix 3 for a list of examples). If patients require co-
administration of a moderate CYP3A4 or PgP inhibitor, 
dose reduction to 5 mg daily or 2.5 mg daily may be 
considered. Due to between subject variability the 
recommended dose adjustments may not be optimal in all
individuals, therefore close monitoring of side effects is 
recommended. If the moderate inhibitor is discontinued, 


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Number of global amendment
1
consider a washout period of at least 2 to 3 days (average 
elimination time for most commonly used moderate 
inhibitors) before the everolimus dose is returned to the 
dose used prior to initiation of the co-administration.
Avoid the use of concomitant potent CYP3A4 inducers (e.g. 
rifampicin, 
phenytoin, 
carbamazepine, 
phenobarbital, 
dexamethasone or St. John’s wort). If patients require co-
administration of a potent CYP3A4 inducer, an everolimus 
dose increase from 10 mg daily up to 20 mg daily should be 
considered using 5 mg increments or less applied on Day 4 
and 8 following start of the inducer. If treatment with the 
inducer is discontinued, consider a washout period of at 
least 3 to 5 days (reasonable time for significant enzyme de-
induction), before the everolimus dose is returned to the 
dose used prior to initiation of the co-administration.
St.John’s Wort 
may decrease everolimus exposure 
unpredictably and therefore should be avoided.
For exemestane: Exemestane is a substrate of CYP3A4. 
Pharmacokinetic study showed that co-medications that 
induce 
CYP3A4 
(e.g. 
rifampicin, 
phenytoin, 
carbamazepine, phenobarbital, dexamethasone or St. John’s 
wort) may significantly decrease exposure to exemestane. 
Since the clinical relevance of this interaction has not been 
evaluated, the co-administration of drugs known to induce 
CYP3A4 may reduce the efficacy of exemestane
Exemestane does not inhibit any of the major CYP 
isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. 
Nevertheless, exemestane should be used cautiously with 
drugs that are metabolised via CYP3A4 and have a narrow 
therapeutic window.”
Rationale for change
Update information as per Afinitor SmPC new version, 
dated 16 December, 2014
Update dose modification recommendations for Exemestane 
according to EU label (US label information has been taken 
out), as per Swedish authorities request.
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
The paragraph:
“In addition, the following concomitant treatments are not 
allowed during the study:
1)
Chronic concomitant bisphosphonate therapy for 
the prevention of bone metastases
Bisphosphonate therapy for the treatment of 
osteoporosis is permitted during the study. 
Bisphosphonate therapy for the management of 
bone metastases is recommended as standard of 
care. Please refer to prescribing information for 


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Number of global amendment
1
details 
of 
administration. 
If 
bisphosphonate 
therapy is initiated after enrollment, the reason for 
its use must be clearly documented”
Has been updated to:
“In addition, the following concomitant treatments are not 
allowed during the study:
1)
Chronic concomitant bisphosphonate therapy for 
the prevention of bone metastases (the use of any 
other agent for the prevention of bone metastasis is 
not allowed during the study).”
Rationale for change
Clarification
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
The paragraph:
7)
The use of concomitant medications that 
prolong the QT/QTc interval (refer to website 
crediblemeds.org for the list of medications) 
Has been updated to:
7) The use of concomitant medications that 
prolong the QT/QTc interval (refer to website 
crediblemeds.org for the list of medications) 
should be avoided, except in those cases where 
treatment is necessary after a risk-benefit 
evaluation by the investigator and provided that 
the drug in question cannot be substituted by any 
other agent.
Rationale for change
Consistency with clinical practice and patient needs.
Section to be changed
Section 4.4 Management of expected adverse events
Description of change
The following paragraph has been added:
“In everolimus SPC, non-infectious pneumonitis, infections, 
hypersensitivity reactions, concomitant use of angiotensin-
converting enzyme inhibitors, oral ulceration, renal failure 
events, and some lab tests and monitoring are described 
under “Special warnings and precautions for use”. For 
updated information regarding warning and precautions of
everolimus and exemestane, please refer to the most current 
version.”
Rationale for change
Update information as per Afinitor SmPC new version, 
dated 16 December, 2014
Section to be changed
Section 4.4.6 Management of infection (related to 
Everolimus)
Description of change
Section created with the following wording:
“Everolimus has immunosuppressive properties and may 
predispose patients to bacterial, fungal, viral or protozoan 


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Number of global amendment
1
infections, including infections with opportunistic 
pathogens. Opportunistic infections such as pneumocystis 
jirovecii (carinii) pneumonia (PJP, PCP) have been reported 
in patients who received everolimus and should be ruled out 
in the differential diagnosis of non-infectious pneumonitis. 
Prophylaxis for PJP/PCP should be considered when 
concomitant use of corticosteroids (e.g. for treatment of 
non-infectious pneumonitis) or other immunosuppressive 
agents are required.
Please follow the most current everolimus SPC or local 
prescribing information for updated recommendations of 
management.”
Rationale for change
Update information as per Afinitor SmPC new version, 
dated 16 December, 2014
Section to be changed
Section 5 
Description of change
Correct the definition of PFS using randomization instead 
of C1V1
Rationale for change
Use BI standard PFS and most widely accepted definition
Section to be changed
5.1.1.2  Secondary endpoints
Description of change
“Phase II part” has been added
Rationale for change
Clarification
Section to be changed
5.1.1.2  Secondary endpoints
Description of change
“clinical benefit” has been updated to “disease control”
Rationale for change
Terminology update
Section to be changed
5.1.1.2  Secondary endpoints
Description of change
“6m” has been updated to “24w”
Rationale for change
Accuracy
Section to be changed
5.1.2.1 Tumor Response  
Description of change
The following sentences have been added:
“For the Phase II part of the study, image acquisition will be 
performed as described in the Imaging Guideline (wich will 
be filed in the ISF). Images will be collected and stored at a 
central facility assigned by the sponsor. The sponsor retains 
the option to perform an independent blinded central review 
of the study images at a later time.”
“For the phase II part, these need to also meet the 
requirements in the Imaging Guideline.”
Rationale for change
If needed, a central independent review of tumor images 
may be conducted at a later time. 
Section to be changed
5.1.2.3  Assessment of disease progression
Description of change
“patients with bone only lesions” has been updated to
“patients with bone lesions”
Rationale for change
Clarification 
Section to be changed
5.2.1 Endpoints of safety
Description of change
The sentence: “For the phase I part, the primary endpoints
are DLT and MTD” has been added
Rationale for change
Clarification
Section to be changed
5.2.1 Endpoints of safety
Description of change
The sentence: “Dose limiting toxicities (primary endpoint 
for Phase I part only)” has been deleted
Rationale for change
DLT is a formal endpoint and should not be listed here. 


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Number of global amendment
1
Section to be changed
5.2.1 Endpoints of safety
Description of change
“Safety 
endpoints” 
has 
been 
replaced 
by 
“Other 
assessments of safety”
Rationale for change
To be more accurate and clarify that the list does not 
correspond to formal endpoints 
Section to be changed
5.2.1 Endpoints of safety
Description of change
“Other 
safety-related 
assessments 
involving 
ECG 
parameters and ECOG score” 
Has been updated to
“Other 
safety-related 
assessments 
involving 
ECG 
parameters and ECOG score will be described with respect 
to possible changes compared to baseline values. Further 
details on the analysis of ECG data will be specified in the 
TSAP.”
Rationale for change
To provide more precise information
Section to be changed
5.2.2.1. Definitions of adverse events
Description of change
The term “Significant adverse events”
Has been updated to
“Adverse events of special interest”
Rationale for change
Terminology consistency through the protocol and the BI 
standards.
Section to be changed
5.2.2.1. Definitions of adverse events
Description of change
DILI definition includes now marked peak aminotransferase 
(ALT, and/or AST) elevations equal or above 10 fold ULN.
Other wording in the section has been refined to fit the 
new company templates.
Rationale for change
Consistency with BI standards.
Section to be changed
5.2.5.2. Vital signs, height and weight
Description of change
The sentence 
“Blood pressure and pulse will be measured after the patient 
has been recumbent for 5 minutes”
Has been updated to
“Blood pressure and pulse will be measured after the patient 
has been recumbent or seated for 5 minutes”
Rationale for change
It’s also allowed to measure blood pressure and pulse if the 
patient has not been recumbent but seated.
Section to be changed
5.2.6 Dose limiting toxicity (DLT)
Description of change
“The primary endpoint of the Phase I part is occurrence of 
Dose Limiting Toxicity (DLT).” has been updated to “The 
primary endpoint of the Phase I part are occurrence of Dose 
Limiting Toxicity (DLT) and determination of MTD.”
AND
Oral mucositis has been added as a synonym term for 
stomatitis
AND
“DLTs occurring after first treatment course and all 
unusual/unexpected AE during the whole treatment will be 
considered for the purpose of recommending the dose for 
phase II part.” has been updated to “Available data of
DLTs occurring after first treatment course and all 
unusual/unexpected AE at any time during treatment will be 














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Section to be changed
10.7 Tumor tissue sample requirements.
Description of change
Footnote “8 to 10 sections of 5μm each are also acceptable” 
and “at least” have been added.
Rationale for change
Clarification


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Number of global amendment
2
Date of CTP revision
30 March 2016
EudraCT number
2013-001110-15
BI Trial number
1280.4
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II Randomized Study of BI 836845 in 
Combination with Exemestane and Everolimus Versus 
Exemestane and Everolimus Alone in Women with Locally 
Advanced or Metastatic Breast Cancer 
To be implemented only after 
approval of the IRB/IEC/Competent 
Authorities
To be implemented immediately in 
order to eliminate hazard –
IRB / IEC / Competent Authority to 
be notified of change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve logistical 
or administrative aspects only
Section to be changed
Flowchart  (all phases)
Description of change
Bone scan reference added 
Rationale for change
Reminder of procedure added to flowchart.
Section to be changed
Flowchart  (phase II part)
Description of change
Footnote # 9 has been refined  
Rationale for change
Consistency with Appendix 10.5
Section to be changed
Abbreviations
Description of change
PTM = Planned Time has been added.
Rationale for change
Omission in previous versions
Section to be changed
3.3.2. Inclusion criteria
Description of change
Inc. criterion #7 added wording: “Both, a) and b) above 
must fulfil the condition described in Section 5.1.2 for 
irradiated tumors Both, a) and b) above must fulfil the 
condition described in Section 5.1.2 for irradiated tumors”
Rationale for change
Clarification 
Section to be changed
3.3.2. Inclusion criteria
Description of change
Inc. criterion #4 has been reworded 
Rationale for change
Consistency with current postmenopausal status definition 
at participating investigational sites. 
Section to be changed
3.3.3. Exclusion criteria
Description of change
“or current presence” added in excl. criterion #14
Reference to relevant section added to excl. criterion #12
“(in lung)” added to excl. criterion #15
Rationale for change
Clarification 
Section to be changed
2.3 Benefit-Risk Assessment
Description of change
Recommendation to monitor weight loss has been added 
added
Rationale for change
Patients well-being
Section to be changed
5.1.2 Assessment of efficacy - Flowchart footnote 15 also 


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Number of global amendment
2
adapted accordingly
Description of change
The following wording has been added 
“Patients who discontinue the trial for any reason other than 
imaging based progressive disease should have a tumour 
assessment (RECIST 1.1) performed at EOTV (exception to 
this are patients who have already had tumor assessment 
within 28 days of EOT visit)”
Rationale for change
Improve accuracy of assessment of efficacy for these 
particular cases
Section to be changed
5.2.2.1 Definitions of adverse events
Description of change
Prenumonitis has been added as AE of special interest
Rationale for change
Decision has been made to closely monitor these AEs. 
Pneumonitis cases will be reported as AESI from the time 
this amendment is approved by Authorities, and in no case a 
retrospective reporting will be mandated.
Section to be changed
5.2.3 Assessment of safety laboratory parameters
Description of change
Phosphorus to be determined
Rationale for change
Patients safety, based on Everolimus SmPC
Section to be changed
5.2.4 Electrocardiogram
Description of change
Clarification added “It is not mandatory to wait for central 
evaluation of ECGs to take clinical decisions, but in case of 
values close to 470ms at screenint visit, it’s strongly 
recommended to ask for central lab report to confirm 
eligibility for patients’ safety.”
Rationale for change
Clarification
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Clarification of the DMC tasks (2 pre-defined analysis )
Rationale for change
It has been decided on project level that the DMC performs 
two additional pre-specified looks for efficacy.
Section to be changed
4.1.5.1 Blinding
Description of change
Clarification of the process to keep the trial team blinded 
while the DMC is looking at unblended data
Rationale for change
Following the decision to add two interim looks by the 
DMC, blinding process has been clarified
Section to be changed
5.1.1.1 Primary endpoint and 5.1.1.2 Secondary endpoints
Description of change
Definitions of the endpoints have been updated
Rationale for change
Follow the Reference document to the CTP SOP, for 
oncology trials (001-MCS-40-106_RD-22)
There is no change regarding the content, but the wording is 
now harmonised with the RD
Section to be changed
5.2.1 Endpoints of safety
Description of change
Definitions of the endpoints have been updated
Rationale for change
Follow the Reference document to the CTP SOP, for 
oncology trials (001-MCS-40-106_RD-22)
There is no change regarding the content, but the wording is 
now harmonised with the Reference Document
Section to be changed
5.2.2.1 Definitions of adverse events
Description of change
Wording regarding “Exemption to (S)AE reporting” has 
been added
Rationale for change
PD is already reported as clinical trial endpoint and 
therefore does not need to be reported as an (S)AE. This is 
common procedure in most oncology trials.
Section to be changed
5.3.1 Other endpoints


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Number of global amendment
2
Description of change
Definitions of the endpoints have been updated
Rationale for change
Follow the Reference document to the CTP SOP, for 
oncology trials (001-MCS-40-106_RD-22)
There is no change regarding the content, but the wording is 
now harmonised with the reference document
Further endpoints for phase I part have been added.
Section to be changed
Description of change
Rationale for change
Section to be changed
7.3.1 Primary analyses
Description of change
Derivation of PFS and censoring rules have been added
Rationale for change
Follow the Reference document to the CTP SOP, for 
oncology trials (001-MCS-40-106_RD-22)
Section to be changed
7.3.2 Secondary analyses
Description of change
Analyses of some secondary endpoints has been adapted
Rationale for change
Follow the Reference document to the CTP SOP, for 
oncology trials (001-MCS-40-106_RD-22)
Section to be changed
7.3.4 Interim analyses
Description of change
More detailed description of the two prespecified analyses 
performed by the DMC has been added
Rationale for change
It has been decided on project level that the DMC performs 
two additional predefined looks for efficacy.
Section to be changed
Section 7.6.2 and Table 7.6.3
Description of change
Refine wording and renaming “drop outs” as “permanently 
censored patients” 
Rationale for change
Accuracy
Section to be changed
Appendix 10.5 
Description of change
Clarifications added and timepoints for sampling reduced
Rationale for change
Reduce sampling timepoints and clarify analysis as 
knowledge in the field evolves


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
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Technical Version Number:
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Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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

SAP_001.pdf: 
 
Trial Statistical Analysis Plan 
c02159131-03
BI Trial No.:
1280.4
Title:
A Phase Ib/II Randomized Study of BI 836845 in Combination 
with Exemestane and Everolimus Versus Exemestane and 
Everolimus Alone in Women with Locally Advanced or Metastatic 
Breast Cancer
Including Protocol Amendment 03 [c02243064-12]
Investigational
Product(s):
Xentuzumab, BI 836845
Responsible trial 
statistician(s):
Phone: +
Date of statistical 
analysis plan:
25 APR 2018 REVISED
Version:
Revised
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9.2.4
Random coefficient model used to evaluate the appropriateness QT 
interval correction methods for heart rate..................................................69
9.2.5
Technical details on handling of ECG recordings......................................71
10
HISTORY TABLE...............................................................................73


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LIST OF TABLES
Table 5.1.2: 1
Derivation rules for PFS.............................................................................13
Table 5.2.2.2: 1
Derivation rules for Time to Progression...............................................16
Table 5.2.2.2: 2
Derivation rules for Duration of Objective Response............................18
Table 5.2.2.2: 3 
Derivation rules for Duration of Disease Control..................................19
Table 6.2: 1
Important protocol violations..........................................................................32
Table 6.6: 1
Rules for imputations of missing or incomplete dates ....................................40
Table 6.7.2: 1
Nominal time-points and windows for imaging.........................................42
Table 7.8.1: 1
Adverse events by user defined AE categories ..........................................54
Table 7.8.4: 1 Maximum acceptable time deviations between PK blood sampling and ECG 
recording during the trial, Phase II part ...........................................................................58
Table 10: 1
History table ....................................................................................................73




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Term
Definition / description
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DC
Disease Control
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DMS
Data Management and Statistics
ECG
Electrocardiogram
ECGS
ECG set
eCRF
Electronic Case Report Form
Emax
Maximum measurement of pharmacodynamic parameter
ENR
Enrolled Set
EOT
End of Treatment
EOTV
End of Treatment Visit
FDA
Food and Drug Administration
FU
Follow-up
HR
Hazard Ratio
ICH
International Conference on Harmonisation
 
 
IPV
Important Protocol Violation
IRT
Interactive Response Technology


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Term
Definition / description
ITT
Intent-to-Treat
LLT
Lowest Level Term
LLOQ
Lower Limit of Quantification
LSMeans
Least-Squares Means
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
Max
Maximum
MQRM
Medical Quality Review Meeting
MMRM
Mixed-effects model for repeated measures
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MS
MTD Set
NE
Not Evaluable
OR
Objective Response
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival
PPS
Per Protocol Set
PR
Partial Response
PR interval
ECG interval from the onset of the P wave to the beginning of the QRS 
complex
PT
Preferred Term
PV
Protocol violation
Q1
25th percentile
Q3
75th percentile
QRS
Combination of the Q, R and S waves
QT
ECG interval from the beginning of the QRS complex to the end of the 
T wave


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Term
Definition / description
QTc
Generic term for QTcF and QTcB intervals
QTcB
QT interval, corrected by Bazett’s formula
QTcF
QT interval, corrected by Fridericia’s formula
RD
Reference Document
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual Effect Period
RP2D
Recommended Phase II Dose
RPM
Report Planning Meeting
RS
Randomised Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Stable Disease
SIR
Synoptic Interim Report
SMQ
Standardised MedDRA Queries
SOC
System Organ Class
SOP
Standard Operating Procedure
TCM
Trial Clinical Monitor
TMCP
Translational Medicine and Clinical Pharmacology
TSAP
Trial Statistical Analysis Plan
TTP
Time to Progression
TS
Treated Set
UDAEC
User-Defined Adverse Event Category
ULN
Upper Limit of Normal
URPM
Unblinded Report Planning Meeting
V
Visit
WHO-DD
World Health Organisation - Drug Dictionary


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3
INTRODUCTION
As per International Conference of Harmonisation (ICH) E9 (8), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP (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 Ingelheim’s (BI) internal reference (1).
The trial consists of two parts, the first part is the dose escalation phase (Phase Ib) and the 
second part is the randomised phase (Phase II).
The TSAP describes the analysis for both parts of the trial. After the Phase Ib part, safety 
analyses were performed and documented in a Synoptic Interim Report (SIR) (see Section 
9.1) (c03569433-01).
In general, study or trial medication refers to the combination of xentuzumab with 
exemestane and everolimus, as well as the combination of exemestane and everolimus or the 
monotherapy of any of the aforementioned medications.
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 ENDPOINTS
Best overall response to trial medication will be determined according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (see Appendix 10.4 of the CTP) 
recorded from first administration of trial medication (Phase Ib part) or from randomisation 
(Phase II part) until the earliest of disease progression, death or last adequate tumour 
assessment before new anti-cancer therapy. Details about derivation of best overall response 
are given in Section 5.4.7.
All timepoints utilised for Progression Free Survival (PFS) assessment, should be used for the 
evaluation of all RECIST 1.1 based endpoints.
5.1.1
Phase Ib
The primary endpoints are 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 28 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 28 days will be used.
Patients that have a DLT event before Cycle 1 Visit 1 (C1V1) may have to be replaced. This 
DLT will not be taken into consideration for the MTD determination. Other reasons for 
replacing patients are described in CTP Section 3.3.5.
The MTD and the safety profile (including DLTs occurring after first treatment course), will 
be the basis to define the Recommended Phase II Dose (RP2D) to be used for the phase II 
part of this trial and further trials in the development of xentuzumab in combination with 
exemestane and everolimus.
5.1.2
Phase II
The primary endpoint for the Phase II part of the study is PFS based on investigator 
assessment.
PFS is defined as the time from randomisation until radiological tumour progression 
according to RECIST guideline (version 1.1) (R09-0262) or death from any cause, whichever 
occurs earlier. 
Tumour assessments are planned to be performed at screening and then every 8 weeks after 
randomisation until week 48 and every 12 weeks thereafter. After amendment 3 of the CTP 
(see also Section 4.2), the imaging schedule has been made more flexible. However, it was 
decided to keep the initial planned schedule for the definition of time windows for censoring 
rules (see also Section 6.7.2).


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For each follow-up imaging timepoint an overall tumour response will be determined 
according to RECIST 1.1. The overall tumour response for each imaging timepoint will be 
selected from the following categories: Complete Response (CR); Partial Response (PR); 
Stable Disease (SD); Progressive Disease (PD); Non-CR/Non-PD; Not Evaluable (NE).
For details on the imaging process and RECIST 1.1 evaluation, see Sections 5.1.2 and 10.4 of 
the CTP.
Derivation of endpoint PFS
Derivations below are described in days. However, the endpoints below will be presented in 
months in the outputs produced for the CTR.
For patients with 'event' as an outcome for PFS: (according to RECIST version 1.1)
∀
PFS [days] = date of outcome - date of randomisation + 1.
For patients with 'censored' as an outcome for PFS: (according to RECIST version 1.1)
∀
PFS (censored) [days] = date of outcome - date of randomisation + 1.
The censoring rules for PFS (i.e. outcome and date of outcome) are given in Table 5.1.2: 1.
Clinical disease progression will not be considered for determination of a PFS event, unless 
the outcome of the progression is death.
If patients would have their radiological examinations over a number of days, i.e. target 
lesions assessed on day x, non-target lesions assessed on day y and new lesion (if applicable) 
on day z, the following rules will be applied: 
∀
If the overall response is PD, the earliest date of multiple assessments will be taken.
∀
If the overall response is SD, Non-CR/Non-PD, PR, CR or NE, the latest of multiple 
assessment dates will be taken, i.e. in the case of SD, Non-CR/Non-PD, PR, CR, the 
latest of multiple dates will be used to censor the patients.
Imaging assessments for which NE is assigned as the overall response at an imaging time-
point are considered to be missed assessments. Please note that NE does not indicate lack of 
progression.
Table 5.1.2: 1 Derivation rules for PFS
Situation
Outcome 
(event or 
censored)
Date of outcome
No baseline radiological assessment
Patient with death on or 
before the second 
planned radiological 
assessment
Event 
Date of death


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Table 5.1.2: 1 Derivation rules for PFS (cont.)
Situation
Outcome 
(event or 
censored)
Date of outcome
Patient without death or 
patient with death after 
second performed 
radiological assessment
Censored
Date of randomisation (or first 
treatment administration, in non-
randomised trials)
Without post-baseline radiological assessments
Vital status is unknown 
or patient is known to be 
alive
Censored
Date of randomisation  (or first 
treatment administration, in non-
randomised trials)
Death prior or on the 
second planned 
radiological assessment
Event
Date of death
Death beyond the second 
planned radiological 
assessment
Censored
Date of randomisation  (or first 
treatment administration, in non-
randomised trials)
With baseline and post-baseline radiological assessments BUT no other anti-cancer 
therapy
Alive and not 
progressed, no more than 
one consecutively missed 
radiological assessments
Censored
Date of last radiological assessment
Alive and not 
progressed, two or more 
consecutively  missed 
radiological assessments
Censored
Date of last radiological assessment 
prior to missed radiological 
assessments
Progressed, zero or one 
missed radiological 
assessment prior to 
progression 
Event
Date of radiological assessment of 
progression


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Table 5.1.2: 1 Derivation rules for PFS (cont.)
Situation
Outcome 
(event or 
censored)
Date of outcome
Progressed, but two or 
more consecutively  
missed radiological 
assessments prior to 
progression
Censored
Date of last radiological assessment 
prior to missed assessment
Death but no 
progression, zero or one 
missed radiological 
assessment prior to death
Event
Date of death
Death without 
progression, but two or 
more consecutively  
missed radiological 
assessments prior to 
death
Censored
Date of last radiological assessment 
prior to missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer 
therapy started before 
progression or death
Censored
Date of last radiological assessment 
before subsequent anti-cancer therapy
No baseline and/or post-
baseline imaging and 
subsequent-anti cancer 
therapy started prior to a 
death
Censored
Date of randomisation (or first 
treatment administration, in non-
randomised trials)
In order to identify that consecutive imaging timepoints are missing for a given patient, a 
nominal time point [8, 16, 24, 32, 40, 48 weeks, and every 12 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.
Last evaluable imaging
An evaluable radiological image for the censoring of PFS is an image for which an overall 
response assessment of SD, Non-CR/Non-PD, PR or CR has been assigned. This is used for 
censoring of patients without progression at end of trial, or censoring prior to missed 
assessments, or censoring prior to subsequent anti-cancer therapy.


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5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Other secondary endpoints
5.2.2.1
Phase Ib
There are no secondary endpoints.
5.2.2.2
Phase II
Time to progression (TTP)
TTP is defined as the time from randomisation until tumour progression according to 
RECIST 1.1.
For patients with 'event' as an outcome for TTP: 
∀
TTP [days] = date of outcome - date of randomisation +1.
For patients with 'censored' as an outcome for TTP: 
∀
TTP (censored) [days] = date of outcome - date of randomisation +1.
Patients without a progression event at the time of the primary analysis will be censored at 
the time of the last evaluable radiological image. An evaluable radiological image for 
censoring of time to progression is an image for which an overall response assessment of SD, 
Non-CR/Non-PD, PR or CR has been assigned. This is used for censoring of patients without 
progression at end of trial, or censoring prior to missed assessments, or censoring prior to 
subsequent anti-cancer therapy.
More detailed censoring rules are indicated in Table 5.2.2.2: 1.
Table 5.2.2.2: 1
Derivation rules for Time to Progression
Situation
Outcome (event or 
censored)
Date of outcome
No baseline radiological 
assessment
Censored
Date of randomisation (or first treatment 
administration, in non-randomised trials)
Without post-baseline 
radiological assessments
Censored
Date of randomisation (or first treatment 
administration, in non-randomised trials)
With post-baseline radiological assessments BUT no subsequent anti-cancer therapy
Alive and no tumour 
progression, no more than one 
consecutively missed 
radiological assessments
Censored
Date of last radiological assessment


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Table 5.2.2.2: 1
Derivation rules for Time to Progression (cont.)
Situation
Outcome (event or 
censored)
Date of outcome
Alive and not progressed, two 
or more consecutively missed 
radiological assessments
Censored
Date of last radiological assessment prior to 
missed radiological assessments
Tumour progression, zero or 
one missed image prior to 
progression 
Event
Date of radiological assessment of 
progression
Progression, two or more 
consecutively missed 
radiological assessments prior 
to progression
Censored
Date of last radiological assessment prior to 
missed assessments
Death but no progression
Censored
Date of last radiological assessment prior to 
death
With post-baseline radiological assessments AND subsequent anti-cancer therapy
Subsequent anti-cancer 
therapy started before 
progression
Censored
Date of last radiological assessment before 
subsequent anti-cancer therapy
Objective response (OR)
OR is defined as best overall response of CR or PR, where best overall response is 
determined according to RECIST 1.1 from randomisation until the earliest of disease 
progression, death or last evaluable tumour assessment before start of subsequent anti-cancer 
therapy. 
Time to OR
Time to objective response is defined as the time from randomisation until first documented 
CR or PR.
Time to objective response will only be calculated for patients with an objective response:
∀
Time to OR [days] = date of first documented CR or PR - date of randomisation +1.
Duration of OR
Duration of objective response is defined as the time from first documented CR or PR until 
the earliest of disease progression or death among patients with objective response.
Duration of objective response will only be calculated for patients with an objective response. 
For patients with disease progression or death:
∀
Duration of OR [days] = date of outcome – date of first assessment indicating OR + 1.


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For patients without disease progression or death:
∀
Duration of OR (censored) [days] = date of outcome – date of first assessment 
indicating objective response + 1
The censoring rules for duration of OR are given in Table 5.2.2.2: 2.
Table 5.2.2.2: 2
Derivation rules for Duration of Objective Response
Situation
Outcome (event or 
censored)
Date of outcome
No other anti-cancer therapy
Alive and not progressed, no 
more than one consecutively 
missed radiological 
assessments 
Censored
Date of last radiological assessment
Alive and not progressed, two 
or more consecutively missed 
radiological assessments 
Censored
Date of last radiological assessment prior to 
missed radiological assessments
Progressed, zero or one missed 
radiological assessment prior 
to progression 
Event
Date of radiological assessment of 
progression
Progressed, but two or more 
consecutively missed 
radiological assessments prior 
to progression
Censored
Date of last radiological assessment prior to 
missed assessments
Death but no progression, zero 
or one missed radiological 
assessment prior to death
Event
Date of death
Death without progression, but 
two or more consecutively 
missed radiological 
assessments prior to death
Censored
Date of last radiological assessment prior to 
missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer 
therapy started before 
progression or death, no more 
than one consecutively missed 
radiological assessments prior 
to start of subsequent anti-
cancer therapy 
Censored
Date of last radiological assessment before 
initiation of subsequent anti-cancer therapy


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Only radiological assessments after first assessment indicating objective response will be 
taken into consideration.
Disease control (DC)
DC is defined as best overall response of CR or PR, or SD ≥24 weeks, or Non-CR/Non-PD 
for ≥24 weeks where best overall response is defined according to RECIST version 1.1 from 
date of randomisation until the earliest of disease progression, death or last evaluable tumour 
assessment before start of subsequent anti-cancer therapy (see Section 5.4.7).
Duration of DC
Duration of DC is defined as the time from randomisation until the earliest of disease 
progression or death, among patients with DC.
Duration of DC will only be calculated for patients with a DC. For patients with disease 
progression or death:
∀
Duration of DC [days] = date of outcome – date of randomisation + 1.
For patients without disease progression or death:
∀
Duration of DC (censored) [days] = date of outcome – date of randomisation + 1.
The censoring rules for duration of DC are given in Table 5.2.2.2: 3.
Table 5.2.2.2: 3
Derivation rules for Duration of Disease Control
Situation
Outcome (event or 
censored)
Date of outcome
With baseline and post-baseline radiological assessments BUT no other anti-cancer therapy
Alive and not progressed, no 
more than one consecutively 
missed radiological 
assessments
Censored
Date of last radiological assessment
Alive and not progressed, two 
or more consecutively missed 
radiological assessments
Censored
Date of last radiological assessment prior to 
missed radiological assessments
Progressed, zero or one missed 
radiological assessment prior 
to progression 
Event
Date of radiological assessment of 
progression
Progressed, but two or more 
consecutively missed 
radiological assessments prior 
to progression
Censored
Date of last radiological assessment prior to 
missed assessments
Death but no progression, zero 
or one missed radiological 
assessment prior to death
Event
Date of death


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Table 5.2.2.2: 3
Derivation rules for Duration of Disease Control (cont.)
Situation
Outcome (event or 
censored)
Date of outcome
Death without progression, but 
two or more consecutively 
missed radiological 
assessments prior to death
Censored
Date of last radiological assessment prior to 
missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer 
therapy started before 
progression or death
Censored
Date of last radiological assessment before 
subsequent anti-cancer therapy
No baseline and/or post-
baseline imaging and 
subsequent anti-cancer therapy 
started prior to a death
Censored
Date of randomisation (or first treatment 
administration, in non-randomised trials)


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5.4.2
Treatment exposure
Total treatment duration [days]:
Date of last administration of any trial medication – date of first administration of any trial 
medication + 1.
As the date of first administration corresponds to the first intake of xentuzumab or everolimus 
or exemestane, total treatment duration includes the run-in period in the phase Ib part. Total 
treatment duration therefore also includes time when treatment was temporarily discontinued 
and subsequently reintroduced.
Duration of specific medication exposure [days]:
Date of last administration of specific medication – date of first administration of specific 
medication + 1.
Duration of specific medication exposure will be calculated separately for xentuzumab, 
exemestane and everolimus.
Number of courses initiated [N]:
Course initiated means that the patient received at least one administration of trial medication 
in the initiated course.
Total number of xentuzumab infusions [N]:
Sum of xentuzumab infusions calculated across all courses.
It will be calculated for each patient who received at least one infusion of xentuzumab.


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Number of patients with at least one dose reduction 
Number of patients with at least one dose reduction will be counted.
The number of patients with at least one dose reduction will first be calculated for any 
medication and then separately for each specific medication for which dose reduction is 
allowed. This means that it will be calculated separately for xentuzumab and everolimus.
Time to first dose reduction of specific medication [days]:
Date of first administration of the first reduced dose of specific medication – date of first 
administration of specific medication + 1.
Time to first dose reduction will be calculated only for patients who had a dose reduction.
This will also be calculated separately for patients with a dose reduction of xentuzumab or 
everolimus.
Total dose of specific trial medication [mg]:
Total dose of trial medication will be calculated separately for xentuzumab, exemestane and 
everolimus.
For xentuzumab, this is the sum of the administered doses calculated across all courses and 
this takes into account the dose reductions.
For exemestane and everolimus, this is calculated as the total duration of treatment with this 
medication in days multiplied by the actual dose taken (using the actual dose recorded on the 
Case Report Form (CRF)) for the days the medication was taken. This takes into account the 
dose reductions of everolimus.
This calculation is only an approximation of the total dose taken, since the way the data are 
collected does not allow a more precise calculation.
Dose intensity of specific trial medication during all treatment duration (%):
Dose intensity of trial medication will be calculated separately for xentuzumab, exemestane 
and everolimus:
100*(Total dose of specific trial medication actually received by a patient / Planned total dose 
of specific trial medication during the entire duration of treatment).
The planned total dose is calculated as the total dose of the medication a patient should have 
received from the date of first administration of the medication to the date of last 
administration.
The planned total dose of xentuzumab for each patient is calculated using the following 
formula: planned dose per infusion (e.g. 1000 mg) multiplied by number of visits with 
administration of xentuzumab. 
For exemestane and everolimus, the planned total dose for each patient is calculated using the 
following formula: total duration of treatment with this medication in days multiplied by the 
planned daily dose (e.g. 10 mg, using the dose the patient was assigned (Phase Ib part) or 
randomised to (Phase II part)).
This is done assuming that the initial dose was taken throughout, and dose reduction as 
specified in the protocol will not be considered in the calculation. This means that if a patient 


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had protocol-defined dose reduction due to an AE, the reduced dose will not be used in the 
calculation of the denominator.
For everolimus and exemestane, this calculation is only an approximation of the dose 
intensity, since the way the data are collected does not allow a more precise calculation.


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5.4.6
Electrocardiogram (ECG) assessments and variables
Please refer to Section 9.2.1 for derivation of ECG variables. The generic term QTc for heart 
rate corrected QT intervals comprises the fixed corrections QTcF (Fridericia’s correction) 
and QTcB (Bazett’s correction) intervals. The term ‘on-treatment’ refers to all scheduled 
ECG recordings following the first administration of study medication until end of the 
residual effect period (see also Section 6.1).
Continuous endpoints
∀
Changes in QTcF interval between baseline and on-treatment
∀
Absolute QTcF intervals at baseline and on-treatment
The above endpoints will also be computed for the variables QTcB, uncorrected QT interval, 
heart rate, PR interval and QRS complex. Furthermore, the percentage change will be 
calculated for PR interval and QRS complex.
Categorical endpoints
∀
QTcF intervals ≤ 450 msec, > 450 to ≤480 msec, > 480 to ≤500 msec or > 500 msec
at baseline and maximum on-treatment value
∀
QT intervals ≤ 500 msec, > 500 msec at baseline and maximum on-treatment value
∀
Maximum change from baseline to on-treatment value in QTcF interval ≤ 30 msec, 
30 msec < QTcF interval ≤ 60 msec, > 60 msec
∀
Maximum change from baseline to on-treatment value in QT interval ≤ 60 msec, 
> 60 msec
∀
Increase of the PR interval from baseline ≥ 25%, when the corresponding PR interval 
is > 200 msec
∀
Increase of QRS complex from baseline ≥ 25%, when the corresponding QRS 
complex is > 110 msec


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The categorical endpoints based on the QTcF interval will be derived for the QTcB interval 
correspondingly.
Notable findings are defined as
∀
QTcF change from baseline to on-treatment value > 60 msec at any time on-treatment
∀
new onset of QT/QTcF > 500 msec, where “new onset” denotes the occurrence of a 
finding on-treatment which was not present at baseline
Morphological (qualitative ECG) assessments will include
∀
qualitative ECG findings, like new onset of rhythm, conduction, ST segment, T and U 
wave findings, evidence of myocardial infarction, etc., where “new onset” denotes the 
occurrence of an on-treatment finding, while at baseline this finding was not 
observed.


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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Phase Ib: Patients will be analysed according to the cohort initially assigned. All planned 
analysis 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 Database Lock (DBL) meeting (but prior to DBL).
Phase II: For safety analyses, treated patients will be analysed according to the treatment they 
actually received. For efficacy analyses, the Intent-To-Treat (ITT) approach will be used, i.e. 
patients will be analysed according to the treatment group they were randomised to. 
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 “8-07-other-
sdtm-trial-arms-trial-elements”, which can be found in Data Management and Statistics 
(DMS) folder, Section 8, within Boehringer Ingelheim Regulatory Documents for 
Submission (BIRDS).
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol set (PPS) analysis will be performed for this study, hence, no patient will be 
excluded from the analyses (except those with missing informed consent or not adhering to 
age limit). However patients with potentially important protocol violations (IPVs) will be 
documented. The following list of potentially IPVs in Table 6.2: 1 will be used; note that this 
is a working list and may not be finalised until the final Blinded Report Planning Meeting 
(BRPM) or DBL meeting (but prior to DBL for the primary analysis). Potentially IPVs will 
be handled according to BI standards (6).
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 violations
Category/
Code
Description
Requirements
Excluded 
from
A 
[1]
Entrance criteria not met
A1
Diagnosis of trial disease 
questionable
Inclusion criteria* IN 1 or IN 2 
not met.
None


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Table 6.2 : 1
Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
A2
Prohibited baseline 
condition, diagnosis or 
treatment
At least one of inclusion criteria*
IN 4- 9 or IN 12 is not met
or
At least one of exclusion criteria*
is met.
None
A3
Laboratory result indicating 
inadequate organ function at 
screening
Inclusion criteria* IN 10 or IN 11 
not met 
None
A4
Adequate archival tumour 
tissue not available
Inclusion criterion* IN 3 not met.
None
B 
[1]
Legal Criteria
B1
Informed consent not 
available / not done
Informed consent date missing or 
inclusion criterion* IN 13 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
Calculate age given the date of 
birth and date of informed 
consent. Patients must be ≥ 18 
years old.
All
C 
Trial medication and 
randomisation
C1
[2]
Time window violation for 
procedures performed at 
screening
Screening imaging earlier than 28 
days to first drug intake;
Safety labs, ECG performed 
earlier than 28 days to, or later 
than first drug intake;
Timeframe > 4 days between 
randomisation and first drug 
intake
None


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Table 6.2 : 1
Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
C2
[2]
Trial medication not given 
according to protocol
Dose reduction scheme not 
followed (see CTP section 
4.1.4.3); 
Administration of trial 
medication(s) not compliant. 
Indicated by medical review (i.e. 
where Administration of 
xentuzumab according to the 
protocol = ‘No’ and associated 
comments, or compliance data 
from Exemestane/Everolimus 
with associated comments)
Please note: This excludes the 
investigational treatment given 
outside the boundaries specified 
in the CTP (covered in Category 
C3)
None
C3
[1]
Infusion time for the 
investigational treatment 
outside of CTP specific 
boundaries
Infusion duration of xentuzumab 
given <50 minutes or >200 
minutes (Infusion time should be 
from 60 to 180 minutes, but the 
thresholds above are accepted). 
The exact duration of the infusion 
should be calculated taking 
interruptions into account.
In case of missing administration 
times, the violation will not be 
considered important if 
administration according to 
protocol = ‘Yes’
None
C4
[2]
Patient assignment not 
followed
Patients do not receive the initial 
treatment they were randomised / 
allocated to
None
C4.1
Randomisation not followed
This applies only for phase II part
of the trial
None


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Table 6.2 : 1
Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
C4.2
Treatment allocation not 
followed
This applies only for phase Ib 
part of the trial.
Treatment taken at C1V1 is not 
the treatment assigned at 
screening.
None
D 
[2]
Concomitant medication
D1
Prohibited treatment during 
trial conduct phase
Treatment taken during the 
treatment period as described in 
Section 4.2.2.1 of the CTP.
For phase Ib part only, during 
run-in and course 1:
CYP3A4 strong inhibitors, 
CYP3A4 moderate inhibitors, 
CYP3A4 strong inducers, 
CYP3A4 moderate inducers, 
inhibitors of P-glycoprotein
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 
TSAP Section 6.7.2).
None
F 
[2]
Trial Specific protocol 
violations
F1
Other protocol violations 
affecting patient rights or 
safety
Manual Protocol Violations 
(PVs) will be collectively 
captured.
None
[1] IPV will be derived automatically 
[2] IPV will be identified via individual review at MQRM/Report Planning Meeting 
(RPM)/DBL.
* During the amendments of CTP the inclusion and exclusion criteria were adapted. 
Therefore, the inclusion/exclusion criteria valid at subject’s enrolment have to be considered.
6.3
PATIENTS SETS ANALYSED
The following analysis sets will be defined for this trial:






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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 previous 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 BRPM before database lock at the latest.


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The rules in the Table 6.6: 1 below have been agreed by the trial and project teams, and will 
be used in this trial, if applicable.
Table 6.6: 1
Rules for imputations of missing or incomplete dates
Date
Imputation rule
Date of birth
In case only the year is given: 31st of December
Date of death
Date last known to be alive.
If only year and month are given: this will be imputed with 1st  
of the month for the analysis of OS
Date of first histological 
diagnosis
1st of month if day is missing
1st of January if month also missing
Date of first appearance or 
recurrence of metastasis
1st of month if day is missing
1st of January if month also missing
Date of start of concomitant 
medication
No imputation required
Date of end of concomitant 
medication
No imputation required
Date of start of subsequent 
anti-cancer therapy 
(imputation required only 
for censoring of PFS)
If the day (respectively day and month) of the start date of 
subsequent anti-cancer therapy is missing, then the first of the 
month (respectively 1st January) will be imputed unless this 
date leads to a date before the stop date of study medications. 
In this case, the study medications stop date + 1 day will be 
imputed.
Additionally, all imputed start dates of subsequent anti-cancer 
therapy should be before death date if available.
Date of stop of subsequent 
anti-cancer therapy
No imputation required
Date of end of treatment 
(only for patients still 
ongoing at time of 
snapshot/DBL)
Date of snapshot/DBL
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 C1V1 (before the very first administration of study 
medication) data from preceding visits will be used.




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Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of any study medication. The run-in period in the Phase Ib part is considered 
as time with study medication. If this criterion is not fulfilled then no baseline will be 
derived, except in the following case: if a patient is entered (phase Ib part) or randomised 
(phase II part), but not treated, the last value we have for the patient is considered baseline.
Laboratory values:
Baseline is defined as the latest time-point before the very first administration of any study 
medication.
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.
ECG
Baseline values will be derived from the triplicate at the time-point closest to but prior to the 
first administration of study medication.
6.7.2
Time windows for every RECIST assessment
In order to identify whether consecutive imaging timepoints are missing for a given patient, a 
nominal time point [8, 16, 24, 32, 40, 48 weeks and every 12 weeks thereafter] will be 
assigned to each and every image. This is achieved by creating windows for every RECIST
1.1 assessment. The windows are defined in Table 6.7.2: 1 below. Day 1 corresponds to date 
of randomisation for the Phase II part (for the Phase Ib part it corresponds to the date of first 
drug intake of xentuzumab).
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]
8
57
1 to =< 85
16
113
86 to =< 141
24
169
142 to =< 197
32
225
198 to =< 253
40
281
254 to =<309
48
337
310 to =<379


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Table 6.7.2: 1 Nominal time-points and windows for imaging (cont.)
Nominal time-point [weeks 
from start of therapy]
Due date of scans [days]
Window [days]
60
421
380 to =<463
72
505
463 to =<547
every 12 weeks interval
etc (1)
etc (1)
(1) Due date of scans = (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, she will be said to 
have 'missed an assessment' for that timepoint. 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 (7).
Unless otherwise specified, outputs will be displayed separately for each part of the trial.
Descriptive statistics for continuous variables will generally contain N (number of patients in 
that patient set with non-missing values), Mean, Standard Deviation, Minimum (Min), 25th
percentile (Q1), Median, 75th percentile (Q3), Maximum (Max). In general, means, standard 
deviations, medians, Q1 and Q3 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.
For time-to-event analysis tables, the set of statistics is: number of patients [N (%)], Number 
of patients with event [N (%)], Number of patients censored [N (%)], <Time to event> 
[months] followed by Q1 (25th percentile), Median, Q3 (75th percentile). If not specified 
otherwise, the duration as well as time to event will be displayed in months.
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, if there are missing data for the 
corresponding variable. Percentages will also generally be based on all patients in the 
respective patient set whether they have non-missing values or not.
The primary analysis will include all treated (Phase Ib) or randomised patients (Phase II), 
following the ITT approach (as specified in Section 6.3).
The analyses for the primary endpoint of PFS as well as best overall response, OR, time to 
OR, duration of OR, DC, duration of DC, time to progression, tumor shrinkage, tumor size as 
well as the 
 will be based on data obtained until November 25th 2016. A 
sensitivity analysis for the primary endpoints PFS will be performed using all data. Analyses 
of other RECIST based endpoints will also only utilise data obtained from assessments 
scheduled until November 25th 2016. For overall survival all available data will be used.
Analyses of AEs for the phase II will be split in two parts. The first part considers all AEs 
with onset date on or before the cut-off date 9th of December 2016 (28th of October 2016 + 
length of REP (42 days)) and AEs with onset date after 9th of December 2016. Details are 
given in Section 7.8.1.
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.


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In general, a “Total” column will be displayed in section 15.1 (Trial subjects) of the CTR. In 
Sections 15.2 and 15.3 of the CTR, a “Total” column will be displayed in Phase Ib outputs, 
but not in Phase II outputs.
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:
∀
Weeks = days ÷ 7
∀
Months = days × 12 ÷ 365.25
∀
Years = days ÷ 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.1.1
Disposition of patients
For patient disposition the standard descriptive table from the EOT/CSD (Company Standard 
Displays) catalogue will be populated. Additionally, patients with discontinuations by initial 
treatment and the reasons will be listed and tabulated, overall and for each treatment 
separately. The same output will also contain an overview of discontinued and non-
discontinued, as well as completed and non-completed patients. In Appendix 16.1.9.2, a 
disposition table by country will be produced.
Disposition of patients will also be displayed by visceral involvement.
7.1.2
Important protocol violations
A table and a listing of patients with important protocol violations based on Table 6.2: 1 will 
be created in Section 15.1.3 and Appendices 16.2.3 and 16.1.13.1 (if needed) respectively, of 
the CTR.
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.
For the subgroup of the first tier visceral involvement demographic characteristics as well as 
oncological history will be provided as well.
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 


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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 analysed separately by treatment received. The number of missed doses 
of any medication as recorded on the eCRF will be listed by patient.
7.4
PRIMARY ENDPOINTS
7.4.1
Phase Ib
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 5.1.1). An overall summary of the DLTs (see CTP Section 5.2.6 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. A plot with an 
overview of the phase Ib escalation part (showing the patients and their doses, replaced 
patients as well as patients with DLTs) will be displayed.
At the end of the dose escalation phase, a safety analysis will be performed to determine the 
RP2D. The results will be documented for internal use and communication with the 
participating investigators. (see also in Section 9.1)
7.4.2
Phase II
The primary analysis will be conducted for all patients of the randomised set in the Phase II 
part of this trial; following the changes described in Section 4.2, only response assessments 
until the cut-off date of 25th November 2016 will be used (as described in protocol). For the 
derivation of the censoring rules, the status of the patient (e.g. treatment ongoing / 
discontinued / new anti-cancer therapy) will be taken as of the cut-off date. This means if a
patient was ongoing at the cut-off date, its PFS with cut-off will be censored at last 
assessment before the cut-off, with reason treatment ongoing.
PFS by investigator's assessment is the primary endpoint and will be assessed based on the 
Kaplan-Meier method for each treatment arm separately. Point estimates together with 
confidence intervals (CIs) (based on Greenwood's method) will be provided for median PFS. 


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An estimation of the effect on PFS of xentuzumab plus exemestane plus everolimus 
compared to the effect on PFS of exemestane and everolimus will be given by the hazard 
ratio (HR) and its 95% CI using a stratified Cox proportional hazards model (using visceral 
involvement as stratification factor). The validity of the underlying assumptions of this model 
will be checked. HRs < 1 will favour treatment with xentuzumab plus exemestane plus 
everolimus; p-value from the two-sided log-rank test will be also displayed but it should be 
emphasised here that this is only to be understood in an exploratory way. The Breslow 
method for handling ties will be used. The censoring rules for PFS are as stated in Section 
5.1.2.
7.4.2.1
Subgroup analyses for PFS
Subgroup analyses will be conducted for the primary endpoint of the Phase II part (PFS) as 
follows:
For each of the subgroups specified in Section 6.4 HRs will be produced in order to 
investigate the subgroups. HRs will be obtained from the models fitted for each level of the 
baseline covariate. All Cox models will be adjusted (but not stratified, due to the low number 
of patients) with the stratification factor visceral involvement. However, in the case when 
investigating the stratification factor, the model will not be adjusted.
To provide a statistical framework for interpretation of the consistency of the treatment effect 
interaction p-values will be created using a model adjusted for treatment, stratification factor, 
subgroup and treatment by subgroup interaction. However, in the case when investigating the 
stratification factor, the model will not be adjusted additionally for this factor. For the 
evaluation of the interaction between treatment effect and the baseline variables, all 
subgroups showing an interaction p-value ≤ 0.1 will be considered as potential subgroup and 
might be investigated in more detail.
Forest plots will be produced for the graphical interpretation of subgroup analyses.
Standardized effect size plot
Furthermore, standardized effect size plots (as described below) will be applied to the two 
tiers (defined in Section 6.4). These may also be provided separately, if deemed useful.
Generally, the higher the number of subgroup analyses performed, the higher the probability 
of a positive finding by chance (pure randomness) alone. Therefore, a standardized effect size 
evaluation will be performed in addition in order to consider the number of subgroups, the 
correlation between the subgroups, the observed effect size within the subgroup and the 
sample size of the subgroups. 
Standardized effect size plots will be produced to identify on a permutation basis the 
minimum and maximum difference from the null hypothesis (no treatment effect overall) 
across all subgroups. This illustrates how extreme the results are expected to be by chance 
given the number, the size, and the correlation structure of subgroups. 
For each subgroup the observed standardized effects will be calculated and compared to 
permutation-based confidence bands (5 and 95% percentiles) taking into account the 
multiplicity issues based on permuted datasets (10.000 times). For each permuted dataset the 
standardized effects for each subgroup will be calculated and thereof the maximum of the 
absolute values of the standardized effects are received. Repeating this 10.000 times, we will 


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use the 90th percentile "of the maximum absolute effects which provides us with a 90%-
confidence band [−"; "]. Any subgroups showing an adjusted p-value outside this 90%CI 
are identified. In a stepwise procedure, those subgroups are then excluded and the 
standardized effect method is applied to the remaining subgroups in order to again identify 
the minimum and maximum difference from the null hypothesis (no treatment effect overall). 
The procedure ends in case no selected subgroup for the maximum or minimum is identified.
If deemed appropriate, subgroups with missing values may be excluded from the calculation 
of the standardized effect size plot.
7.4.2.2
Sensitivity analyses for PFS
Using all available data
As a sensitivity analysis, the PFS analysis (without subgroup analysis) will be repeated, using 
all available radiological response assessment data (including those measured after the cut-off 
date from the primary analysis). As for the primary analysis, the randomised set will be used.
Stratification factor based on IRT
The PFS analysis will be repeated, using data from IRT stratification (for the factor visceral 
involvement) instead of using data collected in the CRF. As for the primary analysis, only 
response assessments until the cut-off date of 25th November 2016 will be used.
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
7.5.2.1
Phase Ib
This section is not applicable as no other secondary endpoint has been specified in the 
protocol.
7.5.2.2
Phase II
Secondary endpoints will be analysed descriptively for all patients in the randomised set in 
the second part of this trial. As for the primary analysis, only response assessments until the 
cut-off date of 25th November 2016 will be used for the analysis of all response-based 
endpoints.
Time-to-progression 
TTP will be assessed based on the Kaplan-Meier method for each treatment arm separately. 
Point estimates together with CIs (based on Greenwood's method) will be provided for 
median time to event.


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Objective response
The binary endpoint OR will be analysed in an exploratory manner.
Moreover, logistic regression will be used to test for a difference between the two arms for 
objective response rate. The model will be adjusted for the stratification factor visceral 
involvement by fitting this as an explanatory variable. The exploratory p-value will be 
generated from the likelihood ratio test statistic. An odds ratio and corresponding 95% CI
will be generated using the likelihood ratio CI in order to obtain a direct correspondence 
between the p-value and the odds ratio CI. Odds ratios >1 favour xentuzumab + everolimus + 
exemestane.
Disease control
DC will be analysed similarly to OR, see above.
Time to OR
Descriptive statistics will be calculated for time to OR. This will only be computed for 
patients who have an OR.
Duration of OR
Duration of OR will be assessed based on the Kaplan-Meier method for each treatment arm 
separately. Point estimates together with CIs (based on Greenwood's method) will be 
provided for median time to event and quartiles. This will only be computed for patients who 
have an OR.
Duration of DC
Duration of DC will be analysed similarly to Duration of OR, see above.


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7.7
EXTENT OF EXPOSURE
The variables defined in Section 5.4.2 will be summarised descriptively for each dose cohort 
(Phase Ib) or treatment group (Phase II).
For the phase II part, this variables will also be provided by visceral involvement.
7.8
SAFETY ANALYSES
All safety analyses will be performed on the TS (unless otherwise specified; for example, the 
MTD Set will be used for some safety outputs). Patients in the Phase Ib part of the trial who 
were replaced within or before 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).


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For analysis multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies: 
∀
All AE attributes are identical (Lowest Level Term (LLT), Common Terminology 
Criteria for Adverse Events (CTCAE) grade, action taken with trial medication, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)
∀
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 (4).
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 (R10-4848)).
The analyses of AEs will be based on the concept of treatment-emergent AEs. For the phase 
Ib, that means that all AEs 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 REP will be 
assigned to ‘post-treatment’; these AEs will be displayed in separate tables and listings. First 
drug intake includes the run-in period for Phase Ib part.
For the phase II part it has to be taken into consideration that the sponsor decided to stop 
treatment with xentuzumab on 28th of October 2016, but continued treatment with everolimus 
and exemestane. Therefore, the analysis of on-treatment AEs will be split in two parts:
1) AEs with onset date on or before 9th of December 2016
This includes the following patients:
∀
Patients of both arms who completed the REP on or before 9th of December 
2016, i.e. AEs until the end of REP will be considered.
∀
Patients who stopped xentuzumab on 28th of October 2016 due to sponsor’s 
decision, i.e. AEs with onset date on or before the 9th of December 2016 will 
be considered.
∀
Patients receiving everolimus and exemestane only, i.e. AEs with onset date
on or before 9th of December 2016 will be considered.
2) AEs with onset after 9th of December 2016
This includes the following patients:
∀
Patients who stopped xentuzumab on 28th of October 2016 due to sponsor’s 
decision, i.e. AEs with onset date after 9th of December 2016 will be 
considered.
∀
Patients receiving everolimus and exemestane only, i.e. AEs with onset date 
after 9th of December 2016 will be considered.
Both parts will be analyzed by treatment and a total column will be given.


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For the Phase II part all AEs occurring before first drug intake will be assigned to ‘screening’
and all AEs occurring after the REP will be assigned as ‘post-treatment’.
AEs will be displayed by the initial dose of study medication administered on the first day of 
treatment (or planned to be administered, for the run-in period of the Phase Ib part).
An overall summary of AEs will be presented. The frequency of patients with AEs will be 
summarised by treatment, primary system organ class (SOC) and preferred term (PT). 
Separate tables will be provided for patients with drug-related AEs, AEs leading to dose 
reduction, AEs leading to discontinuation, serious adverse events (SAE), serious drug-related 
AEs, AEs leading to death, other significant AEs, adverse events of special interest (AESI), 
and AEs fulfilling the DLT definition (for phase Ib part only). For the Phase II part an overall 
summary of AEs as well as a table for AEs and SAEs by treatment will be provided for the 
subgroups of visceral involvement.
Sorting order:
In tables presenting SOC and PT, 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 "Missing 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. In the appendix (Section 
16.1.9.2), the categorisation “All grades”, “Grade 1/2”, “Grade 3/4/5”, will be used.
Listings of AEs
AEs will be reported with start and end day as calculated from the first day of treatment with 
study medication. This includes the run-in period for the Phase Ib part.
Incidence and severity of AEs
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and SAEs will be reported by severity according to CTCAE grades.
Other significant AEs
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:
∀
AEs leading to dose reduction of xentuzumab
∀
AEs leading to dose reduction of everolimus


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∀
AEs leading to permanent discontinuation of xentuzumab
∀
AEs leading to permanent discontinuation of everolimus
∀
AEs leading to permanent discontinuation of exemestane
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 grade 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 AESIs
Protocol-specified AESIs are specified in the CTP Section 5.2.2.1. Their incidence will also 
be reported. DLTs are considered as AESIs only in the Phase Ib part.
Adverse events by user defined AE categories (UDAEC)
UDAEC as defined on project level by the pharmacovigilance working group will be derived 
and the latest version will be used for the analysis. The categories will be taken as defined in 
the most recent signed version of the safety Statistical Analysis Plan (SAP) at the time of the 
DBL. These categories can be found in Table 7.8.1: 1. This document is entitled "8-02-sap-
safety-core", which can be found in the Project Data Management and Statistics folder, 
section 8 (project level), within BIRDS. 
Table 7.8.1: 1 Adverse events by user defined AE categories
Term
Group#
Hepatic impairment
Drug related hepatic disorders – comprehensive search
(SMQ)
Hyperglycaemia narrow
Hyperglycaemia/new onset diabetes mellitus (SMQ) –
narrow
Infusion related reaction
IRR (BIcMQ)
Hypersensitivity (SMQ) – narrow
Non-infectious pneumonitis
Interstitial lung disease (SMQ) – narrow 
Renal insufficiency
Acute renal failure (SMQ) – broad
Weight loss
Weight loss (BIcMQ) – broad
Neutropenia
Haematopoietic leukopenia (SMQ) – narrow
Stomatitis
Stomatitis (BIcMQ) – broad
Asthenia
Asthenic conditions (BIcMQ) – narrow
Anemia
Haematopoietic erythropenia (SMQ) – broad
Thrombocytopenia
Haematopoietic thrombocytopenia (SMQ) – narrow
#
This column indicates whether the Term(s) provided in the first column are MedDRA preferred terms 
(PT), Standardised MedDRA Queries (SMQ) or BI customised MedDRA Queries (BIcMQ).
The incidence of AE by UDAEC will be analysed.


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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 (5). For both the phase Ib and the phase II part the on-treatment period as 
considered for the analysis of adverse events of the phase Ib part will be applied for 
laboratory values except for that the baseline laboratory value will be included in the 'on-
treatment' 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 (R10-4848). The 
following outputs will be presented:
∀
Worst CTCAE grade experienced during the on-treatment phase.
∀
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 reference 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" (5), Reference Document 9.
7.8.2.2
Laboratory values of special interest
Hepatic enzyme elevations (potential Hy’s law cases):
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of Alanine Aminotransferase (ALT) and/or Aspartate Transaminase 
(AST) > 3 Upper Limit of Normal (ULN) with total bilirubin ≥ 2ULN and Alkaline 
Phosphatase (ALKP) < 2 ULN. The events can occur in any order, but must occur within 14 
days of the previous event, i.e. the second event must occur within 14 days of the first event, 
and the third event must occur within 14 days of the second event, etc.
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 
Drug-Induced Liver Injury (DILI) cases, are created in accordance with the Food and Drug 
Administration (FDA) DILI guidance (P09-12413).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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7.8.4
ECG
Newly emergent abnormalities will be recorded and analysed as AEs if judged clinically 
relevant by the investigator.
The ECG analyses will be performed using the ECG Set, except those concerning the 
relationship between plasma concentrations and ECG endpoints which will be based on the 
ECG-PK set. All analyses will be based on the centrally evaluated ECG data collected until 
the safety cut-off date of 9th December 2016. Centrally evaluated ECGs recorded after this 
date, will only be presented in listings.
Descriptive analyses (separate analysis of Phase Ib and Phase II parts)
Absolute values and change from baseline in QTcF interval, QT interval, heart rate, PR 
interval, and QRS complex will be summarized descriptively by initial treatment, cycle, day 
and planned time.
Frequency tables will be provided for all categorical endpoints including notable findings and 
qualitative ECG assessments. Frequencies of the increases in QTcF and QT intervals above 
thresholds such as 450 msec, 480 msec, and 500 msec between baseline and on-treatment 
values will be displayed in two-way shift tables by initial treatment.
Notable findings (occurring until the safety cut-off date) of patients in the TS who are 
excluded from the ECG Set will be listed in separate listings which will be presented in 
Section 15 of the CTR.
The QTcB interval as well as the percentage changes for PR interval and QRS complex will 
only be displayed in Listings (Appendix 16.2.8)
Additional statistical analyses will be performed for the Phase II part as described below:
Repeated measures analyses
The endpoint ‘change in QTcF interval between baseline and on-treatment’ will be analysed 
by a linear mixed-effects model for repeated measures (MMRM). This model will include the 
fixed, categorical effects of ‘treatment’ and ‘timepoint’, the ‘treatment-by- timepoint’ 
interaction, as well as the continuous, fixed covariate ‘baseline’ and the ‘baseline-by-
timepoint’ interaction. An unstructured covariance structure will be used to model the within-
patient measurements. The SAS® procedure MIXED will be used, involving the restricted 
maximum likelihood estimation method, and the Kenward-Roger method will be applied to 
adjust standard errors and estimate denominator degrees of freedom. The model is detailed in
Section 9.2.2.
Timepoints will only be included as long as evaluable data in ‘change in QTcF between 
baseline and on-treatment’ from at least 30 patients are still available in any of the treatment 
groups. The choice of 30 patients is relatively arbitrary and is conceived as a compromise, i.e. 
balancing out between precision of the estimates and receiving preliminary information over 
time on the other hand. The analyses of heart rate, QT, PR and QRS endpoints will be aligned 
to the respective QTcF analyses.
For the pairwise comparisons of ’xentuzumab + everolimus+exemestane’ versus 
’everolimus+exemestane ’, the treatment differences at each timepoint will be estimated by 
the difference in the corresponding Least-Squares Means (LSMeans). Two-sided 90% CIs


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based on the t-distribution will also be computed. Having estimated the treatment difference 
at each timepoint by the analysis described above, the timepoint at which the difference is 
largest will be identified.
This analysis will also be performed using the corresponding endpoints based on the QT 
interval, heart rate, PR interval and QRS complex, respectively.
The repeated-measures analysis will also be applied to the absolute on-treatment QTcF 
interval, heart rate, QT interval, PR interval and QRS complex values, respectively. Least 
squares means of ‘treatment-by-timepoint’ and two-sided 95% CIs based on the t-distribution 
will be computed.
Sensitivity analysis
In the model described above, a covariance structure of type ‘unstructured’ will be used to 
model the within-patient measurements. This model does not consider the particular 
underlying time structure, being consecutive pairs of within-day measurements (pre- and 
post-dose measurements approximately 1 hour apart) separated by one (or more) week(s). To 
account for this particular time structure, a modified covariance structure will be used in the 
sensitivity analysis: A two-by-two unstructured covariance matrix will be used to model the 
within-patient measurements on each day (pre- and post-dose measurements). A second two-
by-two unstructured covariance matrix will be used to model the within-patient 
measurements between days; this matrix will be the same for all combinations of days. 
Hence, in this analysis the number of necessary covariance parameter estimates will not
depend on the number of included timepoints. The sensitivity analysis will be restricted to the 
endpoints based on the QTcF interval. The model is detailed in Section 9.2.2.
Exposure-response analyses
The exposure-response analyses will be based on the ECG-PK set. Patients of the Phase Ib
part will not be included as they were pre-treated with ‘everolimus+exemestane’. Data of 
patients receiving everolimus+exemestane alone will be included with xentuzumab plasma 
concentrations set to zero (see also R17-0553).
Pairs of xentuzumab plasma concentrations and QTcF changes from baseline that are not 
time-matched (i.e. a time deviation between PK blood sampling and ECG recording that is 
not acceptable) will be excluded from the analyses. 
The maximum acceptable time deviations between PK blood sampling and ECG recording at 
different time points during the trial are presented in Table 7.8.4: 1 below. Pairs of plasma 
concentrations and QTc changes from baseline with time deviations exceeding those 
specified in the table will be excluded from exposure-response analyses. When the sampling 
time of the blood sample, the time of ECG recording or the time of infusion are not available, 
the pair will also be excluded.


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Table 7.8.4: 1 Maximum acceptable time deviations between PK blood sampling and ECG 
recording during the trial, Phase II part
Timepoint
Pre-dose timepoints
Post-dose timepoints
Both measurements taken 
before “start of infusion”
Both measurements taken not 
earlier than 15 min before “end 
of infusion”
Cycle 1, Day 1
n.a. (Baseline ECG)
Deviation ≤4 h
Cycle 1, Day 8, 15
Deviation ≤6 h
Deviation ≤4 h
Cycles 2 and 3, Day 1
Cycles >3, Day 1
Deviation ≤6 h
n.a.
EoT, FU
(no infusion) Deviation ≤8 h
For further details see also Section 6.6.5.
The relationship between xentuzumab plasma concentrations and QTcF change from baseline 
will be explored using a random coefficient model including a categorical variable 
‘treatment’ with the two levels ‘xentuzumab+ everolimus+exemestane and 
‘everolimus+exemestane’ to estimate the adjusted mean difference between ‘xentuzumab + 
everolimus+exemestane ’ and ‘everolimus+exemestane’ in QTcF change from baseline and 
its two-sided 90% CI at clinically relevant plasma concentrations, which are the geometric 
means of the C1D11:15h, C2D11:15h and C3D11:15h values of the RP2D. The model is detailed 
in Section 9.2.3. For visualization, plasma concentration against QTcF changes from baseline 
will be plotted, as well as the (fixed effect) regression line, its 90% CI and the geometric 
means of C1D11:15h, C2D11:15h and C3D11:15h.
The assumption of a linear relationship will be checked by visual inspection of diagnostic 
plots (presented in Section 16.1.9.2 of the CTR). If linearity is not given, the concentrations 
may be log-transformed prior to the analysis.
To inspect (graphically) whether the peaks of the time-profiles for xentuzumab plasma 
concentrations and QTcF interval changes from baseline coincide, figures of the individual 
time profiles of xentuzumab plasma concentrations and QTcF interval changes from baseline 
will be generated for each patient (presented in Appendix 16.1.9.2 of the CTR), as well as for 
the means (presented in Section 15 of the CTR). Mean time profiles from the patients treated 
with ‘everolimus+exemestane’ alone will be displayed as well.
These analyses will also be performed using the corresponding endpoints based on the QT 
interval and heart rate.
Furthermore, a first sensitivity analysis will be performed using the random coefficient model 
described above including the categorical effect ‘day’, and a second sensitivity analysis will 
be done including the categorical effect ‘time’ with the two levels pre- and post-dose, instead. 
A further analysis will consider the influence of baseline and will include the centered 
baseline as a covariate additionally to the factors used in the first sensitivity analysis. These 
analyses will only be applied to the QTcF changes from baseline.


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Appropriateness of QT interval correction methods for heart rate
To evaluate the appropriateness of the methods, slopes of the relationship of QT, QTcF, and 
QTcB interval versus RR interval (values log-transformed using the natural logarithm) will 
be estimated by applying a random coefficient model (see Section 9.2.4) separately for the 
treatments ‘xentuzumab+ everolimus+exemestane’ and ‘everolimus+exemestane’. These 
analyses will be based on the three single on-treatment ECG recordings per time point. A 
table of the resulting (fixed effect) slopes will be displayed together with two-sided 95% CIs
in Appendix 16.1.9.2 of the CTR.


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7.9.6
Immune response (ADA)
Following the changes described in Section 4.2, immunogenicity will be analysed as follows:
The number and percentage of ADA-positive, ADA-negative and ADA-negative-
inconclusive patients may be presented. Further analyses related to immunogenicity might be 
performed if feasible and considered reasonable, e.g. potential impact on PK or PD 
parameters.






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9
ADDITIONAL SECTIONS
9.1
SAFETY ANALYSIS
After 12 evaluable patients treated at the designated MTD dose completed at least the first 
course of treatment during the phase Ib part, a safety analysis was performed. For this 
purpose a database snapshot was performed. The safety analysis summarised results 
regarding safety and was used for recommendation of the dose of trial medication to be taken 
forward as recommended phase II dose. The selection of the RP2D considered overall safety 
observed during available treatment cycles for all treated patients, including the ones that 
were replaced for the determination of the MTD. These analyses were documented in a SIR 
for the Phase Ib part (c03569433-01).
Disposition of patients, demographic characteristics and oncological history, previous 
therapies (listing), concomitant therapies (listing), exposure (total duration of treatment, 
patients with dose reduction), adverse events and laboratory parameters (listing of laboratory 
values, table of frequency of patients with transitions of CTCAE grades at baseline and worst 
grade on treatment) were shown in the safety analysis.
A version of the TSAP was signed before the snapshot of the safety analysis was performed.
9.2
ECG EVALUATION
This section only applies to the centrally evaluated digital ECG recordings.
9.2.1
Derivation of ECG variables
Three replicate digital ECG recordings will be collected at each time point (see also Section 
9.2.5). Each of the three recorded single ECGs will then be evaluated for cardiac intervals, 
which comprise the RR interval, PR interval, QT interval, and QRS complex. Measurements 
of these intervals will be made on the three (possibly consecutive) cardiac cycles (also 
denoted as beats or waveforms) from the lead chosen (usually lead II). The measurements of 
the cardiac cycles will be stored in the database, i.e., 9 values per time point. All cardiac 
intervals will be given in milliseconds (msec). The three cardiac cycles will be averaged prior 
to the calculation of heart rate and heart-rate-corrected QT intervals (QTc).
Heart rate will be derived from the RR interval as
Heart Rate [beats/min] = 60 000 / RR [msec]
Two Heart Rate-correction methods of the QT interval will be applied:
∀
QTcF is the length of the QT interval corrected for heart rate by Fridericia’s formula:
#
∃
#
∃
sec
1000
sec
3
/1
m
QT
RR
m
QTcF
%
&
∋
(
)
∗
+
,


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∀
QTcB is the length of the QT interval corrected for heart rate by Bazett’s formula:
#
∃
#
∃
sec
1000
sec
2
/1
m
QT
RR
m
QTcB
%
&
∋
(
)
∗
+
,
Further aggregation of the three replicate QT/QTc intervals and heart rates at each scheduled 
time point will be performed using arithmetic means. These values will be used for the 
derivation of the ECG endpoints as they are specified in Section 5.4.6.
9.2.2
Description of the model used for the repeated measures analyses
The model (M1) is described by the following equation
<=>? −"= = , + -> + @? + (-@)>? + (2 + 2?)"= + A=?,
(A=, … , A=C) ~ EC(0, F)
where
i=1,…,I indicates the patient, k=1,…K the on-treatment timepoint and j=1,2
the treatment group,
<=>?
is the QTcF interval measured on patient i receiving treatment j at timepoint 
k,
"=
is the baseline measurement of patient i,
,
is the overall intercept,
->
is the fixed, categorical effect of treatment j, 
@?
is the fixed, categorical effect of timepoint k,
(-@)>?
is the interaction effect between treatment j and timepoint k,
2
is the fixed coefficient for baseline,
2?
is the fixed coefficient for baseline at timepoint k,
A=?
is the random error associated with patient i at timepoint k,
F
is a K-by-K covariance matrix of the type ’unstructured’.
The following SAS code (1) will be used to fit the model:
PROC MIXED DATA=xxxx ORDER=data CL METHOD=REML;
   CLASS patient treat timepoint;
   MODEL ECGep= treat timepoint treat*timepoint base base*timepoint
/DDFM=KR;
   REPEATED timepoint / SUBJECT=patient TYPE=UN R RCORR;
   LSMEANS treat*timepoint/ diffs CL ALPHA=0.10;
RUN; QUIT;


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The variable names (e.g. ’patient’, ’treat’ etc.) given in the SAS code above have to be 
replaced by the respective variable names used in the analysis data set. ECGep corresponds to 
the ‘QTcF change from baseline’.
The variable ‘timepoint’ will be concatenated of ‘day’ and ‘time’. The variable ‘day’ denotes 
the consecutive days with ECG recordings (i.e., C1D1, C1D8, C1D15, C2D1, C3D1 etc.) and 
the variable ‘time’ will have 2 values (0, 1) indicating whether the ECG was recorded before 
(’0’) or after (’1’) drug administration. In terms of SAS code, the interaction ’day*time’ 
corresponds to the effect ’timepoint’.
Therefore, the following SAS code using ‘day’ and ‘time’ as separate class variables will be 
equivalent to the SAS code (1) above:
PROC MIXED DATA=xxxx ORDER=data CL METHOD=REML;
   CLASS patient treat day time;
   MODEL ECGep= treat day*time treat*day*time base base*day*time /DDFM=KR;
   REPEATED day*time / SUBJECT=patient TYPE=UN R RCORR;
   LSMEANS treat*day*time/ diffs CL ALPHA=0.10;
RUN; QUIT;
In case of convergence problems, apply step 1)-6):
1) Set SINGULAR=1E-10 as option in the model statement
2) Set MAXITER=100 and/or MAXFUNC=200 
3) Use option SCORING=4 in the final run to request a Fisher scoring algorithm to be 
used for the first 4 iterations
4) Include the additional statement in the PROC MIXED call:
PERFORMANCE NOTHREAD;
5) Perform an initial run including the statement
ODS OUTPUT COVPARMS=covstart;
followed by a final run using
PARMS / PARMSDATA=covstart;
In the special case with the note “Convergence criteria met but final hessian is not 
positive definite” try instead/in addition
PARMS / OLS;
to request ordinary least squares starting values.
6) One may also use estimates from a simpler model (e.g. using TOEPH) as starting 
values for the run with TYPE=UN
In case that an unstructured covariance matrix still does not converge, even after application 
of the above steps, the Toeplitz structure with heterogeneous variances (TOEPH) will be 
applied.
The statistical model applied as sensitivity analysis will be identical to the model (M1)
described above, with the exception of the covariance structure used to model the within-
patient measurements.


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The following model (M2) will be used (note that the index k is now replaced by the two 
indices d and t):
<=>GH −"= = , + -> + @GH + (-@)>GH + (2 + 2GH)"= + I=H + A=GH,
(I=+, I=) ~ E%(0, J), (A=G+, A=G) ~ E%(0, F)
where
i=1,…,I indicates the patient, d=1,…D the day of ECG recording, t=0, 1 the time 
of ECG recording (0= before and 1= after drug administration), and j=1, 2 the 
treatment group,
I=H
is the random effect associated with patient i at time t; assumed to be independent 
across patients, 
A=GH
is the random error associated with patient i on day d and time t; assumed to be 
independent across day and patient. The A=GH are assumed to be independent of the 
I=H,
J, F
are 2-by-2 covariance matrices of the type ’unstructured’.
The following SAS code will be used to fit this model:
PROC MIXED DATA=xxxx ORDER=data CL METHOD=REML;
   CLASS patient treat day time;
   MODEL ECGep= treat day*time treat*day*time base base*day*time /DDFM=KR;
   RANDOM time / SUBJECT=patient TYPE=UN R RCORR;
   REPEATED time / SUBJECT=patient*day TYPE=UN R RCORR;
   LSMEANS treat*day*time/ diffs CL ALPHA=0.10;
RUN; QUIT;
9.2.3
Description of the random coefficient model used for the exposure-response 
analyses
The relationship between xentuzumab plasma concentrations and ECG endpoints will be 
explored using a random coefficient model which includes a categorical effect 
‘treatment’(with the two levels ‘xentuzumab+ everolimus+exemestane’ and 
‘everolimus+exemestane’), ‘day’ or ‘time’, respectively, as fixed categorical effects (only 
used in the sensitivity analyses), as well as a random intercept and slope for each patient 
(R17-0553, Model ∆QTc3):
<=>? = -> + @?+K= + L= M=>? + NM=>? + A=>?,
(K=, L=) ~ E% (O, J), A=>? ~ PPQ E(0, R%),
where


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i = 1,2,…, I indicates the patient (I = total number of patients across all treatment 
groups, k = 1,2 ,…, Ki the time point and j=1,2 the treatment,
<=>?
is the QTcF change from baseline in patient i receiving treatment j at time point k,
M=>?
is the plasma concentration in patient i receiving treatment j at time point k
->
is the effect of treatment j on intercept,
@?
is the effect of day (or time, respectively) k on intercept (will only be used in the 
sensitivity analyses),
K=
is the random effect on intercept associated with patient i,
N
is the overall slope for the relationship between <=? and M=?
L=
is the random effect on slope associated with patient i,
A=>?
is the random error associated with patient i receiving treatment j at time point k,
and
Σ
is a 2-by-2 unstructured covariance matrix.
The random error is assumed to be independent of random intercept and slope effects.
The following SAS code will be used to fit the model:
PROC MIXED DATA=xxxx METHOD=REML;
CLASS patient treat day1;
MODEL ECGep = conc treat day1/ NOINT CL ALPHA=0.1 ALPHAP=0.1
DDFM=KENWARDROGER;
RANDOM INT conc / TYPE=UN SUBJECT=patient;
ESTIMATE "Pred. value at conc. xx.xx" conc xx.xx treat 1 -1/ CL ALPHA=0.1;
ESTIMATE "Slope estimate" conc 1 / CL ALPHA=0.1;
RUN
QUIT;
1: class variable ‘day’(or ‘time’,respectively) will only be included in the sensitivity 
analyses.
Note that the variable names (e.g. ’patient’, ’conc’ etc.) given in the SAS code above have to 
be replaced by the respective variable names used in the analysis data set. ECGep 
corresponds to ‘QTcF change from baseline’.
The TYPE=UN option causes the two specified random coefficients to have a bivariate 
normal distribution. In case of convergence problems one may also use TYPE=FA0(2), 
which requests a G matrix estimate that is constrained to be nonnegative definite. If the note 
’estimated G matrix is not positive definite’ appears in the SAS log file, the random slope 
might be removed from the RANDOM statement.
9.2.4
Random coefficient model used to evaluate the appropriateness QT interval 
correction methods for heart rate
To evaluate the appropriateness of the QT correction methods, the (fixed effect) slopes will 
be estimated by treatment by applying the following model (R10-2920) separately to patients 


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with the treatments ‘xentuzumab+ everolimus+exemestane’ and ‘everolimus+exemestane’, 
respectively:
<=>? = ,+ + I+= + (S + I=)M=>? + A=>? ,
(IT=, I=) ~ E% (O, J), A=>?~ PPQ E(0, R%),
where i=1,...,I indicates the patient, k=1,…,K the number of the measurement and j=1,2 the 
treatment,
<=>?
is the log-transformed QT interval of measurement k in patient i receiving 
treatment j,
,+
is the overall intercept,
I+=
is the random effect on intercept associated with patient i,
S
is the common slope associated with the relationship between the log-transformed 
QT and RR intervals,
I=
is the random effect on slope associated with patient i,
M=>?
is the log-transformed RR interval of measurement k in patient i receiving 
treatment j,
A=>?
is the random error associated with the measurement k in patient i receiving 
treatment j, and
J
is a 2-by-2 unstructured covariance matrix.
The random effects I+= and I= are assumed to be independent of the random errors A=?.The 
analysis will be based on single ECG recordings that will be log-transformed using the 
natural logarithm.
The following SAS code will be used to fit the model 
PROC MIXED DATA=xxxx CL METHOD=REML;
CLASS patient;
MODEL logQT[or logQTc] = logRR / DDFM= KENWARDROGER ALPHA=0.05 CL;
RANDOM INT logRR / TYPE=UN SUBJECT=patient;
ESTIMATE 'Slope' logRR 1 / ALPHA=0.05 CL;
/* individual slope estimates:*/
ESTIMATE 'Slope f. patient 1' logRR 1 | logRR 1 /SUBJECT 1   ALPHA=0.05 CL;
ESTIMATE 'Slope f. patient 2' logRR 1 | logRR 1 /SUBJECT 0 1 ALPHA=0.05 CL;
/* etc. */ 
RUN;


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Note that the variable names given in the SAS code above have to be replaced by the 
respective variable names used in the analysis data set.
The TYPE=UN option causes the two specified random coefficients to have a bivariate 
normal distribution. In case of convergence problems one may also use TYPE=FA0(2), 
which requests a G matrix estimate that is constrained to be nonnegative definite. If the note 
’estimated G matrix is not positive definite’ appears in the SAS log file, the random slope 
might be removed from the RANDOM statement.
9.2.5
Technical details on handling of ECG recordings
In this section, administration of comparator treatment means administration of 
everolimus+exemestane.
Due to safety reasons the CTP allowed for additional unscheduled ECG monitoring. 
Therefore, the following process will be applied to select the scheduled three single ECG
recordings to be included in the analyses.
Within patient, visit and planned time, all single ECG recordings (scheduled or unscheduled) 
will be ordered by ECG date and time.
Screening: The last three single ECG recordings available will be selected.
Baseline time point:
ECG date and time will be compared with xentuzumab infusion start date and time (or date 
and time of comparator treatment administration for patients of Phase II not receiving 
xentuzumab, respectively).
If less than or equal to three single ECG recordings are available prior to start of first infusion 
or time of first drug administration, all of these values will be selected.
If more than three single ECG recordings are available prior to start of infusion or time of 
drug administration, only the three single ECG recordings closest to (but prior to) infusion 
start time or time of drug administration will be selected.
On-treatment time points:
Only ECGs recorded after start of first xentuzumab infusion (or first administration of 
comparator treatment for patients of Phase II not receiving xentuzumab, respectively) will be 
taken into account.
The following selection will be performed at each time point (PTM) within a visit:
If less than or equal to three single ECG recordings are available, all single ECG recordings
will be selected.
If more than three single ECG recordings are available, the three single ECG recordings
being closest to the planned time point will be selected. As the duration of an infusion may 
deviate from the planned duration of one hour, the selection of ECG recordings will be based 
on the actual end of infusion time. For patients not receiving an infusion, the planned time 
point is one hour after administration of the comparator treatment.
End of treatment (EOTV, FU): The first three single ECG recordings will be selected.


Boehringer Ingelheim
TSAP for BI Trial No.: 1280.4
Page 72 of 73
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All measurements which were not selected will be excluded from the statistical analyses. All 
excluded single ECG recordings will be listed in a separate listing in Appendix 16.2.8 and the 
reason for exclusion will be given.