Clinical trial NCT01938846
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2013-09-05; Completion date: 2017-06-22
Enrollment: 90 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the trial is to determine the maximum tolerated doses (MTD) of BI 860585 alone and in combination with exemestane or paclitaxel. To determine the MTDs, patients are entered sequentially into escalating dose cohorts. Secondary objectives are objective response and disease control according to RECIST criteria version 1.1

Detailed description:

Arms: arm 1: Multiple ascending doses of BI 860585 administered continuously in a 28-day cycle, including food interaction cohorts arm 2: Multiple ascending doses of BI 860585 in combination with fixed dose paclitaxel arm 3: Multiple ascending doses of BI 860585 in combination with fixed dose exemestane
Interventions: intervention 1: BI 860585 intervention 2: exemestane intervention 3: BI 860585 intervention 4: BI 860585 intervention 5: paclitaxel
Intervention descriptions: intervention 1: BI 860585 multiple dose escalation, once daily intervention 2: exemestane once daily intervention 3: BI 860585 multiple dose escalation, once daily intervention 4: BI 860585 multiple dose escalation, once daily intervention 5: paclitaxel once weekly

Protocol documents:
Prot_001.pdf: 
Clinical Trial Protocol
Doc. No.: c01837011-07
EudraCT No.:
BI Trial No.: 
2013-000765-36
1325.1 
BI 860585
BI Investigational
Product(s): 
Title:
An open label phase I dose finding study of BI 860585 administered 
orally in a continuous dosing schedule as single agent and in 
combination with exemestane or with paclitaxel in patients with various 
advanced and/or metastatic solid tumours.
Clinical Phase:
I
Trial Clinical 
Monitor:
Tel.: 
Fax: 
Co-ordinating 
Investigator:
 
 
Tel.: 
 
Fax: 
Status:
Final (Revised Protocol based on global amendment n.1 and n.2)
Version and Date:
Version: 3.0            
Date: 13 Feb 2015
Page 1 of 158
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
TITLE PAGE


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 2 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Available
Name of active ingredient:
BI 860585
Protocol date:
Trial number:
Revision date:
13 Feb 2015
30 Apr 2013
1325.1
Title of trial:
An open label phase I dose finding study of BI 860585 administered orally in a 
continuous dosing schedule as single agent and in combination with exemestane or 
with paclitaxel in patients with various advanced and/or metastatic solid tumours
Co-ordinating 
Investigator 
 
 
Trial site(s):
Multicentre
Clinical phase:
I
Objective(s):
To investigate: the maximum tolerated dose (MTD), safety, pharmacokinetics, 
and anti-tumour activity of BI 860585 as 
monotherapy and in combination with exemestane or with paclitaxel.
Methodology:
Uncontrolled, open label, multiple dose escalation followed by one or more expansion 
cohorts in each treatment arm
No. of patients: 
total entered:
Approximately 168 
each treatment:

Arm A (BI 860585): approximately 30 patients (including food interaction 
cohorts) + approximately 18 patients in expansion cohort

Arm B (BI 860585 + exemestane): approximately 30 patients + approximately 30 
patients in expansion cohorts

Arm C (BI 860585 + paclitaxel): approximately 30 patients + approximately 30 
patients in expansion cohorts
Diagnosis :
Patients with confirmed advanced and/or metastatic solid tumours


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 3 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Available
Name of active ingredient:
BI 860585
Protocol date:
Trial number:
Revision date:
13 Feb 2015
30 Apr 2013
1325.1
Main criteria
for inclusion:

In the single agent arm (Arm A): patients with confirmed advanced and/or 
metastatic solid tumours relapsed or refractory to current standard therapies.

In the combination arms (Arm B, Arm C) patients with confirmed advanced 
and/or metastatic solid tumours relapsed or refractory to current standard 
therapies and where the use of exemestane or paclitaxel would be considered 
appropriate by the investigator. In addition, patients enrolled into the expansion 
part of the study must have measurable progressive disease.
Test product(s):
BI 860585
dose:
Starting dose of BI 860585 is 5 mg/day
mode of admin.:
Oral, continuous daily dosing (28-days cycle)
Combination product:
Exemestane or Paclitaxel
dose:

Exemestane: 25 mg/day, standard fixed dose (Arm B)

Paclitaxel: 80 mg/m2, standard combination dose (with a 25% dose reduction in 
the first dose level combination cohort, Arm C) 
mode of admin.:

Exemestane: Oral, continuous daily dosing (28-day cycle)

Paclitaxel: Intravenous infusion, once every week (28-day cycle)
Duration of treatment: A minimun of one treatment cycle. Patients are eligible for repeated cycles until 
progression of disease or undue toxicity
Criteria for efficacy:
Objective response rate according to RECIST criteria version 1.1 (CR/PR), clinical 
benefit rate/disease control (CR/PR/SD), duration of objective response and of clinical 
benefit rate.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 4 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Available
Name of active ingredient:
BI 860585
Protocol date:
Trial number:
Revision date:
13 Feb 2015
30 Apr 2013
1325.1
Pharmacokinetics:

Pharmacokinetics of BI 860585 monotherapy during single and multiple dosing

Pharmacokinetics of BI 860585 during multiple dosing in combination with 
exemestane or with paclitaxel (including drug-drug interaction (DDI) of BI 
860585 in combination with exemestane or with paclitaxel)
 
 
 
Criteria for safety:

DLT (dose limiting toxicities)

Incidence and intensity of adverse events graded according to National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, 
version 4.03)

Laboratory parameters

ECGs and vital signs 

Adverse events of special interest (e.g. drug induced liver injury (DILI), 
stomatitis, mucositis, cutaneous rash, laboratory abnormalities such as 
hypertriglyceridemia, hypercholesterolaemia and hyperglycaemia)
Statistical methods:
Descriptive statistics and exploratory data analysis


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 5 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
FLOW CHART (CYCLE 1)
Trial Period
Screening
Treatment Cycle 1
EOTb
FU(s)c
Visits*
Screening
1a
2
3
4a
5§
Days (± window)
-28 to -1
-7 
to -
1**
1
2#
8±1
15±1
22±1
23±1##
28+1
0-7 
days 
after 
last 
drug 
intake
EOT 
+28
days 
(±7)
Informed consent 
(IC)
X
Demographics
X
Medical history
X
Inclusion/Exclusion 
criteria
X
X
Physical 
examination
X
X
X
Xt
Vital signsd
X
X
X
X
X
X
X
X
Xs
Xt
ECOG performance 
score
X
X
X
X
Body weight
X
X
X
Height
X
ECGe
X
Xu
X
Xv
Xv
Xv
X
X
X
Xs
Xt
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Clinical disease 
assessmentf
X
X
X
X
Tumour 
Assessmentg
X
X
X
FDG – PETh
(optional)
X
X
Laboratory
Safety Parameters i
X
X
X
X
X
X
Xs
Xt
Coagulation i
X
X
X
X
X
X
Xs
Xt
Urinalysis i
X
X
X
X
X
X
X
X
Xs
Xt
eGFR analysis j
X
X
Serum pregnancy 
test k
X
X
Blood Glucose 
Level Monitoring l
X-------------------------------------------------------- X
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 6 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Trial Period
Screening
Treatment Cycle 1
EOTb
FU(s)c
Visits*
Screening
1a
2
3
4a
5§
Days (± window)
-28 to -1
-7 
to -
1**
1
2#
8±1
15±1
22±1
23±1##
28+1
0-7 
days 
after 
last 
drug 
intake
EOT 
+28
days 
(±7)
Sign separate 
consent form 
X
 
 
 
 
Drug 
Accountability
Compliance check
X
X
Xs
Completion of 
diary
X---------------------------------------------------------X
Treatment 
administration
BI 860585 
dispensation
X
Arm A
BI 860585 
administrationq
X-------------------------------------------------------X
Arm B
BI 860585 
administrationq
X-------------------------------------------------------X
Exemestane 
dispensation
X
Exemestane 
administration
X
X-------------------------------------------------------X
Arm C
BI 860585 
administrationq
X-------------------------------------------------------X
Paclitaxel infusion
X
X
X
X
X
X
End of active trial 
treatment
X
Others
Patient status 
follow-up
X
Eligibility for 
further cycle
X
 
*       Visit code indicates cycle number and visit number, i.e. Visit 2 Cycle 1 will read C1V2 and Visit 4 Cycle 2 
will read C2V4.
**     Arm B and Arm C will begin treatment on Day -7 and will start PK sampling.
#       Only in Arm A: patients recruited for the food interaction cohorts should have a PK sampling on Day 3 (24h 
after BI 860585 intake on Day 2). See Appendices 10.1.1 and 10.1.3 for further details.
##     Only in Arm C: patients should have a PK sampling on Day 24 (24h after BI 860585 intake on Day 23). See 
Appendices 10.1.1 for further details.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 7 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
§
This visit can be done on the same day as C2V1, if an additional cycle is indicated.
a.
Patient may be hospitalized in order to guarantee adequate convenience during the visits requiring most 
frequent PK sampling.
b.
End of Treatment (EOT) visit to be performed within 7 days from last drug intake: for patients who 
discontinue prematurely it must be performed as the last visit followed by follow-up visit(s) where applicable. 
c.
All patients will undergo one Follow-Up (FU) Visit 28 days after EOT. Additional FU visits (visit or phone 
contact) will take place at 8-week intervals or earlier only for patients who discontinue for reasons other than 
disease progression. FUs will continue until progression or death, lost to follow-up or start of another anti-
cancer drug.
d.
Vital signs (blood pressure, pulse after 2 minutes supine rest and temperature) once at any time during the 
visit.
e.
ECG should always be performed in triplicate (to explore QTc). ECG matched with PK sampling time points
should be done before the PK sampling. In case of drug related Grade 3 or 4 toxicity, every effort should be 
made to collect an ECG (triplicate) matched with a PK sample; date and time of the ECG and of the most 
recent drug intake need to be recorded.
f.
Clinical disease assessment at baseline and after every treatment cycle: in case of suspected progressive 
disease, it is advised to confirm progression using MRI or CT.
g.
An existing scan can be used as screening scan, if obtained within 4 weeks prior to start of treatment. EOT 
imaging is optional if the previous exam was performed in the past 4 weeks. 
h.
For patients in the expansion cohorts (optional): in addition to traditional imaging and in case the 
investigator and the sponsor find it appropriate, an FDG-PET may be done at any time during the patient’s 
participation in the trial, to evaluate  tumour metabolic responses. An existing FDG-PET, if obtained within 4 
months prior to start of treatment, can be used as screening FDG-PET.  
i.
Laboratory assessments will be evaluated locally. Please refer to Section 5.2.3 for a detailed description of 
laboratory assessments. 
j.
For eGFR analysis at Day 2 and Day 22, 24 hours urine should be collected after BI 860585 administration 
(at Day 1 and Day 21), please refer to Section 5.2.3.
k.
A serum βHCG pregnancy test must be performed at screening in women of childbearing potential within 7 
days of starting treatment.
l.
Fasting blood glucose level measured by glucometer once a day starting from Day 2.Values will be recorded 
in patient diary.
m.
For patients in the dose escalation and expansion parts of the study. Please refer to Appendix 10.1.1 for a 
detailed description of pharmacokinetic and biomarker sampling.
n.
For all patients, in case of DLTs or drug related Grade 3 or 4 toxicity, every effort should be made to collect 
PK blood sample(s) together with ECG (ECG should always be performed BEFORE PK sampling); date and 
time of the sample(s) and of the most recent drug intake (before PK sample) need to be recorded for such 
sample(s). 
 
 
 
r.
In case of occurence of cutaneous rash of Grade ≥ 3 a skin biopsy will be performed in order to determine the 
pathology of rash and rule out eventual leucocytoclastyc vasculitis (rarely reported with rapalogs).
s.
If this examination was already done on Day 28 of the first cycle, and was done within the past two weeks, 
this examination does not need to be performed again in this visit.
t.
Mandatory for first follow-up visit. Optional, for additional FU visits.
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 8 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
y.
For details please refer to Sections 5.3.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 9 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
FLOW CHART (CYCLE 2 AND SUBSEQUENT CYCLES)
Trial Period
Treatment Cycle 2 and subsequent 
cycles
EOTa
FU(s)b
Visits*
1
2
3
4
5**
Days
1
8±3
15±3
22±3
28±3
0-7 days after 
last drug 
intake
EOT + 
28 days
(±7)
Physical examination
X
X
Xn
Vital signsc
X
X
X
X
X
Xm
Xn
ECOG performance score
X
X
X
Body weight
X
X
ECG
X
Xd
X
Xn
Concomitant therapy
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
Clinical disease assessmente
X
X
X
Tumour Assessmentf
X
Xm
X
FDG – PET (optional)
X
Laboratory
Safety Parametersg
X
X
X
X
X
Xm
Xn
Coagulationg
X
X
X
X
X
Xm
Xn
Urinalysisg
X
X
X
X
X
Xm
Xn
eGFR analysis
Xo
Serum Pregnancy Test h 
X
Blood Glucose Level Monitoringi
     X-------------------------------------------------------X
 
 
 
 
Drug Accountability
Compliance check
X
Xm
Completion of diary
     X-------------------------------------------------------X
Treatment administration
BI 860585 dispensation
X
Arm A
BI 860585 administrationk
     X-------------------------------------------------------X
Arm B
BI 860585 administrationk
     X--------------------------------------------------------
X
Exemestane dispensation
X
Exemestane administration
    X--------------------------------------------------------X
Arm C


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 10 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Trial Period
Treatment Cycle 2 and subsequent 
cycles
EOTa
FU(s)b
Visits*
1
2
3
4
5**
Days
1
8±3
15±3
22±3
28±3
0-7 days after 
last drug 
intake
EOT + 
28 days
(±7)
BI 860585 administrationk
    X--------------------------------------------------------X
Paclitaxel infusion
X
X
X
X
X
End of active trial treatment
X
Others
Patient status follow-up
X
Eligibility for further cycle
X
Skin Biopsyl
X
* Visit code indicates cycle number and visit, i.e. Visit 2 Cycle 1 will read C1V2 and Visit 4 Cycle 2 will read C2V4
** can be on the same day as Visit 1 of the next cycle if an additional cycle is indicated
a.
End of Treatment (EoT) visit to be performed within 7 days from last drug intake: for patients who discontinue 
prematurely it must be performed as the last visit.  
b.
All patients will undergo one Follow- up (FU) Visit 28 days after EOT. Additional FU visits (visit or phone 
contact) will take place at 8-week intervals or earlier only for patients who discontinue for reasons other than 
disease progression. FUs will continue until progression or death, lost to follow-up or start of another anti-cancer 
drug.
c.
Vital signs (blood pressure, pulse after 2 minutes supine rest and temperature) once at any time during the visit.
d.
In case of drug related Grade 3 or 4 toxicity, every effort should be made to collect an ECG (triplicate) matched 
with a PK sample; date and time of the ECG and of the most recent drug intake need to be recorded.
e.
Clinical disease assessment after every treatment cycle, in case of suspect progressive disease, it is advised to 
confirm progression using MRI or CT.
f.
CT or MRI imaging: response assessment every 2 cycles starting at the end of Cycle 2; a scan at EOT visit is 
optional in case a scan was already done in the previous 4 weeks. For patients in the expansion cohorts, in addition 
to traditional imaging and in case the investigator and the sponsor find it appropriate, an FDG-PET may be done 
at any time during the patient’s participation in the trial, to evaluate tumour metabolic responses.
g.
Laboratory assessments will be evaluated locally. Please refer to Section 5.2.3 for a detailed description of 
laboratory assessments.
h.
A serum βHCG pregnancy test must be performed at EOT in women of childbearing potential.
i.
Fasting blood glucose level measured by glucometer once a day. Values will be recorded in patient diary.
j.
For all patients, in case of DLTs or drug related Grade 3 or 4 toxicity, every effort should be made to collect a PK 
sample; date and time of the sample and of the most recent drug intake (before PK sample) need to be recorded for 
such samples.
k.
Drug intake should be 30 minutes after start of breakfast and as long as no different instructions are given.
l.
In case of occurance of cutaneous rash of Grade ≥3 a skin biposy will be performed in order to determine the 
pathology of rash and rule out eventual leucocytoclastyc vasculitis (rarely reported with rapalogs).
m.
If this examination was already done on Day 28 of previous cycle, and was done within the past two weeks, this 
examination does not need to be performed again in this visit.
n.
Mandatory for first follow-up visit. Optional, for additional FU visits.
o.
Additional eGRF analysis at the beginning of subsequent cycles will be optional (investigator’s judgement) and in 
case of serum creatinine increase and/or protenuria occurrence.
p.
In case of intra-patient dose escalation, in any treatment arm, every effort should be made to collect PK and PD
samples as indicated in Table 10.1.1: 5 ;date and time of the sample and of the most recent drug intake (before PK 
sample) need to be recorded for such samples.
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 11 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART (CYCLE 1) ..............................................................................5
FLOW CHART (CYCLE 2 AND SUBSEQUENT CYCLES).......................9
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................20
1.2.2
Exemestane............................................................................................21
1.2.3
Paclitaxel................................................................................................22
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 23
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................23
2.2
TRIAL OBJECTIVES.......................................................................................23
2.3
BENEFIT - RISK ASSESSMENT ...................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.1.1
Administrative structure of the trial...................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................33
3.3
SELECTION OF TRIAL POPULATION ......................................................34
3.3.1
Main diagnosis for study entry............................................................34
3.3.2
Inclusion criteria...................................................................................34
3.3.3
Exclusion criteria ..................................................................................35
3.3.4
Removal of patients from therapy or assessments.............................36
3.3.4.1
Removal of individual patients................................................36
3.3.4.2
Discontinuation of the trial by the Sponsor .............................37
3.3.4.3
Replacement of patients...........................................................37
4.
TREATMENTS........................................................................................ 38
4.1
TREATMENTS TO BE ADMINISTERED....................................................38
4.1.1
Identity of BI investigational product and combination 
product(s)...............................................................................................38
4.1.2
Method of assigning patients to treatment groups ............................39
4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each patient .......45
4.1.4.1
BI 860585 in Arms A, B and C................................................45


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 12 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.1.4.1.1Treatment Discontinuation and Dose reduction scheme for BI 
860585......................................................................................46
4.1.4.2
Exemestane in Arm B..............................................................48
4.1.4.3
Paclitaxel in Arm C..................................................................49
4.1.5
Blinding and procedures for unblinding ............................................49
4.1.6
Packaging, labelling, and re-supply ....................................................49
4.1.7
Storage conditions.................................................................................50
4.1.8
Drug accountability ..............................................................................50
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................51
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................51
4.2.2
Restrictions............................................................................................51
4.2.2.1
Restrictions regarding concomitant treatment .........................51
4.2.2.2
Restrictions on diet and life style.............................................52
4.3
TREATMENT COMPLIANCE.......................................................................52
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 54
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................54
5.1.1
Endpoint(s) of efficacy..........................................................................55
5.1.2
Assessment of efficacy...........................................................................55
5.2
SAFETY..............................................................................................................55
5.2.1
Endpoint(s) of safety.............................................................................55
5.2.2
Assessment of adverse events...............................................................56
5.2.2.1
Definitions of adverse events...................................................56
5.2.2.2
Adverse event and serious adverse event reporting.................59
5.2.3
Assessment of safety laboratory parameters......................................60
5.2.4
Electrocardiogram................................................................................61
5.2.5
Assessment of other safety parameters...............................................62
5.3
OTHER...............................................................................................................62
5.3.1
Other endpoint(s)..................................................................................62
5.3.2
Other assessment(s) ..............................................................................62
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................64
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................64
5.5.1
Pharmacokinetic endpoint(s)...............................................................64
5.5.2
Methods of sample collection...............................................................65
5.5.2.1 Plasma sampling for pharmacokinetic analysis.......................65
5.5.2.2 Urine sampling for pharmacokinetic analysis..........................66
5.5.3
Analytical determinations ....................................................................66
5.5.3.1
Analytical determination of BI 860585 concentrations in 
plasma and urine ......................................................................66


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 13 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
5.5.3.2
Analytical determination of exemestane or paclitaxel 
concentrations in plasma..........................................................67
 
6.
INVESTIGATIONAL PLAN.................................................................. 69
6.1
VISIT SCHEDULE............................................................................................69
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................69
6.2.1
Screening and run-in period(s)............................................................70
6.2.2
Treatment period(s)..............................................................................71
6.2.3
End of treatment and follow-up period ..............................................73
6.2.3.1
End of treatment visit...............................................................73
6.2.3.2
Follow-up visits .......................................................................73
6.2.4
Completion of study..............................................................................73
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 75
7.1
STATISTICAL DESIGN - MODEL................................................................75
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................75
7.3
PLANNED ANALYSES....................................................................................75
7.3.1
Primary analyses...................................................................................75
7.3.2
Secondary analyses ...............................................................................76
7.3.3
Safety analyses.......................................................................................76
7.3.4
Interim analyses ....................................................................................77
7.3.5
Pharmacokinetic analyses ....................................................................78
7.4
HANDLING OF MISSING DATA ..................................................................78
7.4.1
Drug concentration - time profiles ......................................................78
7.4.2
Pharmacokinetic parameters...............................................................79
7.5
RANDOMISATION ..........................................................................................79
7.6
DETERMINATION OF SAMPLE SIZE ........................................................79
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 81
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................81
8.2
DATA QUALITY ASSURANCE .....................................................................81
8.3
RECORDS..........................................................................................................82
8.3.1
Source documents .................................................................................82


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 14 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
8.3.2
Direct access to source data and documents.......................................82
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................82
8.4.1
Listedness...............................................................................................82
8.4.2
Expedited reporting to health authorities and IECs/IRBs................82
8.5
STATEMENT OF CONFIDENTIALITY.......................................................83
8.6
COMPLETION OF TRIAL..............................................................................83
9.
REFERENCES......................................................................................... 84
9.1
PUBLISHED REFERENCES...........................................................................84
9.2
UNPUBLISHED REFERENCES.....................................................................86
10. APPENDICES .......................................................................................... 87
10.1
PHARMACOKINETIC ANALYSES..............................................................87
10.1.1 Blood sampling time schedule..............................................................87
10.1.2 Derivation of pharmacokinetic parameters........................................95
10.2
CLINICAL EVALUATION OF LIVER INJURY .........................................98
10.2.1 Introduction...........................................................................................98
10.2.2 Procedures .............................................................................................98
10.3
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCORE ...............................................................................99
10.4
MODIFICATION OF DIET IN RENAL DISEASE FORMULA...............100
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 101


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 15 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
ABBREVIATIONS
AE
Adverse Event
ALT
Alanine amino transferase
aPTT
Activated partial thromboplastin time
AST
Aspartate amino transferase
AUC
ATP
Area under the Curve
Adenosine TriPhosphate
AUC(ss)
Area under the plasma concentration-time curve (at steady state)
BC
Breast Cancer
β HCG
BUN
Human chorionic gonadotropin
Blood urea nitrogen
BLQ
Below limit of quantification
CA
Competent Authority
CDER
Center for Drug Evaluation and Research
CHF
Congestive Heart Failure
CI
Confidence Interval
Cmax(ss)
Maximum measured plasma concentration (at steady state)
 
CML
Local Clinical Monitor 
CPK
CR
Creatinine Phospokinase
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
CT
Contract Research Organization
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
DDI
Drug Drug Interaction
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DM&T
Drug Metabolism and Transport
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eGFR
EOT
Estimated Glomerular Filtration Rate
End of Treatment
EudraCT
European Clinical Trials Database
FDA
FDG-PET
Food and Drug Administration
Positron emission tomography (PET) with [18F]fluorodeoxyglucose


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 16 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
FFPE
Formalin fixed paraffin embedded
FU
Follow-up
GCP
Good Clinical Practice
HbA1C
HR
Glycated hemoglobin
Hormone Receptor
IB
Investigator’s Brochure
IC
Informed Consent
ICH
International Conference Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
International Normalised Ratio
IRB
Institutional Review Board
ISF
Investigator Site File
Ki
λz(ss)
Inhibition constant
Terminal rate constant of the analyte in plasma (at steady state)
LC-MS/MS
MDRD
Tandem Mass Spectrometry
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
MRT
Mean Residence Time
MRTpo(ss)
Mean Residence Time of the analyte in the body after oral administration 
(at steady state)
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
mTORC1
Mammalian Target of Rapamycin complex 1
mTORC2
Mammalian Target of Rapamycin complex 2
NC
Not calculated
NOAEL
No Observed Adverse Event Level
OC
Ovarian Cancer
OPU
Operative Unit
OS
Overall Survival
PCC
Protocol Challenge Committee
PD
Pharmacodynamics
PFS
Progression Free Survival
PI3K
Phosphoinositide 3-kinase
PIK3CA
Phosphatidylinositol-4,5-bisphosphate 3-kinase
PK
Pharmacokinetics
PP
Poly-Propylene
PR
Partial Response
PRP
Platelet Rich Plasma
PTEN
Phosphatase and Tensin homolog
q.d.
quaque die (once a day)
RBC
Red Blood Cell
RBD
RDC
Relevant Biological Dose
Remote Data Capture


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 17 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
RP2D
Recommended Phase II Dose
SAE
Serious Adverse Event
SD
Stable Disease
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SUSAR
S6K
Suspected Unexpected Serious Adverse Reaction
S6 Kinase
TBA
Trial BioAnalyst
TCM
TCPK
Trial Clinical Monitor
Trial Clinical Pharmacokineticist
TDMAP
Trial Data Management and Analysis Plan
tmax(ss)
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma (at steady state)
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
t1/2(ss)
Terminal half-life of the analyte in plasma (at steady state)
ULN
Upper Limit Normal
Vss
Volume of distribution after intravenous infusion at steady state
Vz
Apparent volume of distribution during the terminal phase λz after 
intravenous infusion
Vz/F(ss)
WBC
WHO
Apparent volume of distribution during the terminal phase λz (at steady 
state)
White Blood Cell
World Health Organization


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 18 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Cancer is a leading cause of death globally accounting for nearly 7.4 million deaths in 2004. 
WHO projects deaths from cancer worldwide to continue rising, with an estimated 12 million 
deaths in 2030. Most patients with locally advanced and/or metastatic tumours invariably 
succumb to their disease. There is therefore a substantial need for novel therapeutic strategies 
to improve the outcome of patients with advanced or metastatic malignancies who have failed 
conventional therapies, or for whom no therapy of proven efficacy exists. In recent years, a 
number of novel compounds targeting specific cellular components have been developed 
based on increasing understanding of cancer biology and cell regulation.
The PI3K/AKT/mTOR pathway plays an important role in the regulation of metabolism, 
survival and proliferation of mammalian cells. The mTOR component of this pathway 
comprises at least two different complexes: the rapamycin sensitive mTOR complex 1 
(mTORC1) and the rapamycin insensitive mTOR complex 2 (mTORC2). The mTOR 
complexes, being the main downstream effectors in the PI3K/AKT pathway exert a central 
role in regulating: cell growth, proliferation, metabolism, angiogenesis and cell survival-
processes.
In many human cancers this pathway is frequently hyperactivated. Targeting the 
PI3K/AKT/mTOR axis in one, or more of its components, may therefore play a critical role 
for cancer therapy.
Figure 1.1: 1
The PI3K/AKT/mTOR pathway plays a central role in regulating 
critical cell functions including proliferation, cell energy and nutrient 
status, modulating the signals induced by the upstream network which 
includes growth factors, insulin and cell surface receptors. 
cell growth, protein translation
cell survival
glucose metabolism
proliferation
P
RTK
P
PI3K
P
PTEN
PH
AKT
Thr308
Ser473
P
PH
PDK1
P
PIP3
PIP2
TORC2
TORC1
Raptor
S6K
4EBP
Rictor
p85
S6


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 19 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Preclinical and clinical emerging data are showing that hyperactivation of the
PI3K/AKT/mTOR pathway has a high prevalence in malignancies such as hormone positive 
breast cancer (R12-4136), endometrial (R12-5640), cervical and ovarian cancer (R12-5641, 
R12-5627, R12-5639). In some instances the pathway hyperactivation seems to be related to 
aberrancies in one of its components such as for instance: PIK3CA mutation or PTEN loss.  
In addition it is frequently hyperactivated (even in the absence of a clear detectable mutation) 
in several tumours which have acquired resistance to standard treatment as recently 
demonstrated in the Phase III Bolero 2 trial in hormone receptor positive (HR positive) 
metastatic breast cancer (R12-5635).
Finally the PI3K/mTOR/AKT signalling pathway plays a critical role in the maintenance, 
progression as well as in the resistance to current therapies of several cancers (R12-5637, 
R12-4136, R12-4137).
The first generation of mTOR inhibitors was derived from the immunosuppressive drug 
rapamycin. Rapamycin and its analogs, called rapalogs, act as allosteric inhibitors of
mTORC1 and their therapeutic success is believed to be limited due to the incomplete 
suppression of mTORC1, absence of inhibition of mTORC2, as well as to a feedback-
activation of PI3K/AKT signalling via S6K feedback loop and via mTORC2 mediated AKT 
phosphorylation.
A new generation of mTOR inhibitors has emerged in the early clinical development, they 
are ATP-competitive inhibitors and target the kinase domains of mTOR, fully inhibiting 
mTORC1 as well as mTORC2 and potentially exerting a more sustained inhibition of the 
PI3K/AKT/mTOR pathway with respect to rapalogs.
BI 860585 is one of this new class of compounds being a highly potent and selective ATP-
competitive mTOR (mTORC1 and mTORC2) serine/threonine kinase inhibitor.
 
Pre-clinical data on BI 860585 have shown broad anti-proliferative activity in tumour cell 
lines of various tumour types including luminal breast cancer, ovarian and endometrial 
cancer. Tumour growth inhibition was observed in several preclinical in vivo models 
Data from early clinical trials with PI3K/mTOR inhibitors (i.e. rapalogs and some 
mTORC1/mTORC2 inhibitors) demonstrated that objective response rates achieved with 
single-agent therapy have been modest. It is expected that mTOR inhibition in combination 
with other anticancer agents, including chemotherapy and targeted therapies, may prove to be 
more effective as it may induce a ”synthetic lethality” and subsequent tumour regression. 
Moreover the addition of an mTOR inhibitor may contribute to reverse acquired resistance to 
treatment (R12-5646, R12-5637, R12-5635).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 20 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
1.2
DRUG PROFILE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 21 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2
Exemestane
Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the 
natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is 
processed to an intermediate that binds irreversibly to the active site of the enzyme causing 
its inactivation, an effect also known as "suicide inhibition". By being structurally similar to 
enzyme targets, exemestane permanently binds to the enzymes, preventing them from 
converting androgen into estrogen.
Exemestane is rapidly absorbed and has an oral bioavailability of 42 %. It reaches peak 
plasma concentrations within 2 hours following the oral administration of a 25 mg dose. The 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 22 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
half-life of the drug is between 24 and 30 hours. This is significant since it is quite shorter 
than for the non-steroidal inhibitors. Exemestane exhibits an excellent safety profile in 
humans, having no significant drug toxicity at doses up to 600 mg/day and it is exceptionally 
well tolerated by most users (R13-1535).
Exemestane is extensively metabolized by CYP 3A4 (based on in vitro studies), but recent 
studies show contribution of multiple CYPs, including also CYP 4A11 and CYP 1A1/2 (R13-
1651). Concomitant administration of the strong CYP 3A4 inhibitor ketoconazole had no 
effects on exemestane PK (R13-1656). Administration of the strong CYP 3A4 inducer 
rifampin decreased exemestane AUC by 54%. Based on this, there is limited risk of undue 
effect of BI 860585 on exemestane PK. There is a low risk that exemestane acts as an 
inhibitor or inducer and in that way affects the PK of BI 860585 (R13-1543).
1.2.3
Paclitaxel
Paclitaxel is a clear colourless to slightly yellow viscous solution. Paclitaxel is an anti-
microtubule agent approved for the treatment of various solid tumours. Paclitaxel promotes 
the assembly of microtubules from tubulin dimers and stabilises microtubules by preventig 
depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation 
of the microtubule network that is essential for vital interphase and mitotic cellular functions. 
In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell 
cycle and multiple asters of microtubules during mitosis. In this trial, paclitaxel shall be 
administered once weekly at a dose of 80 mg/m2 intravenously over 1 hour (with a 25% dose 
reduction in the first dose cohort, i.e 60 mg/m2). The average elimination half-life of 
paclitaxel is 5.8 hours.
In vitro and in vivo studies have demonstrated that paclitaxel is extensively metabolised by 
the liver to 3 primary metabolites. Cytochrome P450 enzymes of the CYP 3A and CYP 2C 
subfamilies appear to be involved in hepatic metabolism of paclitaxel: in most individual the 
major enzyme for paclitaxel metabolism is CYP 2C8 and it is metabolized to a lesser extent
by CYP 3A4 (R13-1650). The clinical significance of inhibition of these pathways has not 
been demonstrated. Single doses of the strong CYP 3A4 inhibitor ketoconazole did not alter 
the PK of paclitaxel. Inducing agents did decrease paclitaxel AUC up to 52%. Based on this,
there is a risk that BI 860585, being an inhibitor of CYP 2C8, CYP 3A4, and others, may
affect paclitaxel PK (R13-1542).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 23 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
There is a substantial need for novel therapeutic strategies to improve the outcome for
patients with cancer. Gynecological malignancies including breast and ovarian cancer 
account for approximately 500 000 and 200 000 new cases per year respectively worldwide. 
Human breast cancer is one of the best characterized solid tumours (R05-1606, R12-5638). 
Molecularly targeted drugs have dramatically changed the natural history of some disease
subtypes in the adjuvant setting (R00-0994, R05-1607 and R05-1609). However, once the 
disease has become metastatic, factors such as tumour burden, tumour microenvironment, 
altered immunological environment, resistance mechanisms, escape pathways and feedback 
loops limit the effectiveness of single modality regimens. 
Advanced and relapsed ovarian cancer is still an unmet medical need, with 4.2% of cancer 
deaths in women attributable to it, depending on the tumour stage, as many as 80% of 
patients are at risk of relapse after “the established” first line best option for advanced ovarian 
cancer (platinum-based chemotherapy i.e. carboplatin-paclitaxel). In case of platinum-failure, 
several chemotherapy options are available (e.g. paclitaxel, topotecan, etc.). However these 
options show only limited clinical efficacy.
Given the mode of action and the available clinical data for compounds targeting the 
PI3K/AKT/mTOR pathway, it is expected that the addition of BI 860585 to endocrine, 
chemotherapy and/or other targeted therapies in the clinic might contribute to effectively 
reverting refractoriness and prolonging PFS in advanced metastatic cancers.
 
 
The present study is the first-in-man study to provide the safety profile of BI 860585 as single 
agent and in combination with exemestane or with paclitaxel for the recommendation of the 
Phase II dose and schedule of treatment for further trials in the development of BI 860585.
 
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to determine:

Maximum Tolerated Dose (MTD) of BI 860585 in monotherapy.

MTD of BI 860585 in combination with exemestane.

MTD of BI 860585 in combination with paclitaxel.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 24 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
The safety profile of BI 860585 will further be evaluated at the recommended dose(s) and 
schedule(s) [MTD and/or relevant biological dose(s)] in patients with various tumour types 
(i.e. expansion cohorts).
Please refer to Section 5.2 for a description of safety endpoints.
Secondary objectives will be to:

Investigate preliminary anti-tumour activity in all evaluable and in all measurable
patients (please refer to Section 5.1.1 for a description of efficacy endpoints).

To determine the PK profiles of BI 860585 (during single and multiple dosing of BI 
860585 in monotherapy Arm A), of exemestane (without and with BI 860585
multiple dosing in Arm B) and of paclitaxel (without and with BI 860585 multiple 
dosing in Arm C) (see Section 5.5).
2.3
BENEFIT - RISK ASSESSMENT
Most patients with locally advanced and/or metastatic tumours will succumb to their disease. 
Thus, there is a substantial need for novel therapeutic strategies to improve the outcome for 
patients with advanced and/or metastatic malignancies.
BI 860585 has shown broad anti-proliferative activity in tumour cell lines and in various 
xenograft models (including luminal breast cancer, ovarian and endometrial cancer).   
Toxicity studies have suggested that BI 860585 has an acceptable safety profile in animal 
models and a safe starting dose in humans has been determined.  


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 25 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
In repeat-dose toxicity studies up to 4 weeks in rats and Beagle dogs, toxicities were mostly 
dose dependent and the main target organs were: lymphoid and hematopoietic system, 
kidney, gastro-intestinal tract, adrenal and pituitary glands (in rats) and blood vessels 
(vasculitis in dogs). Except for the vascular changes in dogs, all other BI 860585 treatment 
related changes were either completely reversible or ameliorated during the 4-week recovery 
period (see also Section 1.2.1 of Clinical Trial Protocol (CTP) and IB, Doc. No: c02093461).
Safety pharmacology studies showed no toxicologically meaningful adverse cardiac, 
respiratory, or neurological effects of BI 860585. There is no evidence of mutagenic potential 
of BI 860585 (see IB). An in vitro local tolerance study using human skin constructs 
classified BI 860585 (the succinate salt) as being irritant to the skin. Cancer patients 
participating in BI 860585 clinical trials should avoid direct exposure of the unprotected skin 
and eye to sunlight or equivalents for a period of one week after the last administration of BI 
860585.
The estimated safe starting dose for clinical trials in cancer patients is 5 mg/day, based on 
data from 4-week toxicology studies in rats and dogs (see IB). BI 860585 has not been tested 
in humans prior to this trial.
Adverse events as stated in section 1.2.1 of the protocol are expected and will be managed 
with adequate monitoring and supportive care.
Since rare cases of skin leucocytoclastic vasculitis have been observed and reported as related 
to the administration of rapalogs since 1999 (R13-1504), and considering this is a First in 
Human study, a conservative approach will be taken and a diagnostic skin biopsy will be 
performed in case of Grade > 3 skin rash, to rule out the potential onset of vasculitis.
Clinical data available to date for other mTORC1/2 inhibitors suggest limited clinical 
efficacy of these agents as single agents. Therefore, an early combinatory strategy with other 
therapies will likely optimize the efficacy of BI 860585. It is expected that the side effect 
profile of the combinations agents may differ from that of BI 860585 and therefore these 
agents may be combined avoiding overlapping toxicities.
BI 860585 was an in vitro inhibitor of various CYP enzymes (see Section 1.2.1). Both 
exemestane and paclitaxel are metabolized by multiple CYPs including those likely to be 
inhibited by BI 860585 (see Sections 1.2.2 and 1.2.3). 
The potential for drug-drug interactions with CYP3 A4 substrates, must be considered prior 
to and during therapy with BI 860585. Nisoldipine (a calcium channel blocker) and HMG 
CoA-reductase inhibitors (such as lovastatin, simvastatin, and atorvastatin), metabolized by 
CYP3 A4, are predicted as high risk for increased exposure. Their concomitant use during 
treatment with BI 860585 should be avoided and replaced by an alternative drug. If their 
concomitant use cannot be avoided and no alternative is available then  the prescribed dose 
should be reduced by half with close monitoring for potential adverse reactions.
Exemestane reported side effects (most commonly expected, as per previous clinical trials, 
are mild and comprise peripheral edema, fatigue, hot flashes, arthralgia, myalgia, headache 
and nausea) will be carefully monitored, and in case of worsening after the addition of BI


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 26 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
860585, unplanned PK samples may be performed to rule out exceptional exposures related 
to drug - drug interaction. Should the above mentioned side effects be equal or exceed Grade
3 they will fulfil the DLT criteria (see Section 5.2.1) and determine drug decrease or 
discontinuation (see Section 4.1.4).
Paclitaxel reported side effects include myelosuppression, hypersensitivity reactions, 
arthralgia, myalgia, peripheral neuropathy, fatigue, nausea, vomiting, and diarrhoea. These 
side effects will be carefully monitored, and in case of worsening after the addition of BI
860585, unplanned PK samples may be performed to rule out exceptional exposures related 
to drug - drug interaction. Should the above mentioned side effects be equal or exceed Grade 
3 they will fulfil the DLT criteria (see Section 5.2.1) and determine drug decrease or 
discontinuation (see Section 4.1.4).
In addition should a combination arm prove unsafe such arm will be terminated. Finally 
should the single agent arm prove unsafe the trial will be terminated.
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.
Moreover, cardiac monitoring by serial 12-lead ECGs will also be implemented in order to 
investigate cardiovascular effects (including QT prolongation) in relation to PK.
In conclusion, cancer patients with advanced disease treated with BI 860585 may benefit 
from tumour stabilization and alleviation of disease related symptoms with an acceptable 
quality of life. The potential benefit of a single agent and combination therapy with BI 
860585 is anticipated to outweigh the risks.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 27 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This study is a multicentre, open label Phase I dose escalation study using a 3+3 design, 
followed by one or two expansion cohorts in each treatment arm.
The dose escalation part of the trial is designed to determine the MTDs of BI 860585 as a 
single agent and in combination with exemestane or with paclitaxel in patients with advanced 
and/or metastatic solid tumours.
Furthermore, as a result of data collected during the dose escalation part of the study, one or
more doses [MTD and/or relevant biological dose(s)], shown to have a favourable safety, PK
and PD profile, will be chosen and further investigated in one or two expansion cohorts, in 
each treatment arm.
This expansion part will further evaluate BI 860585 in order to confirm the safety profile of 
the selected dose(s) of BI 860585 as a single agent and in combination with exemestane or 
with paclitaxel, and assess preliminary anti-tumor activity, PK and PD profiles, in patients
with various tumour types.
Ultimately this expansion part of the trial is aimed to determine a Recommended Phase II 
Dose (RP2D) for each treatment arm which is expected to be the most relevant biological
dose (RBD) and not necessarily the MTD.  
The dose escalation part of the study will be characterized by 3 distinct treatment arms 
running in parallel but not starting enrolment simultaneously. The staggered recruitment in 
the three treatment arms will include: initial characterization (safety and PK parameters) of 
BI 860585 single agent followed by enrolment in the combination arms. Enrolment in the 
combination arms will be opened not before any CTCAE Grade ≥ 2 has been observed in the 
single agent arm (Arm A).
The starting dose of BI 860585 for the combination arms will be determined during the dose 
escalations of BI 860585 single agent. Parameters that will be taken into account to fix the 
combination starting dose of BI 860585 in Arm B and Arm C will be: absence of drug related 
CTCAE Grade ≥2 dose toxicity in the relevant dose level cohort as well as exploratory PK 
interim results in addition to discussion and agreement with the principal investigators (see 
Figure 3.1: 1).
The current BI 860585 combination dose level will always be at least one dose level below
the actual BI 860585 single agent dose level. This will imply that combination arm 
recruitment may be put on hold until the current full single agent dose level cohort is 
completed. 
The three treatment arms will follow separate fixed dose-escalation designs with dose de-
escalation steps:

Arm A will be a classical 3+3 dose-escalation design (multiple ascending doses of BI 
860585 administered continuously in a 28-day cycle) in patients with unselected solid 
tumours who progressed before inclusion. 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 28 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Once MTD is determined, an expansion cohort of approximately 18 patients will be 
included at the MTD level.

Arm B will be a classical 3+3 dose-escalation design with BI 860585 being 
administered in multiple ascending doses in combination with fixed dose exemestane 
in patients with progressed metastatic disease and in whom the administration of 
exemestane may be considered as appropriate. This arm will only start recruiting once 
the combination starting dose of BI 860585 has been fixed (see above paragraph for 
parameters to fix the combination starting dose). 
Once MTD is reached one or two expansion cohorts of approximately 15 patients 
each, will be opened for enrollment. 
However enrollment in the expansion cohorts could be anticipated (before reaching 
MTD), after thorough discussion and agreement between the sponsor and the 
investigator, in order to explore an intermediate dose level displaying a favorable
combination of safety, PK and PD profiles during the dose escalation.
It could therefore be envisioned that one expansion cohort will be opened at MTD or 
one level below MTD, and in addition, there might be chances that an intermediate 
dose level displaying a favorable combination of safety, PK and PD profile might also 
be explored after thorough discussion and agreement between the sponsor and the 
investigator.

Arm C will be a classical 3+3 dose-escalation design with BI 860585 being
administered in multiple ascending doses in combination with fixed dose paclitaxel at 
initial 75% of standard dose followed by standard combination dose, in patients with 
progressed metastatic disease in whom the administration of paclitaxel may be 
considered as appropriate. This arm will start recruiting only once the combination 
starting dose of BI 860585 has been fixed (same as Arm B). 
Once MTD is reached one or two expansion cohorts of approximately 15 patients 
each, will be opened for enrollment. 
However enrollment in the expansion cohorts could be anticipated (before reaching 
MTD), after thorough discussion and agreement between the sponsor and the 
investigator, in order to explore an intermediate dose level displaying a favorable 
combination of safety, PK and PD profiles during the dose escalation. 
It could therefore be envisioned that one expansion cohort will be opened at MTD or 
one level below MTD, and  in addition, there might be chances that an intermediate 
dose level displaying a favorable combination of safety, PK and PD profile might also 
be explored after thorough discussion and agreement between the sponsor and the 
investigator.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 29 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Figure 3.1: 1: Study outline 
To determine the MTD in each of the three treatment schedules, patients will be treated at 
escalating dose levels independently in each arms until at least one out of three patients of a 
cohort experiences a DLT during the first treatment cycle (for definition of DLT see Section 
5.2.1). For each treatment arm, the MTD is defined as the dose that is one dose cohort below 
the dose at which two or more out of six patients experienced DLT. i.e., the MTD is defined 
as the highest dose studied for which the incidence of dose-limiting toxicity is no more than 
17% (i.e. 1/6 patients) during the first course.
Single agent cohort :
solid tumors
ARM A
Combinations:
Patients who may benefit of  standard drug
ARM B
ARM C
BI 860585
MTD based on 
safety + 
Weekly 
Paclitaxel 
Expand 
combination at 
MTD and/or 
relevant 
biological dose(s) 
BI 860585 dose 
escalation +
Weekly 
Paclitaxel 
Lowest safe 
tested dose of 
BI 860585 + 
Weekly 
Paclitaxel
Lowest safe 
tested dose of 
BI 860585 + 
fixed dose 
exemestane
BI 860585 
MTD based on 
safety +
Exemestane   
BI 860585 
dose 
escalation + 
fixed dose 
exemestane
Expand 
combination at 
MTD and/or 
relevant 
biological dose(s)
Expand at 
MTD
Single agent 
Low dose 
levels
PK/PD
safety
BI 860585 
Single agent 
dose 
escalation: 
low doses
BI 860585 
Single agent 
dose 
escalation: 
intermediate 
doses
Single agent 
MTD based 
on safety
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 30 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
As mentioned above, approximately 30 additional patients with measurable disease will be 
treated at the MTD and/or relevant biological dose(s), in one or two expansion cohorts, in
each of the treatment  arms. This expansion part will evaluate anti-tumour activity in addition 
to the other current objectives (safety, pharmacokinetic and pharmacodynamic profiles of BI 
860585 as a single agent and in combination with exemestane and with paclitaxel).
The observation period for DLT is the first cycle only (the first 28 days). However, relevant 
safety information of all treatment cycles, including any delays in start of a subsequent cycle 
due to drug related AEs, will be considered for the recommendation of the dose for Phase II 
studies.
The starting dose of BI 860585 single agent will be 5 mg daily based on toxicology findings 
(see also Section 1.2.1). BI 860585 will be taken daily in the morning 
 
in a continuous daily dosing schedule during 28-day cycles. 
Until the occurrence of any drug related AEs (Adverse Event) according to Common 
Terminology Criteria for Adverse Events (CTCAE) Grade ≥2, the dose will be doubled for 
the next dose cohort. Dose escalation steps after the occurrence of drug related AEs ≥ Grade 
2 are described in Section 4.1.3.
For each treatment arm, and for each new dose level, the first patient will be observed for at 
least 7 days of treatment in the first cycle before the next 2 patients can start treatment. 
Moreover before opening treatment in higher dose level cohorts, all patients at an ongoing 
dose level must have completed the first cycle (4 weeks) treatment (BI 860585 with or 
without exemestane or paclitaxel).
The above mentioned criterion does not apply to the expansion cohorts since patients may be 
allowed to enter simultaneously.
Patients eligible for treatment in Cycle 2 will not start before the Day 28 (+1 day) procedures 
are completed at the end of Cycle 1. Starting from Cycle 2 onwards, a window of ± 3 days is 
allowed for the start of the next cycle. Visits procedure of Day 28 of Day 1 of the next cycle 
can be combined into one visit. 
If a patient has a treatment break of more than 14 days (e.g. due to drug related toxicity or
other medical reasons) he/she must be removed from the trial.
During the dose escalation part of the study, patients will be replaced if they withdraw for a 
reason other than DLT before completing the first treatment cycle or miss more than one visit 
during their first treatment cycle (if the information that needs to be collected during this visit 
is not available and makes the patient non-evaluable for determining DLT). Patients will also 
be replaced if more than 7 doses of BI 860585 are missed during their first treatment cycle 
for reasons other than toxicity. Patients who withdraw due to DLT will not be replaced.
Patients will be replaced if more than 7 doses of exemestane or more than one dose of 
paclitaxel are missed during their first treatment cycle.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 31 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Blood PK samplings (Arms A, B and C) and urine PK sampling (Arm A) during 24 hours
after drugs administration in Cycle 1 may require a one night hospital stay for the patient, 
according to hospital procedures. However, all other visits from first cycle and all visits from 
subsequent cycles will be performed in an outpatient setting except if medically or 
operationally justified, at the discretion of the investigator.
 
 
 
 
 
 
 
 
 
 
 
   
 
  
Home glucose monitoring will be done once a day starting on Day 2 on Cycle 1 and continue 
until the end of treatment. Patients will record values in patient diary. 
A clinical disease assessment will be performed after every treatment cycle (28 days) and a 
tumour response assessment by imaging after completion of every other treatment cycle
(approximately every 8 weeks, starting at the end of Cycle 2). Thereafter, starting end of 
Cycle 6, tumour assessment may be every 3 cycles (prior to the start of Cycles 10, 13, 16 etc).
Based on clinical assessment and on tumour response assessment, the investigator will decide 
on whether a patient will continue therapy.
Imaging may be performed within 7 days of the start of the respective treatment cycle. 
For patients with measurable lesions and for all patients included in the expansion cohorts, 
tumour assessment according to RECIST criteria version 1.1 by CT or MRI will be 
performed at the investigator’s site. The same radiographic procedure must be used 
throughout the course of the study.
In addition, if considered appropriate by the investigator and the sponsor, patients in the 
expansion cohorts, may undergo FDG-PET assessment at baseline and during their 
participation in the trial, in order to evaluate their metabolic response to treatment (see Flow
chart) (R14-1468 , R14-1470) .


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 32 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Patients will be eligible for a further treatment cycle until progression of disease or undue 
toxicity or until one of the withdrawal criteria as specified in Section 3.3.4 is present, 
whichever comes first.
Patients experiencing DLT are eligible for further treatment with BI 860585 at one dose level
below as soon as recovery from drug related toxicities allows further treatment (within 14
days) and in agreement with investigator’s judgement upon discussion with sponsor. A 
patient may decrease the dose twice during the trial to the next lower dose level tested 
because of DLT occurrence, but not below the study starting dose. See Section 4.1.4 for intra-
patient dose reductions.
Patients enrolled in the expansion part and who experience a DLT will undergo dose 
reduction in the same way as patients treated in the dose escalation part but the occurrence of 
a DLT will not lead to a change in MTD.
Intra-patient dose escalation is normally not allowed. If exceptionally deemed necessary by 
the investigator, based on his/her clinical judgement, it may be permitted only after 
discussion between the investigator and the sponsor and not to a higher dose than one already 
tested and confirmed not to be above the MTD. In case of intra-patient dose escalations,
every effort should be made to collect additional PK and PD plasma samples as indicated in 
Table 10.1.1:5.
In case of DLTs or drug related Grade 3 or 4 toxicity, every effort should also be made to 
collect a PK blood sample together with ECGs (triplicate).
If a patient has to discontinue the study medication, the end of treatment (EOT) visit should 
be performed within 7 days of last drug administration with all necessary assessments as 
described in Section 6.2.3.
The first follow-up visit is mandatory for all patients and should be performed 28 days (±7
days) after the EOT visit.
Additional follow-up visits will be conducted at 8-week intervals or earlier for patients who 
discontinue the trial for other reasons than tumour progression (e.g. adverse events) until 
disease progression, start of other anti-cancer treatment, withdrawal of consent or lost to 
follow-up.
Follow-up visits may also be performed by telephone interview in case the patient is unable 
to visit the investigator.
All adverse events with onset within 28 days after the last study drug administration are
considered as on treatment. Post treatment adverse events should be reported until last 
follow-up visit. An event leading to death should always be reported as a serious AE (SAE). 
Detailed specifications regarding adverse events can be found in Section 5.2.2.
3.1.1
Administrative structure of the trial
The study will be performed by investigators specialized in the treatment of advanced cancers
and experienced in Phase I trials in oncology.  


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 33 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
It is planned to start the trial in about a total of 4 sites, in Italy and Belgium. More centers and 
other countries may subsequently be initiated in order to compensate for recruitment delays.
Each decision on dose escalation steps will be taken in agreement between the sponsor and 
the principal investigators in each site during regular teleconferences. An internal data Safety 
Monitoring Committee (SMC) will be composed by the study investigators and BI medical 
representative. Functions and responsibilities of the SMC will be described in a Charter.
Approval of the entry of a new patient into any cohort will be confirmed and documented in a 
fax or e-mail between the sponsor and the investigator.
Imaging for tumour response assessment, ECGs and safety laboratory investigations that 
include routine standard parameters will be performed at the investigator’s site.  
Pharmacokinetic analysis will be performed centrally by BI (Biberach an der Riß). 
 
Further details on CROs and logistics will be given in the Investigator Site File (ISF) and/or
the laboratory manual.
The study medication will be shipped directly from the central depot to the investigator’s 
pharmacy, where it will be stored according to the storage requirements as described in the 
ISF and/or pharmacy manual. The pharmacist will deliver the necessary amount for an 
individual patient to the investigator upon his/her request, according to the procedure 
described in the pharmacy manual.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A traditional "3+3" dose escalation design with toxicity guided approach is chosen for this 
study. There are limitations for this traditional design including recruitment of too many 
patients to sub-therapeutic doses of the new drug and longer timelines would be needed to 
complete a Phase I trial.
To overcome these limitations, an attempt is made to minimize the number of sub-therapeutic 
dose levels (the dose of BI 860585 will be escalated by 100% until occurrence of drug-related 
CTCAE Grade 2 AE).
Also, given the mode of action and the available clinical data for compounds targeting the 
same pathway it is expected that a combinatory strategy either with endocrine, chemotherapy 
and/or other targeted therapies may result in the most efficacious therapeutic option of BI 
860585 in the clinic.
Finally in order to provide an opportunity to better define the appropriate dose range and
administration schedule of the RP2D, expansion cohorts will further evaluate the safety 
profile of BI 860585 at the recommended dose(s) and schedule(s) as well as assess early 
signs of anti-tumour activity in patients with multiple tumour types in whom treatment with 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 34 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
BI 860585, in monotherapy or in combination with exemestane or in combination with 
paclitaxel, may give clinical benefit.  
3.3
SELECTION OF TRIAL POPULATION
An estimated 168 patients will be entered into the trial.
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.
3.3.1
Main diagnosis for study entry
Patients with confirmed diagnosis of advanced, non-resectable and/or metastatic solid 
tumours, who have failed conventional treatment or for whom no therapy of proven efficacy 
exists, or who are not amenable to established treatment options will be eligible for the study 
if the investigator considers them suitable candidates for treatment with an investigational 
serine/threonine kinase inhibitor.
Patients will be selected based on the presence of active growing tumours, or progressive
disease, based on serial imaging before inclusion into the trial, and/or clinical evaluation. For
the combination arms, patients will furthermore be selected based on whether treatment with 
either exemestane or paclitaxel would be considered appropriate, according to the 
investigator’s opinion. In addition, patients in the expansion cohorts must have measurable 
documented/proven progressive disease, according to RECIST criteria. 
Patients included in the escalation part are not eligible to enter the expansion part of the trial.
3.3.2
Inclusion criteria
1. Patients with histologically or cytologically confirmed diagnosis of advanced, 
measurable or evaluable, non-resectable and/or metastatic solid tumours, which has 
shown to be progressive;
2. Patients who have received previous standard of care therapy for their disease and 
have progressed;
3. Age ≥ 18 years;
4. Life expectancy ≥ 3 months;
5. Written informed consent in accordance with International Conference on
Harmonisation/Good Clinical Practice (ICH/GCP) and local legislation;
6. Eastern Cooperative Oncology Group (ECOG), (R01-0787) performance score 0-2.
Additional inclusion criteria for the combination arms:
7. Patients must have confirmed progressive disease within the last 6 months, (in case of 
measurable disease, progression should be confirmed according to Response 
Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1 (R09-0262)


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 35 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
8. Patients carrying a tumour for whom treatment with either exemestane or paclitaxel
would be considered appropriate by the investigator.
Additional inclusion criteria for expansion part:
9. Patients must have measurable progressive disease within the last 6 months 
documented/proven according to RECIST criteria version 1.1.
10. Patients entering the expansion cohorts must also have:
-
Arm A: any advanced/metastatic solid tumour suitable for biopsy and must have 
provided informed consent for biopsy and biomarker analysis.
-
Arm B: any cytologically or histologically confirmed ER+ (estrogen receptor 
positive) advanced/metastatic solid tumours for which treatment with exemestane 
would be considered appropriate by the investigator.
-
Arm C: any advanced/metastatic solid tumour for which treatment with paclitaxel 
would be considered appropriate by the investigator.
3.3.3
Exclusion criteria
1. Serious concomitant non-oncological disease/illness considered by the investigator to 
be incompatible with the protocol;
2. Patients with untreated or symptomatic brain metastases. Patients with treated, 
asymptomatic brain metastases are eligible if they are stable (defined as no change on 
CT scan or MRI for minimum of two months AND no change in steroid dose for a 
minimum of four weeks, unless change due to intercurrent infection or other acute 
event) or have normal brain MRI scan at screening and be at least 4 weeks post-
radiation or surgery for brain metastasis;
3. Second malignancies requiring active therapy except for adequately resected cervix 
carcinoma in situ, and resected non-melanomatous skin cancers (including basal cell 
carcinoma and squamous cell cancer);
4. Clinical Congestive Heart Failure (CHF) Grade III-IV;
5. Myocardial infarction within the last 6 months prior to inclusion, or symptomatic
coronary artery disease;
6. Absolute neutrophil count <1500/mm3;
7. Platelet count <100,000/mm3;
8. Total bilirubin >1.5 x upper limit of normal value ( including known Gilbert’s 
syndrome);
9. Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) greater
than 3 x upper limit of normal value (if related to liver metastases greater than 5 x
upper limit of normal value);
10. Serum creatinine > 1.5 x upper limit of normal value;
11. Pregnancy or breastfeeding;
12. Women or men who are sexually active and unwilling to use a medically acceptable 
method of contraception. Effective methods of birth control are defined as those 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 36 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
which result in a low failure rate (i.e. less than 1% per year) when used consistently 
and correctly such as implants, injectables, combined oral contraceptives, some 
intrauterine devices, sexual abstinence or vasectomy since more than 2 months for 
male patients or for the partner. Barrier methods of contraception are accepted if 
condom or occlusive cap is used together with spermicides (e.g. foam, gel). Female 
patients will be considered to be of childbearing potential unless surgically sterilised 
by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at 
least one year;
13. Patients unable to comply with the protocol;
14. Known or suspected active drug or alcohol abuse;
15. Patients with known HIV/hepatitis/active infectious disease considered by the 
investigator to be incompatible with the protocol;
16. Patients unable to take oral medication (BI 860585 may not be crushed or 
administered via a gastrostomy tube);
17. Chronic diarrhoea or other gastrointestinal disorders that may interfere with the
absorption of the study medication;
18. Treatment with anti-cancer-therapies: cytotoxic or standard chemotherapy,  
immunotherapy, radiotherapy, biological therapies, molecular targeted or other
investigational drugs, within four weeks of the first treatment with the study
medication (or within one week for non-cytotoxic drugs);
19. Patients must have recovered from any previous surgery and have had no major 
surgery within the last 28 days prior to start of trial medication in the opinion of the 
investigator;
20. Continuation of CTCAE Grade ≥ 2 therapy-related toxicities from prior anti-cancer 
therapies, prior surgery, at the time of the first administration of the study medication 
(except alopecia);
21. Hypersensitivity to combination drugs or excipients;
22. Patients with a history of uncontrolled diabetes mellitus.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient has to be taken off study treatment if:

The patient withdraws consent. Patients are free to discontinue their participation in
this study at any time without the need to justify their decision. (In this event, the 
patient will be asked to have their end of treatment assessments and the data collected 
until the point in time when withdrawal occurred will be included in the final analysis 
of the trial data. No further follow-up will be performed in case the patient does not
agree to follow-up).

There is a longer than 14-day treatment break due to any drug related AE or other 
medical reasons. If an interruption of more than 2 weeks is necessary and clinically 
justified, the patient may continue study treatment after discussion and agreement 
between the investigator and the sponsor.

The patient is no longer able to participate in the study (e.g. due to severe adverse
events, surgery, disease progression, concomitant diagnoses, concomitant therapies or


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 37 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
administrative reasons, occurrence of a second cancer). The investigator may also stop 
the patient’s participation if the patient is no longer able to attend the visits i.e. due to 
worsening of the disease.

If eligibility criteria are violated in such a way that it might put the patient at risk if
they continue the trial treatment, or the patient fails to comply with the protocol (e.g.
non-compliance to study visits or to study treatment).

The patient develops a third episode of DLT after two dose reductions; only 2 dose 
reductions are allowed for the same patient, but not below the study starting dose (see 
Section 4.1.4 for management of toxicity).
As soon as a patient permanently stops trial treatment, the EOT visit has to be performed as 
soon as possible and within 7 days.
Every effort should be made to follow-up the patient in case an AE is still ongoing at the time
of withdrawal. After withdrawal, the patient can receive the standard available treatment for 
his/her condition.
3.3.4.2
Discontinuation of the trial by the Sponsor
Boehringer Ingelheim (BI) 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.
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial.
3.3.4.3
Replacement of patients
Patients will be replaced for analysis of the primary endpoint (MTD) in cases of:

Patient's withdrawal during the first course of treatment for reasons other than DLT,
e.g. patient no longer wishes to participate, or lost to follow up during first course.

Patients who do not experience DLT but miss more than one visit during the first
course of treatment.

Patients who do not experience DLT but miss > seven doses of BI 860585 or 
exemestane or > one dose of paclitaxel administration in the first treatment course.

Patients who are non-evaluable with respect to DLT.
Patients that have been replaced might continue treatment in the trial, however, these patients 
will not be considered for analysis of the primary trial endpoint.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 38 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and combination product(s)
Substance (INN): 
BI 860585
Pharmaceutical form: 
Film-coated tablets
Source: 
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength: 
5 mg, 30 mg, 100 mg and 150 mg film coated tablets 
Daily dose: 
Depending on dosing schedule (refer to Section 4.1.3)
Duration of dose: 
Continuous daily dosing; one cycle consists of 28 days.
Patients are eligible for repeated treatment cycles in the absence
of disease progression and undue adverse events 
Route of administration: 
Oral
Posology: 
Once daily, in the morning
 
to swallow without 
crushing, with 240 mL water
Substance (INN): 
Exemestane
Pharmaceutical form: 
Tablets
Source: 
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength: 
25 mg tablets 
Daily dose: 
25 mg
Duration of dose: 
Continuous daily dosing; one cycle consists of 28 days.
Patients are eligible for repeated treatment cycles in the absence
of disease progression and undue adverse events 
Route of administration: 
Oral
Posology: 
Once daily, in the morning after a meal, to swallow without 
crushing, with 240 mL water
Substance (INN): 
Paclitaxel
Pharmaceutical form: 
Concentrate for intravenous infusion
Source: 
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength: 
30 mg/5 mL, 100 mg/16.7 mL multidose vials
4-weekly dose: 
80 mg/m2 in one hour infusion (starting with 25% dose 
reduction - refer to Section 4.1.3)
Duration of dose: 
Continuous weekly dosing; one cycle consists of 28 days.
Patients are eligible for repeated treatment cycles in the absence
of disease progression and undue adverse events
Route of administration: 
Intravenous infusion according to package insert or summary of 
product characteristics (SPC)
Posology: 
Once every week


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 39 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.1.2
Method of assigning patients to treatment groups
Patients meeting the inclusion criteria and none of the exclusion criteria and who have given 
informed consent will receive BI 860585 treatment according to the available dose-level 
(cohort) at Visit 1 of the first cycle, as determined by the sponsor in agreement with the 
investigator.  Treatment with exemestane or paclitaxel will begin on Day -7 of Cycle 1.
Each eligible patient will be assigned the lowest available medication number of the given 
dose cohort. Site personnel will have to enter the medication number in the electronic Case 
Report Form (eCRF).
The investigator will notify the sponsor by fax (or e-mail) if a patient qualifies for
participation in this study. The sponsor will inform the investigator by fax (or e-mail) about 
the respective dose tier allocated to a patient. 
During the dose escalation in each treatment arm, and for each new dose level, the first 
patient entering the new dose level must have completed at least 7 days of treatment in the 
first cycle before the next 2 patients can start treatment in the same dose level cohort. At least 
3 patients will be treated at each dose level (cohort).
Moreover before opening treatment in higher dose level cohorts all patients at an ongoing 
dose level must have completed the first cycle (4 weeks) treatment (BI 860585 with or 
without exemestane or paclitaxel).
The above mentioned criterion does not apply to the expansion cohorts since patients may be 
allowed to enter simultaneously.
Enrolment in the 3 treatment arms will not begin simultaneously. After the combination dose 
for BI 860585 has been established (see Section 3.1 for criteria), patients will be assigned to 
individual arms (Arm B and Arm C) based on the clinical judgment of the investigator. 
Please refer to Table 4.1.3:1 for dose escalation rules.
4.1.3
Selection of doses in the trial
For Arm A, BI 860585 monotherapy, and as a result of the pre-clinical data, a starting dose of 
5 mg per day was determined to be the safe starting dose in humans.
The starting dose of BI 860585 for the escalating combination arms will be determined 
during the dose escalations of BI 860585 single agent. Enrolment in the combination arms 
will be opened not before any CTCAE Grade ≥ 2 has been observed in the single agent arm 
(Arm A). Parameters that will be taken into account to fix the combination starting dose of BI 
860585 will be: absence of drug related CTCAE Grade ≥ 2 dose toxicity in the relevant dose 
level cohort as well as exploratory PK interim results in addition to discussion and agreement 
with the principal investigators. In accordance with the current SPC, exemestane will be 
administered at a standard fixed dose of 25 mg daily and paclitaxel at the standard 
combination fixed dose of 80 mg/m2 in approximately 1 hour infusion, given weekly (with a 
25% dose reduction in the first dose level, i.e. 60 mg/m2).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 40 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Researchers have investigated the use of weekly and every three weeks taxanes regimens in 
advanced breast cancer in an effort to improve therapeutic efficacy and toxicity profile of 
taxanes. A meta-analysis of randomized controlled trials that compared weekly
and every three weeks taxanes regimens in advanced breast cancer has shown that no 
difference was found for PFS (6 studies, 1610 patients, random effect model HR 1.02, 95%CI 
0.81–1.30 p = 0.860); while OS was statistically higher among patients receiving weekly 
paclitaxel (5 studies, 1471 patients, fixed effect model pooled HR 0.78, 95%CI 0.67–0.89 p = 
0.001). Overall, the incidence of serious adverse events, neutropenia, neutropenic fever and 
peripheral neuropathy were significantly lower in weekly taxanes schedules.
In conclusion the use of weekly paclitaxel regimens is therefore recommended for the 
treatment of locally advanced/metastatic cancer where paclitaxel is indicated and is advisable 
as a combination scheme for new agents testing (R13-1537, R13-1643).
All patients receiving paclitaxel should be premedicated as indicated in Section 4.1.4.3.
During dose escalation of BI 860585 the general assumption is that for the first dose levels 
100% dose increase will be implemented until occurrence of any drug-related toxicity of 
CTCAE Grade 2 or higher. In general, as soon as any patient of an ongoing dose cohort 
experiences drug-related toxicity of CTCAE Grade 2, escalation steps of no more than 50% 
will be allowed thereafter. Should a DLT (see Section 5.2 for definition) be observed in 1/6 
patients treated in a cohort and escalation continues, this will be in steps of no more than 
35%. Please refer to the table below for rules of dose escalation.  


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 41 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 4.1.3: 1
General Rules for BI 860585 dose escalation
• If no drug-related AE of CTCAE grade 2 or higher has occurred until this time: 
Number of patients with 
drug-related CTCAE Grade 
2 or higher at a given dose 
level 
0 out of 3 
Start with the next dose cohort (escalate by 
maximum 100%) 
• If a drug-related AE of CTCAE grade 2 has occurred (but no DLT): 
Number of patients with 
drug-related CTCAE Grade 
2 at a given dose level 
≥ 1 out of 3 Start with the next dose cohort (escalate by
maximum 50%) 
• If DLT has occurred: 
Number of patients with 
DLT at a given dose level 
1 out of 3 
Enter 3 more patients at this dose level: 

If 0 of these additional patients 
experienced a DLT, proceed to the next 
higher dose level (escalate no more 
than 35%). 

If 1 or more of these additional patients 
experienced a DLT, the dose escalation 
will be stopped. Up to 3 additional 
patients will be entered at the lower 
dose level if only 3 patients were 
treated previously at that dose level. 
≥2 out of 3 Dose escalation will be stopped. Up to 3 
additional patients will be entered at the lower 
dose level if only 3 patients were treated 
previously at that dose level.
Number of patients with 
DLT at the highest dose 
level below the maximum 
administered dose 
< 2 out of 6 This is defined as the MTD. (At least 6 
patients evaluable for the safety endpoint must 
be entered at this dose level and a toxicity rate 
of less than 0.33 must be observed in order to
be confirmed as the MTD). 
From Cohort 8 and above, further BI 860585 dose increments will be between 35% and 
50% with respect to preceding dose level if the previous increments have been of 100% 
per each dose level otherwise will follow the current dose increments until MTD dose 
level is reached (see below for examples on dose increment schemes).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 42 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
In any case, dose increments will need to be confirmed after discussion between the sponsor
and the investigators, considering safety data as well as PK data from previous patient 
cohorts, when available, and clinical judgement. 
The proposed doses and schedules may be considered and adjusted during the study based on 
the emerging safety and interim PK data, and after discussion with the investigators. For 
details on the different exploratory interim PK analysis refer to Section 7.3.4. 
During dose escalation, the current BI 860585 combination dose level will always be at least 
one dose level below the actual BI 860585 single agent dose level. This will imply that 
combination arm recruitment may be put on hold until the full single agent dose level cohort 
is completed. 
Intermediate dose levels based on safety, PK parameters and clinical judgement could be 
further explored after discussion between the investigators and sponsor.
Intra-patient dose escalation is normally not allowed. If exceptionally deemed necessary by 
the investigator, based on his/her clinical judgement, it may be permitted only after 
discussion between the investigator and the sponsor.
During the expansion part of the trial, new and eligible patients with at least one measurable 
lesion by RECIST criteria 1.1 will receive the MTD and/or RBDs (relevant biological 
dose(s)) of BI 860585 as determined with data from the dose escalation part of the study and 
after discussion and agreement between the sponsor and the investigators. 
In cases whereby any patient experiences a dose limiting toxicity or any drug related AE, an 
intra-patient dose reduction may be needed according to investigator’s judgement (see 
Section 4.1.4.1.1 for dose modification guidance). In case of DLT or drug related Grade ≥3 
AE additional PK sampling will be performed for analysis together with triplicate ECG.
Table 4.1.3: 2
Example of possible dose incrementation scheme:
Arm A - BI 860585 monotherapy
BI 860585 should be taken after breakfast
 
BI 860585 administration should occur 
approximately 30 minutes after start of the meal.
BI 860585: 
Day 1
Schedule: BI 860585
Cohort 1
5 mg
BI 860585 5 mg Days 1 - 28
Cohorts 2-7
100% dose increments
per each dose level if 
no drug related Grade
2 AEs
(X +100%) mg
Or
BI 860585 (X + 100%) mg Days 1 - 28
Or


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 43 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 4.1.3:2
Example of possible dose incrementation scheme: 
Arm A - BI 860585 monotherapy (continued)
In case of drug related 
Grade 2 AEs dose 
increments will be 
reduced by 50%
(X+ 50%)mg
Or
BI 860585 (X +50%) mg Days 1 - 28
Or
In case of DLT or any 
drug related Grade 3 
AEs dose increments 
will be reduced to 35%
(X + 35%) mg
BI 860585 (X + 35%) mg Days 1 - 28
Cohort > 8
Further BI 860585 dose increments will be between 35% and 50% with 
respect to preceding dose level if the previous increments have been of 
100% per each dose level otherwise will follow the current dose 
increments until MTD dose level is reached.
Table 4.1.3: 3
Example of possible dose incrementation scheme: 
Arm B - BI 860585 plus exemestane
Exemestane will be administered in accordance to the current SPC at a standard fixed dose 
of 25 mg daily. A summary of the SPC is archived in the ISF.
Exemestane: 
Day-7 for the 
first cycle 
only; 
following 
cycles Day 1
BI 860585: Day 
1
Schedule : BI 860585 plus exemestane
(Exe)
Cohort 1
25 mg 
Y mg
Exe 25 mg + BI 860585 Y mg 
Days 1 - 28
Cohorts 2-7
100% dose 
increment per 
each dose level if 
no drug related 
Grade 2 AEs
In case of drug 
related Grade 2 
AEs dose
increments will 
be reduced by 
50%
25 mg 
25 mg
(Y + 100%) mg
Or
(Y + 50%) mg
Or
Exe 25 mg + BI 860585 (Y + 100%) mg 
Days 1 - 28
Or
Exe 25 mg + BI 860585 (Y + 50%) mg    
Days 1 - 28
Or


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 44 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 4.1.3:3
  Example of possible dose incrementation scheme: 
           Arm B - BI 860585 plus exemestane (continued)
In case of DLT or 
any drug related 
Grade 3 AEs
dose increments 
will be reduced to 
35%
25 mg
(Y + 35%) mg
Exe 25 mg + BI 860585 (Y + 35%) mg    
Days 1 - 28
Cohort > 8
25 mg 
Further BI 860585 dose increments will be between 35% and 
50% with respect to preceding dose level if the previous 
increments have been of 100% per each dose level otherwise 
will follow the current dose increments until MTD dose level 
is reached.
Table 4.1.3: 4
Example of possible dose incrementation scheme: 
Arm C - BI 860585 plus paclitaxel
Paclitaxel will be administered in accordance to the current SPC at a standard fixed dose of 
80 mg/m2 (60 mg/m2 for first dose cohort). A summary of the SPC is archived in the ISF.
Paclitaxel: 
Day -7 for 
the first 
cycle only; 
following 
cycles Day 1
BI 860585: 
Day 1
Schedule
BI 860585 plus paclitaxel
Cohort 1
60 mg/m2
Z mg
Paclitaxel 60 mg/m2 Days 1, 8, 15, 22 and 28
+ BI 860585 Z mg Days 1 - 28
Cohort 2
80 mg/m2
Z mg
Paclitaxel 80 mg/m2 Days 1, 8, 15, 22 and 28
+ BI 860585 Z mg Days 1 - 28
Cohorts 3-7
100% dose 
increment per 
each dose level 
if no drug 
related Grade 2 
AEs
In case of drug 
related Grade 2 
AEs dose
increments will 
be reduced by 
50%
80 mg/m2
Or
80 mg/m2
Or
(Z + 100%)mg
Or
(Z +50%) mg
Or
Paclitaxel 80 mg/m2 Days 1, 8, 15, 22 and 28
+ BI 860585 (Z +100%) mg Days 1 - 28
Or
Paclitaxel 80 mg/m2 Days 1, 8, 15, 22 and 28
+ BI 860585 (Z +50%) mg Days 1 - 28
Or


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 45 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 4.1.3:4
Example of possible dose incrementation scheme:    
           
Arm C - BI 860585 plus paclitaxel  (continued)
In case of DLT 
or any drug 
related Grade 3 
AEs dose
increments will 
be reduced to 
35%
80 mg/m2
(Z + 35%) mg
Paclitaxel 80 mg/m2 Days 1, 8, 15, 22 and 28 
+ BI 860585 (Z +35%) mg Days 1 - 28
Cohort > 8
80 mg/m2
Further BI 860585 dose increments will be between 35% and 
50% with respect to preceding dose level if the previous
increments have been of 100% per each dose level otherwise 
will follow the current dose increments until MTD dose level 
is reached.
4.1.4
Drug assignment and administration of doses for each patient
4.1.4.1
BI 860585 in Arms A, B and C
Patients will start treatment at Visit 1 of the first Cycle within their assigned dose-cohort. At 
the beginning of each cycle patients will be dispensed two bottles containing 16 tablets each. 
BI 860585 should be taken orally, once a day in the morning, at the same time each day after 
meals, 
 to ensure a dose interval of approximately 24 
hours. The tablet should be swallowed with a glass of 240 mL water and should not be 
chewed or crushed.
Patients may continue to take study medication if BI 860585 is well tolerated and they 
experience at least disease stabilisation or an improvement of disease-related symptoms.  
In case a dose of BI 860585 is missed, patients should take the next scheduled dose at the 
usual time. Patients with emesis should not take a replacement dose.
If a patient suffers from a drug related AE requiring a delay of treatment, a drug-free interval 
of maximum 2 weeks is allowed. If a longer drug-free interval is required, the patient must be 
withdrawn from the study.
The exact time of trial medication intake and food intake should be recorded in the patient’s
diary and eCRF as this information is crucial for proper evaluation of PK and other data.
After having received the first dose of BI 860585 on Day 1 of Cycle 1, patients will undergo 
a 24-hour PK blood sampling on Days 1 to 2, as well as Days 22 to 23. A 24-hour urine 
collection will also be implemented in order to determine eGFR.
In addition, and only for Arm A 
 a 24-hour PK urine 
collection will be implemented (see Appendix 10.1.1 and Flow Chart).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 46 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
4.1.4.1.1 Treatment Discontinuation and Dose reduction scheme for BI 860585
In case of BI 860585 treatment-related adverse events, study medication may have to be 
discontinued temporarily. In case of DLT study medication must be interrupted.
Patients with DLT or treatment-related toxicities may continue therapy only after recovery 
from the event to baseline or CTCAE Grade 1.  In case of DLT, therapy should continue only 
with a reduced dose of BI 860585.
The reduced dose will be valid for all following treatment cycles in the individual patient.
A reduction of the dose will be allowed twice for an individual patient during the whole trial. 
Likewise, the treatment has to be discontinued in case the event does not recover sufficiently 
(i.e. to Grade 1 or less/or to baseline within 14 days).
To continue treatment with further cycles, the following criteria must be met:

Absence of disease progression (see also Section 5.1.1)

In case of treatment interruption due to drug-related AEs, toxicities must recover 
to CTCAE Grade ≤ 1 or to baseline conditions within 14 days.

For AEs that do not require a treatment interruption, a toxicity CTCAE Grade 2 
may be acceptable, provided that the investigator considers it safe for the patient 
to continue treatment.
The schemata below summarize recommendations for dose interruptions, reductions or 
discontinuation of BI 860585 in the management of treatment related toxicities 
(haematological, diarrhoea, nausea, vomiting, other non-haematological and liver):
Table 4.1.4.1.1:1
Recommendations for dose modifications of BI 860585 treatment 
related toxicities
Haematological toxicity 
BI 860585 dose
interruption/discontinuation
scheme
CTCAE Grade 4 neutropenia lasting ≥ 
7 days
CTCAE Grade ≥ 3 documented 
infection with neutropenia
CTCAE Grade ≥3 febrile neutropenia
CTCAE Grade 3 thrombocytopenia 
associated with bleeding requiring 
transfusion
CTCAE Grade 4 thrombocytopenia
CTCAE Grade 4 anaemia
1st
occurrence
Interrupt BI 860585 until 
recovery to Grade ≤ 1, start with 
BI 860585 at the dose level 
immediately below the current 
dose 
2nd
occurrence
Interrupt BI 860585 until 
recovery to Grade ≤1, start with 
BI 860585 at the next lower dose 
level 
3rd
occurrence
Discontinue BI 860585


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 47 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 4.1.4.1.1:1 
Recommendations for dose modifications of BI 860585 treatment 
related toxicities  (continued)
Non-Haematological toxicity
(Diarrhoea/Nausea/Vomiting)
BI 860585 dose 
interruption/reduction scheme
Diarrhea
CTCAE Grade 2 diarrhea persisting 
for 2 or more consecutive days (48 
hours) despite adequate anti-
diarrhoeal medication/hydration.
CTCAE Grade 2 nausea and/or
vomiting persisting for 7 consecutive 
days despite antiemetic treatment/ 
hydration.
1st
occurrence
Maintain BI 860585 dose 
2nd occurrence
or
no recovery 
from first 
occurrence to 
Grade ≤ 1 
within 7 days
Interrupt BI 860585 until 
recovery to Grade ≤ 1, if 
treatment interruption < 7 days, 
continue BI 860585 at same 
dose
If treatment interruption ≥ 7 
days, continue BI 860585 at 
the dose level immediately 
below the current dose
3rd
occurrence
Interrupt BI 860585 until 
recovery to Grade ≤ 1, 
continue BI 860585 at the next 
lower dose level.
4th
Occurrence
Discontinue BI 860585.
Non-Haematological toxicity
BI 860585 dose 
interruption/reduction scheme
CTCAE Grade ≥3 non-
haematological toxicity despite the 
use of adequate/maximal medical 
interventions and or prophylaxis as 
dictated by local institutional clinical 
practices or the judgment of the 
investigator (example stomatitis, 
rash, mucositis, pneumonitits,  
hypercholesterolaemia).
Any Grade 3 hyperglycaemia that 
does not recover to Grade ≤ 1 within 
2 weeks of adequate therapy.
1st
occurrence
Interrupt BI 860585 until 
recovery to Grade ≤ 1, start 
with BI 860585 at the dose 
level immediately below the 
current dose
2nd
occurrence
Interrupt BI 860585 until 
recovery to Grade ≤1, start 
with BI 860585 at the next 
lower dose level 
3rd
occurrence
Discontinue BI 860585 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 48 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 4.1.4.1.1:1  
Recommendations for dose modifications of  BI 860585 treatment 
related toxicities  (continued)
Liver toxicity
BI 860585 dose 
interruption/reduction scheme
Drug-induced liver injury (DILI) as 
described in Section 5.2.2.1
1st
occurrence
Interrupt BI 860585 until AST 
and ALT ≤ 5x ULN (baseline)
and total bilirubin ≤ 1.5x ULN, 
start with BI 860585 at the 
dose level immediately below 
the current dose
2nd
occurrence
Interrupt BI 860585 until AST 
and ALT ≤ 5x ULN (baseline) 
and total bilirubin ≤ 1.5x ULN, 
start with BI 860585 at the next 
lower dose level
3rd
occurrence
Discontinue BI 860585.
Any patient enrolled in the expansion part who experiences a DLT will undergo dose 
reduction in the same way as patients treated in the dose escalation part but the occurrence of 
a DLT will not lead to a change in MTD. However, any DLTs occurring in the expansion 
cohort will be considered in the evaluation of the RP2D.
If there is a combined elevation of transaminases and total bilirubin please follow the
instructions in Section 10.2.
In case of hyperglycaemia Grade ≥2, co-medication with metformin will be implemented 
according to metformin SPC.
In case of cutaneous rash Grade ≥3, a diagnostic skin biopsy will be performed in order to 
rule out any potential vasculitis related rash. In case of vasculitis related rash, BI 860585 
should be discontinued.
In the event of any unrelated (S)AE, the investigator may choose to pause BI 860585 for up 
to 14 days to allow the patient to recover, but no dose reduction should occur.
Every delay of a treatment cycle, or dose reduction, should be immediately communicated to 
the sponsor. 
4.1.4.2
Exemestane in Arm B
Exemestane will be administered starting on Day – 7 of the first Cycle in accordance to the 
current SPC at a standard fixed dose of 25 mg daily. Treatment in subsequent cycles will 
begin on Day 1. Exemestane will be administered in the morning after a meal, approximately 
at the same time as BI 860585.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 49 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
In accordance with the SPC, general supportive care, including frequent monitoring of vital 
signs and close observation of the patient, is indicated.
No dose reduction/adjustment is foreseen for exemestane. Therefore in case of 
discontinuation of exemestane due to any drug-related AE, patients who have not 
experienced DLTs may remain in the study until disease progression and might continue with 
BI 860585 monotherapy.
4.1.4.3
Paclitaxel in Arm C
Paclitaxel will be administered starting on Day – 7 of the first Cycle at the investigator’s site 
and will be prepared and administered in accordance with current SPC. Treatment in 
subsequent cycles will begin on Day 1. 
Paclitaxel will be administered weekly at a dose of 80 mg/m2 in approximately one hour 
infusion (starting at a dose of 60 mg/m2 for the first dose level cohort) and approximately at 
the same time as BI 860585.
Date and time of start and end of infusion, the exact amount of paclitaxel given at each 
infusion and initials of the person administering the drug will be documented in the eCRF or 
study medication form.  
All patients should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Such premedication may consist of corticosteroids, 
diphenhydramine (or equivalent histamine H1 antagonists), and cimetidine (or equivalent 
histamine H2 antagonists).
Patients must be given supportive care during therapy in accordance with the current SPC and 
institutional guidelines. 
In case of paclitaxel drug–related adverse events, dose delays and adjustments may be 
implemented in accordance with the current SPC.
For patients who experience any drug related AE, a paclitaxel dose reduction is foreseen 
according to current SPC dose modification guidance. 
In addition, in case of discontinuation of paclitaxel due to any drug-related AE, patients who 
have not experienced DLTs may remain in the study until disease progression and might 
continue with BI 860585 monotherapy.
4.1.5
Blinding and procedures for unblinding
This trial will be performed according to an open design and will be handled in an open 
fashion throughout the study i.e. also for the purpose of data cleaning and preparation of the 
analysis. This seems to be justified because the potential negative impact on bias seems to be 
low and does not outweigh practical considerations. 
4.1.6
Packaging, labelling, and re-supply
BI 860585 tablets will be supplied in poly-propylene, child-resistant, tamper-evident bottles.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 50 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Each bottle will contain 16 tablets. The necessary bottles of medication for each treatment 
cycle will be dispensed on Day 1 of each cycle regardless of the number of tablets remaining 
in the bottles from the previous cycle, which will be collected. In the event of a necessary 
dose reduction, the patient will return to the clinic and new medication will be dispensed, at 
the new dose level.
Paclitaxel will be supplied as multiple use vials containing 30 mg/5 mL or 100 mg/16.7 mL 
concentrate solution for infusion. One box will contain a single vial. 
Exemestane will be supplied as 25 mg tablets. Tablets will be supplied in carton boxes each 
containing blisters, with a total of  45 tablets.
All study medication will be labeled according to local regulations. For details on packaging 
and the description of the label, refer to the ISF.
4.1.7
Storage conditions
BI 860585 and combination drugs (exemestane or paclitaxel), will be provided by the sponsor 
and must be stored in a secure, limited access storage area under the storage conditions stated 
on the drug label. A temperature log must be maintained to make certain that the drug 
supplies are stored at the correct temperature. If the storage conditions are found to be outside 
the specified range, an immediate contact must be established with the local clinical monitor 
as provided in the list of contacts, in the ISF.
4.1.8
Drug accountability
The investigator and/or pharmacist 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 
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 CTP.
The investigator and/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 product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator and/or pharmacist will maintain records to adequately document that the patients 
were provided with doses specified by the CTP and reconcile all investigational product(s) 
received from the sponsor. At the time of return to the sponsor, the investigator and/or 
pharmacist must verify that all unused/used or partially used drug supplies have been 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 51 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
returned by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication to reverse the effects of BI 860585, exemestane and paclitaxel are not 
available. Potential side effects of these treatments should be treated symptomatically. For 
exemestane and paclitaxel please refer to the current SPC.
Patients should receive full supportive care including transfusions of blood and blood 
products, antibiotics, analgesia etc., according to local practice/guidelines where appropriate. 
Anti-emetic medication should be prescribed according to local practice.
Symptomatic treatments of tumour-associated symptoms are allowed. All concomitant (non-
oncological) therapies to provide adequate care, may be given as clinically necessary and
should be recorded in the eCRF.
For symptom control palliative radiotherapy may be permitted after consultation with the
sponsor and will be considered on a case by case basis. The impact of any palliative 
radiotherapy administered on evaluable lesions must be documented.
Generic name, indication and dates of administration will be documented. If patients receive 
parenteral nutrition during the trial, the components need not to be specified in detail. It 
should be indicated as ‘parenteral nutrition’ and the eCRF be completed.
If a patient needs anaesthesia, it will be sufficient to indicate ‘anaesthesia’ without specifying 
the details.
Episodes of hypercholesterolaemia or hypertriglyceridemia should be managed with 
appropriate medical therapy and be monitored. Stomatitis and/or mucositis should be 
managed with topical analgesic mouth treatments (e.g. benzocaine, butylaminobenzoate, 
tetracaine hydrochloride,) with or without topical corticosteroids (i.e. triamcinolone oral 
paste). Hyperglycaemia (fasting glucose value > 160 mg/dL (> 8.9 mmol/L), should be 
managed with appropriate medical therapy (metformin) and monitored.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, or 
radiotherapy within 4 weeks (within 1 week for hormone treatment) prior randomisation until 
the end of treatment visit are not allowed during the study treatment.
Any concomitant medication should be reduced to the clinically necessary minimum on the
days of BI 860585 administrations.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 52 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
BI 860585 is an in vitro inhibitor of various CYP P450 enzymes with Ki values in the range
of 2 to 10 µM (see Section 1.2.1). A drug-drug interaction can be considered likely therefore 
caution should be exercised when combining BI 860585 with substrate drugs of CYP P450 
enzymes.
Nisoldipine (a calcium channel blocker) and HMG CoA-reductase inhibitors (such as 
lovastatin, simvastatin, and atorvastatin), metabolized by CYP 3A4, are predicted as high risk 
for increased exposure. Their concomitant use during treatment with BI 860585 should be 
avoided and replaced by an alternative drug. If their concomitant use cannot be avoided and 
no alternative is available then the prescribed dose should be reduced by half with close 
monitoring for potential adverse reactions. 
During treatment with exemestane or paclitaxel, patients should not receive any of the 
prohibited medications as listed in the current SPC.
4.2.2.2
Restrictions on diet and life style
No dietary restrictions apply for BI 860585.
Cancer patients participating in BI 860585 clinical trials should avoid direct exposure of the 
unprotected skin and eye to sunlight or equivalents for a period of one week after the last 
administration of BI 860585.
For exemestane or paclitaxel please refer to their respective SPC.
4.3
TREATMENT COMPLIANCE
Patients will take the first dose of BI 860585 at the trial site. Subsequent doses will be taken
according to what is described in Section 4.1.4. Patients will record the date and time of each
medication intake in a paper diary to help with the compliance check. 
Each time the patient comes to the study site for a visit, he/she will bring his/her medication
bottles, and patient diary, and a compliance check should be performed by the site. In case a 
patient does not follow the protocol instructions for daily intake of the medication, this will 
be discussed between the patient and the investigator or between the patient and the research 
nurse.
Discrepancies between the number of tablets remaining and the number of tablets the patient 
should have taken should be documented and explained, whenever possible. 
Before the start of the next cycle, any remaining medication from the previous cycle should 
be collected. If the patient is eligible for a further cycle of treatment, new bottles must be 
dispensed at the beginning of each new cycle.
Patients experiencing emesis should not take a replacement dose. These episodes should also 
be noted in the patient diary and the eCRF.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 53 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
If a patient suffers from an AE requiring a delay of treatment, a drug-free interval of 
maximum 2 weeks is allowed. If a longer drug-free interval is required, the patient must be 
withdrawn from the study.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 54 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
5.
VARIABLES AND THEIR ASSESSMENT
The endpoints are categorized as follows and explained in more detail in the sections below:
Primary endpoints:

Maximum tolerated dose in each treatment arm (based on number of dose limiting 
toxicities (DLTs) in first course of each treatment arm.

Number of DLTs in first course of each treatment arm
Secondary endpoints:

Objective response rate (CR, PR per RECIST criteria version 1.1).

Disease control rate/clinical benefit rate (CR/PR/SD per RECIST criteria version 1.1).

Duration of objective response (CR/PR), defined as time from first objective response 
to the time to progression or death.

Duration of clinical benefit (CR/PR/SD), defined as time from first clinical benefit to 
progression or death.

AUC0-24(ss), AUC0-oo, t1/2(ss), tmax(ss) and Cmax(ss) of BI 860585 administered as single
agent and with combination agents. 
5.1
EFFICACY - CLINICAL PHARMACOLOGY 
There is no primary efficacy endpoint. The primary aim of the trial is to establish the safety 
of the BI 860585 single agent, the safety of the combination of BI 860585 with exemestane 
or with paclitaxel in patients with various advanced and/or metastatic solid tumours, and to 
determine the MTD of the single agent treatment and the combination regimens. MTD will 
be measured through DLT observed during the first treatment cycle.
In the expansion part, there is no primary efficacy endpoint, as the primary goal is the 
confirmation of safety with regard to the selected dose level(s) and treatment schedule (s) of 
BI 860585 in monotherapy and in combination with exemestane or with paclitaxel.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 55 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
5.1.1
Endpoint(s) of efficacy
Efficacy variables are secondary endpoints and will be evaluated by descriptive statistics in 
this Phase I study. The following endpoints will be considered to explore the anti-tumour 
activity of BI 860585:

Objective response rate (Complete response/CR, Partial Response/PR per RECIST 
criteria version 1.1).

Disease control rate/clinical benefit rate (CR/PR/SD per RECIST criteria version 1.1)

Duration of objective response (CR/PR), defined as time from first objective response 
to progression or death.

Duration of clinical benefit (CR/PR/SD), defined as time from first clinical benefit to 
progression or death.
5.1.2
Assessment of efficacy
Tumour response, in patients with measurable or evaluable disease, will be evaluated locally 
by site according to the response evaluation criteria in solid tumours (RECIST criteria 
version 1.1) according to the time schedules specified in the Flow Chart. During the trial
patients will be re-evaluated approximately every 8 weeks at protocol specified visits starting 
from Cycle 2.
The baseline scan should be performed within four weeks prior to the initial treatment with 
the study medication and the investigator along with his/her radiologist will record the target 
(a maximum of five target lesions, no more than two in the same organ) and non-target 
lesions at baseline in the eCRF. The same radiological procedure should be used throughout 
the study at baseline and for all repeated measurements.
Lesions in previously irradiated areas may not be considered measurable at baseline unless 
the lesions occurred after irradiation.
Tumour assessment as well as clinical and safety assessments will contribute to the decision 
for continued patient participation in the trial.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
The determination of the MTD in each of the treatment arms is the primary objective for the 
study. It will be defined in view of DLT during the first cycle only.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 56 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
The following will qualify as a dose limiting toxicity:
Related toxicity category
Criteria defining a DLT
Haematologic

CTCAE Grade 4 neutropenia lasting ≥ 7 days

CTCAE Grade ≥ 3 documented infection with neutropenia

CTCAE Grade ≥ 3 febrile neutropenia

CTCAE Grade 3 thrombocytopenia associated with bleeding 
requiring transfusion

CTCAE Grade 4 thrombocytopenia 

CTCAE Grade 4 anaemia
Non hematologic

Any Grade ≥ 3 non hematologic toxicities despite the use of 
adequate/maximal medical interventions and or prophylaxis 
as dictated by local institutional clinical practices or the 
judgment of the investigator

Any Grade 3 hyperglycaemia that does not recover to Grade 
≤1 within two weeks of adequate therapy 
Re-Treatment Delay

Any toxicities that result in a > 14 days delay in Cycle 2 
Day1 dosing
Any DLTs occurring after the start of the second cycle will be considered for the evaluation 
of the Recommended Phase II Dose (RP2D) of BI 860585.  
Any DLTs occurring in the expansion cohorts will be considered in the evaluation of the 
RP2D but will not lead to a change in MTD.
All information about DLTs, AEs and other safety related information occurring throughout 
the trial will be collected and descriptively analysed for this purpose. 
5.2.2
Assessment of adverse events
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.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
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 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 57 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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.
Life-threatening in this context refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if more 
severe.
Every new occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.
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 judgment 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. 
The causal relationship must be provided by the Investigator for all potential trial drugs, i.e. the 
BI trial drug and for all other trial drugs (such as any active comparator or placebo and for trial 
procedure). 
The reason for the decision on causal relationship needs to be provided in the (e)CRF and on the 
SAE form (if applicable).
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 and SAE form (if applicable).
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 and SAE form (if applicable), if they are judged clinically 
relevant by the investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 58 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Adverse events of special interest (AESI)
Adverse events of special interest are to be reported in an expedited manner similar to 
Serious Adverse Events, even if they do not meet any of the seriousness criteria – for details 
please see Section 5.2.2.2.
The following are considered as adverse events of special interest:
1. Any DLT: for details on drug-related events that qualify as DLTs see Section 5.2.1.
2. Although rare, drug-induced liver injury is under constant surveillance by sponsor and 
regulators. 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 is important for patient safety.  
Hepatic injury is defined by the following alterations of liver parameters: 
For patients with normal liver function at baseline:

an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN 
For patients with impaired function tests at baseline:

an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of 
bilirubin ≥ 2 fold ULN measured in the same blood draw sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN 
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the "DILI checklist" provided in 
the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab 
results (ALT, AST, total bilirubin) available, the investigator should make sure these 
parameters are analysed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.
For patients experiencing a DILI/ potential DILI study medication should be interrupted
and investigators should contact sponsor for guidance.
3. Based on the knowledge of potential adverse events from other similar compounds (e.g. 
everolimus), other adverse events of special interest are:


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 59 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
-
Hypercholesterolaemia 
-
Hypertriglyceridemia
-
Stomatitis
-
Mucositis
-
Skin Rash
-
Hyperglycaemia 
All CTCAE grades should be reported (including values obtained with home glucose 
monitoring device).
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, and AESIs occurring during the course of the 
clinical trial (i.e. from signature of informed consent onwards through to the end of the 
follow-up phase) 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. 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. 
Adverse events with onset within 28 days after the last administration of therapy with study 
medication are considered as on treatment. Adverse events which are not yet recovered at the 
end of treatment (EOT) visit will be followed up until recovery or, in case of persistence, 
until sufficient characterisation of the toxic effects has been achieved and the investigator and 
the local clinical monitor agree to not further pursue them. All adverse events (AEs, SAEs 
regardless of relatedness) occurring during all follow-up visits and until the final follow-up 
visit will also be reported by the investigator. After the last per protocol contact (i.e. after 
follow-up period) the investigator does not need to actively monitor patients for AEs. 
However, if the investigator becomes aware of SAEs or AESIs that occurred after the last per 
protocol contact, the SAEs and AESIs should be reported by the investigator to the sponsor if 
considered relevant by the investigator
Hospitalisations already planned prior to informed consent, without worsening of the pre-
existing condition, need not be reported as a SAE.
The investigator must report the following events using paper process SAE form via fax
immediately (within 24 hours) to the sponsor: SAEs and non-serious AEs, which are relevant 
for a reported SAE or AESI, and protocol-specified adverse events of special interest 
(AESIs).    
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 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 60 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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. For follow-up information the same rules and timeline apply as for initial 
information.
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). 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. 
Screening failures: 
SAEs occurring in patients after having discontinued in the trial due to screening failures, i.e. 
after the screening period and who did not receive any trial medication, are to be reported if the 
Investigator considered the SAE related to the screening procedure. SAEs which occurred during 
the screening period are to be reported according to standard procedures.
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female patient has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
immediately report any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be immediately reported (within 24 hours) to the defined unique 
entry point for SAE forms of the respective BI OPU (country-specific contact details will be 
provided in the ISF). The outcome of the pregnancy associated with the drug exposure during 
pregnancy must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring 
Form for Clinical Trials and not the SAE form is to be completed. The ISF will contain the 
Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
For examples of acceptable methods of contraception see Section 3.3.3.
5.2.3
Assessment of safety laboratory parameters
Fasting laboratory assessment samples will be collected at the time points specified in the 
Flow Chart during each treatment cycle and analysed in a laboratory facility at (or close to) 
the investigational site.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 61 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Adverse events are to be graded according to the CTCAE version 4.03.
Category 
Test Name 
Haematology: 
Red blood cell count (RBC), reticulocytes, haemoglobin, white 
blood cell count (WBC) and differential, platelets 
Biochemistry: 
Fasting glucose, HbA1C, sodium, potassium, magnesium, 
calcium, creatinine, aspartate amino transferase (AST), alanine 
amino transferase (ALT), gamma glutamyl transferase (GGT), 
alkaline phosphatase, lactate deshydrogenase, total and indirect 
bilirubin, urea/BUN, total protein , albumin, uric acid, lipase, 
total cholesterol, triglycerides, creatine phosphokinase (CPK).
Renal function will be monitored with GFR (MDRD formula)
and serum creatinine and urea values and recorded in the eCRF. 
In addition, during Cycle 1, GFR will be estimated based on 
Creatinine clearance measured through collection and analysis 
of 24-hour urine at C1V1 and C1V4.
Coagulation parameters 
Prothrombin time (PT), international normalised ratio (INR) 
where therapeutically indicated and activated partial 
thromboplastin time (aPTT). 
Urine examination: 
pH, glucose, erythrocytes, leukocytes, proteins (including 
albuminuria), nitrite will be analyzed by dipstick (semi-
quantitative measurements: -, +, ++, +++, ++++). 
In case of abnormal findings, these should be confirmed by an 
additional dipstick test followed by further investigations (e.g. 
microscopic examination, analysis of 24 hour urine, creatinine 
measurements etc.) and findings documented.
Pregnancy test : 
β-HCG testing in serum will be performed as outlined in the 
Flow Charts at screening (within 7 days prior to first drug 
intake) and at the end-of-treatment visit in women of 
childbearing potential. 
In case of toxicity or abnormal lab values, adequate and more frequently blood sampling is at 
the discretion of the investigator.
5.2.4
Electrocardiogram
In Cycle 1, a standard triplicate 12-lead resting ECG matched with PK samples will be 
performed locally at the time points specified in the Flow Charts and in Appendix 10.1.1.
Thereafter, before start of study drug intake, at the start of every cycle on Day 1, and also at 
EOT. In case of drug related Grade 3 or 4 toxicity, every effort should be made to collect an 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 62 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
ECG (triplicate) matched with a PK sample. (All ECGs must be performed before PK 
sampling and after 5 minutes rest in supine position).
Changes in ECG will be recorded as an (S)AE in the eCRF, if they are judged clinically 
relevant by the investigator.
5.2.5
Assessment of other safety parameters
Physical examination will be performed at screening, on Day1 of each cycle prior to study
medication intake, and at the EOT visit.
Vital signs (blood pressure, body temperature and pulse rate after 2 minutes supine rest) will
be recorded at the screening visit, at every visit of the treatment cycles and at the EOT visit.
Height will be documented only once during the trial at screening.
Body weight and ECOG performance score will be performed at the time points specified in 
the Flow Chart.
Other safety examinations may be taken throughout the course of the study when required 
and deemed appropriate by the investigator. 
5.3
OTHER
5.3.1
Other endpoint(s)
Not applicable.
5.3.2
Other assessment(s)
Demographics (sex, birth date, race if it is not prohibited by the local laws, ethnicity) will be 
collected during the screening visit.
Relevant concomitant diagnoses and/or therapies present at study entry and/or during the 
study will be recorded in the eCRF.
History of cancer will also be obtained during screening and reported in the eCRF:

Type of cancer

Date of the first histological diagnosis (month and year may be sufficient) 

Primary tumour site 

Differentiation grade (not specified, undifferentiated, poorly differentiated, 
moderately differentiated, well differentiated)

Tumour stage according to the tumour, (lymph) node, metastasis (TNM) classification 
at diagnosis


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 63 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Previous surgery and radiotherapy

Previously administered chemotherapy, tyrosine kinase inhibitors treatment, vaccine-
therapy, antibodies therapy, immuno-therapy, and hormone-therapy including start 
and end dates (month and year may be sufficient)

Previous neoadjuvant, adjuvant or palliative therapy 

The date of tumour progression after previous line(s) of therapy for advanced or
metastatic disease

Number and location of metastatic sites at screening
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 64 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
5.4
APPROPRIATENESS OF MEASUREMENTS
Adverse events will be graded according to the NCI CTC AE criteria version 4.03 (R10-
4848).
The tumour response will be evaluated by means of the RECIST criteria version 1.1 that is 
well established and scientifically accepted (R09-0262).
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Pharmacokinetic profiles of BI 860585 (in plasma and in urine), exemestane and paclitaxel
(only in plasma) will be investigated. 
5.5.1
Pharmacokinetic endpoint(s)
Standard plasma and urine PK parameters as listed in Appendix 10.1.2 will be calculated 
after single and repeated dosing (steady state) for:

Paclitaxel

Exemestane

BI 860585
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 65 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
5.5.2
Methods of sample collection
A detailed time schedule for PK blood and urine sampling is given in Appendix 10.1.1.
5.5.2.1 Plasma sampling for pharmacokinetic analysis
A total amount of approximately a maximum of 120 mL blood will be taken from each 
patient during the first cycle of treatment for pharmacokinetic purposes 
 
 
For quantification of analyte plasma concentrations, approximately (but at least) 4 mL of 
blood will be taken from the forearm in a potassium-ethylenediamine-tetraacetic acid blood 
drawing tube at the timepoints specified in Appendix 10.1.1. Samples in Arm C will be taken 
from the opposite arm of paclitaxel infusion.
A total of three plasma aliquots will be generated (with about 0.7 mL plasma in each aliquot)
from each blood sample. The first aliquot will be used primarily for PK bioanalysis of BI 
850585 plasma concentrations, the second aliquot will be used for investigations regarding 
the drug metabolism (Arm A) or regarding the coadministered drugs (exemestane in Arm B 
or paclitaxel in Arm C) and the third aliquot will serve as a back-up sample for any of the 
other two aliquots. 
Every effort should be made to collect the blood samples very closely to the planned times.
Date and time of drug administration (including start/stop of infusions and potential 
interruptions), blood collection as well as details on food condition at all visits where PK 
sampling is performed must be recorded in the eCRF.
Also, if vomiting occurs on PK sampling days, after intake of BI 860585, the time of the 
onset of the episode(s) should be recorded in the eCRF.
Correct, complete and legible documentation of drug administrations and blood sampling 
times as well as adequate handling and identification of PK samples are mandatory to obtain 
data of adequate quality for the PK analysis. In order to allow the sample identification, the 
labels of the PK tubes have to contain at minimum: trial number, aliquot designation (e.g. 
"Plasma BI 860585" "Plasma exemestane" "Plasma paclitaxel" "Plasma DM&T" "Urine BI 
860585" "Plasma optional"), patient number, visit number, sample number and planned time 
(PTM).
PK plasma samples may also be used for the identification/quantification of metabolites as 
well as for methodological investigations such as the generation of further stability data or 
assay validation. However, only data related to the specified analytes or potential metabolites 
will be generated by these additional investigations. Primarily, samples from Days 22-23 
from the cohorts receiving BI 860585 doses close to the therapeutic dose in Arm A 
(monotherapy arm) will be used for these experiments. The control samples will be the 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 66 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
predose PK samples of these corresponding cohorts on Day 1 of Cycle 1 (just before the first 
BI 860585 administration).
The plasma samples must be stored at -20°C or below at the clinical sites until shipment on
dry ice to Boehringer Ingelheim via the Logistic CRO.
The samples will be discarded after completion of the additional investigations but not later 
than 3 years following availability of the final Clinical Trial Report (CTR).
Details on sample collection, preparation of plasma aliquots, handling, storage and shipment
are provided in the ISF/lab manual.
5.5.2.2 Urine sampling for pharmacokinetic analysis
In order to avoid adsorption losses of the analyte, polypropylene (PP) urine collection 
containers will be used for sample collection. All urine collection containers will be prefilled 
with 3 mL of Tween 20. 
A blank urine sample will be collected on Day 1 of Visit 1 prior to first drug administration 
and two 2 mL aliquots of the well-mixed urine retained to check for analytical interference. A 
protocol start time of -2:00 and a stop time of -2:00 will be used for database setup. All urine 
voided during the sampling intervals described in Appendix 10.1.1 will be collected in 
containers pre-filled with Tween 20. Patients have to empty their bladder at the end of each 
sampling interval. The urine weight for each collection interval will be documented by 
recording the weight of the empty and the filled container (both with lid plus Tween 20). 
Volume will be assumed equal to weight, i.e. 1 kg = 1 L, without correction for specific 
gravity of urine). After thorough mixing of the collected urine, two 2 mL aliquots will be 
stored at -20°C or below at the clinical site until shipment for bioanalytical measurement.
Correct, complete and legible documentation of sampling times as well as adequate handling 
and identification of PK samples are mandatory to obtain data of adequate quality for the PK 
analysis. The samples will be discarded after completion of the additional investigations but 
not later than 3 years following availability of the final CTR.
Details on sample collection, preparation of urine aliquots, handling, storage and shipment
are provided in the ISF/lab manual.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 860585 concentrations in plasma and urine
BI 860585 plasma concentrations will be determined by a validated assay based on liquid 
chromatography coupled to tandem mass spectrometry (LC-MS/MS). The procedure and 
specification of the analytical method will be available at the bioanalytical site (Department 
of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co. 
KG, 88397 Biberach, Germany or an authorized CRO).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 67 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Investigations on the drug metabolism of BI 860585 will be conducted in the Drug 
Metabolism & Transporter group, Drug Metabolism and Pharmacokinetics Germany, 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 
5.5.3.2
Analytical determination of exemestane or paclitaxel concentrations in plasma
Exemestane and paclitaxel plasma concentrations will be determined by validated assays
based on LC-MS/MS. The individual procedures and specifications of the analytical methods
used throughout the study are available at the bioanalytical site. (
 
or an Authorized CRO).
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 68 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 69 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and none of the exclusion criteria and who have given their 
written informed consent, are eligible for participation in the study.
Patients will visit the clinical site at the time points and acceptable time windows specified in 
the corresponding Flow Charts. If a patient misses a scheduled visit, and the patient reports to 
the investigator between the missed visit and the next scheduled visit, the missed visit should 
be done with the actual date and the reason should be given for the delayed visit. Thereafter 
the originally planned schedule should be implemented.
Patients may be hospitalized during Cycle 1 for the first day of treatment and
 
 on Day1 and Day 22 respectively, at the discretion of the investigator (see 
Appendix 10.1.1).
Treatment with BI 860585 will begin on Day 1 of Cycle 1 and will be administered according 
to a continuous dosing schedule. Once the decision is taken (for any reason) for a patient to 
stop the treatment with BI 860585, an end of treatment (EOT) visit should occur as soon as 
possible and within 7 days.
After the EOT visit, the patient should undergo a follow-up evaluation during a visit (or at
least a phone contact if a visit is not possible), 28 days ± 7 days after the EOT visit.
If the patient was not discontinued because of withdrawal of consent, disease progression or
treatment with another anti-cancer drug, he/she should continue to undergo follow-up visits 
every 8 weeks until disease progression or death, lost to follow-up, withdrawal of consent or 
treatment with another anti-cancer therapy.
The study will be conducted according to the principles of Good Clinical Practice.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The procedures required at each study visit are presented in the study Flow Charts of this 
CTP. Listed below are the key procedures required:

Registration of all AEs occurring from signature of Informed Consent Form (ICF) until 
the last follow-up visit.
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 70 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 

For measurable disease, tumour assessment (based on CT or MRI scan) according to 
RECIST criteria version 1.1 must be performed at the end of Cycle 2 and at the end of 
every second cycle thereafter.
6.2.1
Screening and run-in period(s)
Screening procedures may be performed over a period of 21-28 days (from signing of 
informed consent until the very first intake of study medication (BI 860585, exemestane or
paclitaxel). The investigations and assessments will be performed as outlined in the Flow 
Chart and as per the description listed below.
Informed consent
Written informed consent must be obtained
before any screening assessments are
performed (with the exception of tumour
scans as described in footnote g of the Flow 
Chart).
 
 
 
See Section 8.1.
Demographics and Medical History
Section 5.3.2.
Inclusion and exclusion criteria
See Sections 3.3.2 and 3.3.3
Physical examination, vital signs, height 
and body weight
Baseline conditions should be recorded at 
screening and up to start of treatment.
Height recorded only at baseline visit and at no 
further visits. Vital signs include blood 
pressure, pulse rate and body temperature. See
Section 5.2.5.
ECOG performance score
See Appendix 10.3.
ECG
12–lead resting ECG, triplicate. 
See Section 5.2.4
Concomitant therapy
All therapies within 4 weeks of start of 
treatment.
Occurrence of AEs
Beginning from date of consent signature.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 71 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Clinical/Tumour assessment
Evaluable disease, or at least one measurable 
lesion (measurable lesions are mandatory for 
expansion cohorts) according to RECIST 
criteria version 1.1 (R09-0262), including 
review of information to confirm progressive 
disease.
Baseline assessment within 28 days prior to 
start of treatment is acceptable.
FDG-PET
Optional, only for expansion cohorts, in case 
the investigator together with the sponsor find 
it appropriate. 
 
 
 
Safety laboratory
Including haematology, biochemistry, 
coagulation parameters as well as urinalysis. 
See Section 5.2.3.
Serum pregnancy test 
Within 7 days before start of treatment.
β–HCG serum pregnancy test for woman of
childbearing potential (see Section 5.2.3)
6.2.2
Treatment period(s)
At the start of treatment, investigations and assessments will be performed as outlined in the 
Flow Chart and as per the description listed below:
Inclusion and exclusion
Re-check criteria before dosing at C1V1, as per
Sections 3.3.2 and 3.3.3.
Physical examination, and body weight;
vital signs
Performed at Visit 1 for all cycles; Vital signs 
at every visit for each cycle – see Section 5.2.5.
ECOG
At Visit 1 of every cycle.
See Appendix 10.3.
12 - ECG
During Cycle1 triplicate ECGs will be done 
during pre-administration, during 
administration and immediately prior to the end 
of administration of BI 860585.
For Cycle ≥2, ECGs to be taken at the start of 
every cycle on Day 1. See Section 5.2.5.
Concomitant therapy
At every visit.
Occurrence of AEs
At every visit. See Section 5.2.2.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 72 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Tumour assessments
Tumour assessments will be done every 8 
weeks starting at the end of Cycle 2 (and 
within 7 days prior to next cycle i.e. prior to 
Cycles 5, 7 etc.). Thereafter, starting at Cycle 
6, tumour assessment will be every 3 cycles 
prior to the start of Cycles 10, 13, 16 etc by 
RECIST criteria version 1.1 (R09-0262).
Safety lab parameters
Haematology, biochemistry, coagulation and 
urinalysis conducted as per Section 5.2.3 on
Days 1, 8, 15, 22 and 28. 
In Cycle 1 GFR analysis will be measured also
through collection of 24-hour urine starting on 
Day 1 and Day 21.
Blood Glucose Monitoring
Home glucose monitoring measurement will 
occur once a day starting on Day 2 of Cycle 1 
and continue throughout the trial.  
Measurement will be recorded by patients in 
diary. 
 
 
 
Administration BI 860585
Intake will begin on Day 1 of Cycle 1 in all 
treatment arms and continue throughout the 
study. See also Section 4.1.4.
Administration exemestane (Arm B)
To be administered at the same time as BI 
860585.
In Cycle 1, first exemestane intake will begin
on Day -7 (see Table 10.1.1: 3).
For all subsequent cycles intake will begin on 
Day 1, continuous daily administration.
Administration paclitaxel (Arm C)
To be administered at the same time as BI 
860585.
In Cycle 1, first paclitaxel weekly infusion will 
begin on Day -7 (see Table 10.1.1: 4).
For all subsequent cycles infusion will begin 
on Day 1, weekly infusion.
Compliance check
At the end of every cycle. Empty containers 
and unused tablets should be returned by the 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 73 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
patients.
Skin Biopsy
Only if clinically necessary, in case of 
cutaneous rash Grade ≥3.
6.2.3
End of treatment and follow-up period
6.2.3.1
End of treatment visit
The EOT visit will be performed as soon as possible and within 7 days when a patient stops 
active treatment in the study for any reason. For details on assessments please see Flow 
Charts.
If the patient finishes active treatment without having progressive disease, tumour
assessment/imaging must be performed at the time of treatment discontinuation, unless it has
been done within the past 4 weeks. 
In addition to traditional imaging, and if the investigator and the sponsor consider it 
appropriate, patients in the expansion cohorts may undergo an FDG-PET to evaluate tumour 
metabolic responses during treatment or at disease progression.
If active treatment is stopped due to progressive disease, every effort should be made to 
perform imaging at the time point when progression is first noted.  
 
 
 
6.2.3.2
Follow-up visits
Follow-up visits should be performed for all patients who discontinue study treatment
approximately 28 days (± 7 days) after stopping study treatment. Thereafter, additional 
follow-up visits will only be performed for patients who discontinued treatment for reasons 
other than disease progression once every 8 weeks (at least by phone) until disease 
progression or death, lost to follow-up, start of other anti-cancer treatment or completion of 
study. All adverse events occurring during the follow-up period and until last follow-up visit 
will be reported by the investigator. For details on assessments please refer to Flow Chart.
6.2.4
Completion of study
The study will be analyzed and reported once the last patient of the study has experienced at 
least one of the following:

Has been treated for at least 4 cycles

Disease progression

Withdrawal from treatment due to a drug related adverse event 

Fatal event

Lost to follow-up


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 74 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Withdrawal of consent

Start of other anti-cancer treatment
In case patients are still being treated with study medication when the final report of the
trial is being prepared, these patients will be kept on treatment in the trial  and  will then be 
reported in a revised report.  It will be noted in the original report that such a revised report 
will be written.
The trial will be terminated as soon as the last patient ending treatment has completed the 
first follow-up visit.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 75 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial will be performed as an open-label study. The primary objective of the trial is to
determine separate MTDs of BI 860585 alone and in combination with exemestane or
paclitaxel. To determine the MTDs, patients are entered sequentially into escalating dose 
cohorts using the 3+3 design. Based on information from the dose escalation part of the 
study, an overall approximately 78 additional patients with measurable disease will be treated 
at the MTD and/or relevant biological dose(s), in one or two expansion cohorts, in each 
treatment arm. In the expansion phase, the safety of the selected dose level will further be 
evaluated; 
 
Descriptive statistics and exploratory analyses will be applied to summarize the study results.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical tests will be
performed.
7.3
PLANNED ANALYSES
All patients who are treated with at least one single dose of BI 860585 will be included in the
analysis.
7.3.1
Primary analyses
Dose escalation phase:
The primary objective of the trial is to determine the MTD of BI 860585 as a single and a 
combination dose regimen. MTD is defined as the dose at which no more than 1 out of 6 
patients experienced a DLT (or the dose level below the dose at which 2 or more out of 6 
patients experienced drug-related DLT) during the first 28-day treatment cycle.
Section 5.2.1 specifies adverse events that qualify for DLT, and Section 7.3.3 below gives
further information about the safety analyses.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 76 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Expansion phase:
The primary analysis for the expansion phase of this study is to further explore DLTs, AEs 
and other safety related information to confirm the MTD and/ or relevant biological dose(s)
determined in the dose finding phase.
7.3.2
Secondary analyses
Early efficacy signals of BI 860585 will be explored as secondary analyses in this Phase I
study. Objective response and disease control according to RECIST criteria version 1.1 will 
be analyzed descriptively for all treated patients.
Duration of objective response and disease control will be summarized using descriptive 
statistics for all treated patients. 
Tumour shrinkage will be summarized for all treated patients, as well as for patients treated at 
the MTD dose level. Waterfall plots will be used to graphically display efficacy signals in 
terms of tumour shrinkage.
 
 
 
 
 
 
 
 
7.3.3
Safety analyses
Adverse events and laboratory parameters will be evaluated using CTCAE version 4.03. In 
general, adverse events starting on or after the start date of the first administration of BI 
860585 and within 28 days after the last administration of study medication will be
considered as having occurred during the on-treatment period.
Descriptive statistics will be used to describe all abnormalities of potential clinical relevance.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 77 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.3.4
Interim analyses
Phase I safety analysis report:
If considered necessary, as soon as the MTD is determined in the corresponding treatment 
arm, an evaluation of the safety aspects will be performed. Results of this evaluation will be 
documented and archived. If considered appropriate, the results will be combined in one 
report for the different treatment arms. If applicable such an analysis will be defined in more 
detail in the TSAP.
The following un-blinded preliminary PK analysis of BI 860585, exemestane and paclitaxel 
will be performed:
1. After the two first cohorts from Arm A (for a minimum of 5-6 patients) to check the PK 
behavior of BI 860585. In case BI 860585 shows undue accumulation, if needed, the 
dosing regimen of BI 860585 should be adapted.
2. Before start of Arm B 
 to 
understand the PK of BI 860585 before the start of the first combination treatment (with 
exemestane) to adjust, if needed, the PK sampling times and dosing schedules for BI 
860585 in monotherapy arm and in combination arms (in case of short half-life (t1/2), 
adapt daily dose schedule (e.g. from qd to bid).
 
 
 
 
 
The Trial Pharmacokineticist (TCPK) will receive the bioanalytical results to be able to 
perform the interim PK analysis from the Trial Bioanalyst (TBA).
No formal interim report(s) will be written. In contrast to the final PK calculations, the 
interim analysis will be based on planned sampling times rather than on actual times and 
“uncleaned database”. Therefore, deviations of interim and final PK results may occur.
The interim analysis will provide individual and geometric mean plasma concentration-time 
profiles and PK parameters (AUC0-24(ss), AUC0-∞(if feasible), t1/2(,ss), tmax(ss) and Cmax(ss) of BI 
860585, exemestane and paclitaxel with patient identification.
The interim results will be presented to the Investigator/trial team. 
No inferential statistical analysis will be performed on these data.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 78 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.3.5
Pharmacokinetic analyses
Refer to Appendix 10.1.2 for PK parameters to be calculated. The derivation of PK 
parameters is described in detail in the sponsor’s standard operating procedures. All 
evaluable patients who received at least one dose of BI 860585, exemestane or paclitaxel will 
be included in the PK analysis. Patients who are considered as not evaluable will be listed 
with their individual plasma concentrations and individual PK parameters, and will be not 
included in descriptive statistics for plasma concentrations, PK parameters or other statistical 
assessment.
The following descriptive statistics will be calculated for all analytes concentrations as well 
as for all PK parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of 
variation. The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations.
 
 
7.4
HANDLING OF MISSING DATA
Every effort will be made to obtain complete information on all adverse events, with 
particular emphasis on potential dose limiting toxicities.
For the determination of baseline laboratory values, screening values will be imputed if 
laboratory values in visit 1 of the first course are missing/not available before start of first 
treatment.
7.4.1
Drug concentration - time profiles
Concentration data identified with NOS (no sample available), NOR (no valid result), NOA 
(not analyzed), and BLQ (below the limit of quantification) will be ignored and not replaced 
by zero at any time point (applies also to the lag phase including the pre-dose value(s)). 
Descriptive statistics of concentrations at specific time points will be calculated only when at 
least 2/3 of the individuals have concentrations within the validated concentration range. The 
overall sample size to decide whether the “2/3 rule” is fulfilled will be based on the total 
number of samples intended to be drawn for that time point (i.e., BLQ, NOR, NOS, NOA are 
included).


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 79 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
7.4.2
Pharmacokinetic parameters
Non-compartmental pharmacokinetic parameters will be determined using WinNonlin or 
another validated program.
In the non-compartmental analysis, concentration data identified with NOS, NOR and NOA 
will not be considered. BLQ values in the lag phase will be set to zero. The lag phase is 
defined as the period between time 0 and the first time point with a concentration above the 
quantification limit. All other BLQ and NOP values of the profile will be ignored. 
Descriptive statistics of parameters will be calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. Pharmacokinetic parameters which 
cannot be determined will be identified by "not calculated" (NC).
If the predose concentration before the first dose is less than or equal to 5% of Cmax value in 
that patient, the patient’s data without any adjustments can be included in all pharmacokinetic 
measurements and calculations (i.e., the pre-dose value will not be changed to zero). If the 
pre-dose value is greater than 5% of Cmax, the patient should be dropped from all statistical 
evaluations. The individual pharmacokinetic parameters can be calculated and listed 
separately.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case-to-case decision is required whether the value should only be excluded from 
half-life estimation or the complete analysis.
If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g., descriptive statistics) and for graphical presentation.
If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However, the excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.5
RANDOMISATION
In this open-label, Phase I study, randomisation is not applicable. Patients will be assigned,
not randomised, independently and sequentially by the Trial Clinical Monitor to each dose 
level 
 
7.6
DETERMINATION OF SAMPLE SIZE
Sample size will be based on the number of dose levels and number of patients needed in
each dose cohort to reach MTD. 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 80 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Currently, based on pre-clinical efficacy it is assumed that 8 cohorts of 3 patients (i.e. no 
patients with DLT at given level) and 3 cohorts of 6 patients in the BI 860585 monotherapy 
arm and 4 cohorts with 3 patients and 2 cohorts with 6 patients for each combination arm, 90
patients will be necessary for the dose escalation part of this trial.
Together with an assumed number of approximately 30 additional patients for one or more
expansion cohorts of each combination arm and approximately 18 patients in the expansion 
phase of the monotherapy arm, this leads to an expected sample size of approximately 168 
entered patients.
Note that in general, the sample size is induced by the 3+3 design and is subject to different 
random factors.
The trial will be terminated as soon as the last patient ending treatment has completed the 
first follow-up visit. 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 81 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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 patients 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.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
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.
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.
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 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 82 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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
Electronic Case Report Forms (eCRFs) for individual patients will be provided by the 
sponsor, via remote data capture. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical trial monitor, auditor
and inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA)/on 
site monitor and auditor may review all eCRFs, and written informed consents. The accuracy 
of the data will be verified by reviewing the documents described in Section 8.3.1.
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 860585 this is the current version of the Investigator’s Brochure (Doc. No: 
c02093461). For exemestane or paclitaxel this is the SPC. The current versions of these 
reference documents are provided in the ISF. No AE are classified as listed for trial 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.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 83 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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 i.e. the CA.
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 or early termination of the trial. 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 84 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
9.
REFERENCES
9.1
PUBLISHED REFERENCES
R12-5641
Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS et 
al., PIK3CA mutations in patients with advanced cancers treated with 
PI3K/AKT/ mTOR axis inhibitors, Mol Cancer Ther, 2011. 10 (3), 558 – 565.
R12-5635
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, 
Noguchi et al., Everolimus in Postmenopausal Hormone-Receptor–Positive 
Advanced Breast Cancer, New Engl J Med Dec, 2012, 366; 6, 520 - 29.
R12-5637
Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM et al., PIK3CA 
and PIK3CB inhibition produce synthetic lethality when combined with 
estrogen deprivation in estrogen receptor-positive breast cancer, Cancer Res, 
2009. 69 (9), 3955 – 3962.
R12-4136
Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, 
Higham C, Garcia-Echeverria C et al., Hyperactivation of 
phosphatidylinositol-3 kinase promotes escape from hormone dependence in 
estrogen receptor-positive human breast cancer, J Clin Invest, 2010. 120 (7): 
2406–2413.
R12-4137
Musgrove EA, Sutherland RL, Biological determinants of endocrine resistance 
in breast cancer, Nat Rev Cancer, 2009. 9: 631–43.
R12-5646
Blumenthal GM, Early targeted drug development: pilot FDA review of PI3K 
inhibitor phase I studies using a knowledge management database, 47th Ann 
Mtg of the American Society of Clinical Oncology (ASCO), Chicago, 3 - 7 
Jun 2011, J Clin Oncol, 2011. 29 (15, Part 1) (Suppl.), 209S, Abstr. 3060.
R12-5627
Kuo KT, Mao TL, Jones S, Veras E, Ayhan A, Wang TL et al., Frequent 
activating mutations of PIK3CA in ovarian clear cell carcinoma, Am J Pathol, 
2009. 174 (5), 1597 – 1601.
R12-5639
Trinh XB, Dam PA van, Dirix LY, Vermeulen PB, Tjalma WAA, The 
rationale for mTOR inhibition in epithelial ovarian cancer, Expert Opin Invest 
Drugs, 2009. 18 (12), 1885 – 1891.
R12-5640
Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW, PIK3R1 
(p85alpha) is somatically mutated at high frequency in primary endometrial 
cancer, Cancer Res, 2011. 71 (12), 4061 - 4067.
R05-1606
Perou CM, Sorlie T, Eisen MB, Rijn M van de, Jeffrey SS, Rees CA et al., 
Molecular portraits of human breast tumours, Nature, 200. 406, 747 – 752.
R12-5638
Sotiriou C, Pusztai L, Gene-expression signatures in breast cancer, N Engl J 
Med, 2009. 360 (8), 790 – 800.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 85 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
R00-0994
Early Breast Cancer Trialists' Collaborative Group, Tamoxifenfor early breast 
cancer: an overview of the randomised trials, Lancet, 1998. 351: 1451-67
R05-1607
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, 
Smith I et al, Herceptin Adjuvant (HERA) Trial Study Team, Trastuzumab 
after adjuvant chemotherapy in HER2-positive breast cancer, N Engl J Med, 
2005. 353 (16): 1659–72.
R05-1609
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CEJ, Davidson NE et al., 
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast 
cancer, N Engl J Med, 2005. 353, (16): 1673–84.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, 
Dancey J, Arbuck S et al., New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1).Eur J Cancer, 2009. 45, 228 – 247.
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), 
revised June 2010, reprinted June 2010).
website evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pd f (2010)
R01-0787 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol, 1982. 5, 649 – 655.
R13-1504
Campistol JM, Fijter JW de, Flechner SM, Langone A, Morelon E, Stockfleth 
E, mTOR inhibitor-associated dermatologic and mucosal problems.
Clin Transplant 24,2010. 149 – 156.
R12-3463
Snyder PW, Kazacos EA, Scott-Moncrieff JC, HogenEsch H, Carlton WW, 
Glickman LT, et al.,Pathologic features of naturally occurring juvenile 
polyarteritis in beagle dogs.Vet Pathol, 1995. 32 (4), 337 – 345.
R13-1565
Clemo FAS, Evering WE, Snyder PW, Albassam MA, Differentiating 
spontaneous from drug-induced vascular injury in the dog. Toxicol Pathol, 
2003. 31 (Suppl), 25 – 3.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER),2002. 1– 9.
R13-1537
Mauri D, Kamposioras K, Tsali L, Britstianou M, Valachis A, Karathanasi I, 
et al.,Overall survival benefit for weekly vs. three-weekly taxanes regimens in 
advanced breast cancer: a meta-analysis. Cancer Treat Rev, 2010. 36, 69 – 74.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 86 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
R13-1542
Monograph for paclitaxel (M & T drug interaction database, last updated: 
9/27/2007). website.druginteractioninfo.org (access date: 11 April 2013) ; 
Seattle: University of Washington ,2007.
R13-1543
Monograph for exemestane (Aromasin) (M & T drug interaction database, last 
updated: 12/30/2010). website.druginteractioninfo.org (access date: 11 April 
2013) ; Seattle: University of Washington, 2010.
R13-1535
Brueggemeier RW, Overview of the pharmacology of the aromatase 
inactivator exemestane. Breast Cancer Res Treat, 2002. 74, 177 – 185.
R13-1650
Sonnichsen DS, Liu Q, Schuetz EG, Schuetz JD, Pappo A, Relling MV, 
Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol 
Exp Ther, 1995; 275 (2), 566-75.
R13-1643 
Paclitaxel (developed: 1 June 2012). 
website.bccancer.bc.ca/NR/rdonlyres/C2B79918-25BC-4F5C-8975-
8D8016898B63/6314 9/Paclitaxel_monograph_1Apr2013_formatted.pdf 
(access date: 16 April 2013) ; In: Cancer drug manual. BC Cancer Agency, 
2012.
R13-1651
Kamdem LK, Flockhart DA, Desta Z. In vitro cytochrome P450-mediated 
metabolism of exemestane. Drug Metab Dispos. 2011 Jan; 39 (1):98-105
R13-1656
Jannuzzo MG, Spinelli R, Poggesi I, Cicioni P, Böttiger Y, Bertilsson L,
Inhibition of CYP3A4 does not influence exemestane pharmacokinetics (PK) 
in healthy postmenopausal volunteers (HPV). Eur J Cancer, 1999. 35 (Suppl 
4), S294.
R14-1468
Ma W. W, Jacene H, Song D, Vilardell F, Messersmith A.W, Laheru D,
[18F]Fluorodeoxyglucose Positron Emission Tomography Correlates With 
Akt Pathway Activity but Is Not Predictive of Clinical Outcome During 
mTOR Inhibitor Therapy, J Clin Oncol 27:2697-2704
R14-1470
Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et 
al. Measurement of clinical and subclinical tumour response using [18F]-
fluorodeoxyglucose and positron emission tomography: review and 1999 
EORTC recommendations. European Organization for Research and 
Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer, 1999. 
35:1773–1782 
9.2
UNPUBLISHED REFERENCES
Doc. No: c02093461 BI 860585 Investigator’s Brochure. 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 87 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
10.1.1
Blood sampling time schedule
Table 10.1.1: 1
Time schedule for blood sampling and tumour biopsy during Arm A, 
treatment with BI 860585 in fed conditions as monotherapy from Day 
1 to Day 28 (28-day cycle) 
 in 
Cycle 1. 
Visit
Day
eCRF
Time/P
TM
Event
PK Blood 
Sample No*
PK Urine 
Sampling
Analysed 
for
BI 860585*
Analysed 
for
PRP
Tumour 
biopsy
-28 to 
-1
Screening
X$$$
X$
1
1
-0:30
Breakfast 
within 30 min. 
before BI 
860585 adm. 
-0:05
PK Blood
(just before BI 
860585 adm)
A1 + ECG#
X
X
X
0:00
BI 860585 
adm.
0:30
PK Blood
A2
X
1:00
PK Blood
A3
X
X
2:00
PK Blood
A4
X
3:00
PK Blood
A5 + ECG#
X
X
4:00
PK Blood
A6
X
6:00
PK Blood
A7
X
8:00
PK Blood
A8 + ECG#
X
X
2
23:55
PK Blood
(just before BI 
860585 adm.)
A9 + ECG#
X
X
24:00
BI 860585 
administration
2
8±1
167:55
PK Blood
(just before 
drugs adm.)
A10 + ECG#
X
168:00
BI 860585 
adm.
3
15±1
335:55
PK Blood
(just before BI 
860585 adm.)
A11 + ECG#
X
X$$$
336:00
BI 860585 
adm.
339:00
-
X$$$
X$$


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 88 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 10.1.1: 1
Time schedule for blood sampling and tumour biopsy during Arm A, 
treatment with BI 860585 in fed conditions as monotherapy from Day 1 
to Day 28 (28-day cycle) 
 in Cycle 
1 (continued)
4
22±1
503:55
PK Blood
(Just before 
BI 860585 
adm.)
A12 + ECG#
X
X
504:00
BI 860585 
adm.
504:30
PK Blood
A13
X
505:00
PK Blood
A14
X
X
506:00
PK Blood
A15
X
507:00
PK Blood
A16 + ECG#
X
X
508:00
PK Blood
A17
X
510:00
PK Blood
A18
X
512:00
PK Blood
A19 + ECG#
X
X
23±1
527:55
PK Blood
A20 + ECG#
X
X
528:00
BI 860585 
adm.
5
28+1
647:55
PK Blood
(Just before 
BI 860585 
adm.)
A21 + ECG#
X
648:00
BI 860585 
adm.
EOT
X$$$$
# PK samples always taken AFTER ECG measurements
* In case of drug related Grade 3 or 4 toxicity, every effort should be made to collect PK sample(s) together with ECGs
$ For Arm A expansion cohort only: If the patient has an available FFPE tumour tissue sample obtained at least 15 days post 
prior treatment regimen (last treatment before the study drug is started), this sample can be used as the screening sample. 
$$ For Arm A expansion cohort only: Tumour biopsy sample should be taken on Day 15, within 3 to 5 hours after BI 860585 
administration. Actual date and time of biopsy collection should be recorded in the eCRF
$$$ For Arm A expansion cohort only: Screening and Day 15 PRP samples should be taken only from patients that have 
biopsy collected. Samplings should be done on the same day of the tumour biopsy collection.
$$$$ For Arm A expansion cohort only: At End of Treatment visit, biopsy should be taken from those patients with disease 
progression where feasible.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 89 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 90 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 91 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 10.1.1: 3
Time schedule for blood sampling
during Arm B, 
treatment with BI 860585 from Day 1 to Day 28 (28-day cycle) in 
combination with exemestane at steady state in Cycle 1
Visit
Day
eCRF
Time/PT
M
Event
PK Blood 
Sample No*
Analysed 
for
BI 860585*
Analysed 
for
exemestane
-28 to 
-7
Screening
1
-7
-0:05
PK Blood 
(just before exe. 
adm.)
B1 + ECG#
X
-7 to -
1
0:00
Exe. administration
-1
-24:05
PK Blood
(just before exe. 
adm.)
B2 + ECG#
X
-24:00
Exe. administration
-23:30
PK Blood
B3
X
-23:00
PK Blood
B4
X
-22:00
PK Blood
B5
X
-21:00
PK Blood
B6 + ECG#
X
-20:00
PK Blood
B7
X
-18:00
PK Blood
B8
X
-16:00
PK Blood
B9 + ECG#
X
1
-0:05
PK Blood
(just before drugs 
adm.)
B10 + ECG#
X
X
0:00
Drugs adm.
1:00
-
3:00
-
2
24:00
Drugs adm.
2
8±1
167:55
-
168:00
Drugs adm.
3
15±1
335:55
-
336:00
Drugs adm.
339:00
-
4
22±1
503:55
PK Blood
(just before drugs 
adm.).
B11 + ECG#
X
X
504:00
Drugs adm.
504:30
PK Blood
B12
X
X
505:00
PK Blood
B13
X
X
506:00
PK Blood
B14
X
X


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 92 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 10.1.1: 3
Time schedule for blood sampling and tumour biopsy during Arm B, 
treatment with BI 860585 from Day 1 to Day 28 (28-day cycle) in 
combination with exemestane at steady state in Cycle 1 (continued)
4
507:00
PK Blood
B15 + ECG#
X
X
508:00
PK Blood
B16
X
X
510:00
PK Blood
B17
X
X
512:00
PK Blood
B19 + ECG#
X
X
23±1
527:55
PK Blood
B20 + ECG#
X
X
528:00
Drugs adm.
5
28+1
647:55
PK Blood (just 
before drugs adm.).
B21 + ECG#
X
X
648:00
Drugs adm.
EOT
# PK samples always taken AFTER ECG measurements
* In case of drug related Grade 3 or 4 toxicity, every effort should be made to collect PK sample(s) together with ECGs
$ If the patient has an available FFPE tumour tissue sample obtained at least 15 days post prior treatment regimen (last 
treatment before the study drug is started), this sample can be used as the screening sample
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 93 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 10.1.1: 4
Time schedule for blood sampling 
 during Arm C, 
treatment with BI 860585 from Day 1 to Day 28 (28-day cycle) in 
combination with Paclitaxel in Cycle 1
Visit
Day
eCRF
Time/PTM
Event
PK Blood 
Sample 
No*
Analysed 
for
BI 
860585*
Analysed 
for
paclitaxel
-28 to 
-7
Screening
1
-7
-168:05
PK Blood
(just before start of 
pacli. inf.)
C1 + ECG#
X
-168:00
Start of pacli.inf.
-167:05
PK Blood (directly 
before end of pacli. 
inf.)
C2
X
-166:00
PK Blood
C3 + ECG#
X
-164:00
PK Blood
C4
X
-162:00
PK Blood
C5 + ECG#
X
-6
-144:00
PK Blood
C6 + ECG#
X
-5
-120.00
PK Blood
C7
X
1
-0:05
PK Blood
(just before drugs 
adm.)
C8 + ECG#
X
X
0:00
Drugs adm.
1:00
-
3:00
-
2
24:00
BI 860585 adm.
2
8±1
167:55
-
168:00
Drugs adm.
3
15±1
335:00
336:00
Drugs adm.
339:00
4
22±1
503:55
PK Blood
(just before drugs 
adm.)
C9 + ECG#
X
X
504:00
Start of pacli.inf. and 
BI 860585 adm.
504:30
PK Blood
C10
X
505:00
PK Blood (directly 
before end of pacli. 
infusion)
C11
X
X
506:00
PK Blood
C12
X
X
507:00
PK Blood 
C13 + 
ECG#
X
508:00
PK Blood
C14
X
X
510:00
PK Blood
C15
X
X
512:00
PK Blood
C16 + 
ECG#
X
X


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 94 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Table 10.1.1: 4
Time schedule for blood sampling and tumour biopsy during Arm C, 
treatment with BI 860585 from Day 1 to Day 28 (28-day cycle) in
combination with Paclitaxel in Cycle 1 (continued)
4
23±1
527:55
PK Blood (just 
before BI 860585 
adm.)
C17 + ECG#
X
X
552:00
BI 860585 adm.
24±1
551:55
PK Blood (just 
before BI 860585 
adm.)
C18
X
552:00
BI 860585 adm.
5
28+1
647:55
PK Blood (just 
before drugs 
adm.)
C19 + ECG#
X
X
648:00
Drugs adm.
EOT
# PK samples always taken AFTER ECG measurements
* In case of drug related Grade 3 or 4 toxicity, every effort should be made to collect PK sample(s) together with ECGs
 
 
 
Table 10.1.1: 5
Time schedule for additional steady-state PK/PD blood sampling(s) in 
case of intra-patient dose escalation in Cycle 2 or subsequent cycles
(any treatment arm).
Visit
Day
eCRF
Time/PTM
Event
PK Blood 
Sample No
Analysed for
BI 860585 
Analysed for
PRP
4
22±3
503:55
PK Blood
(Just before 
BI 860585 
adm.)
IP1
X
X
504:00
BI 860585 
adm.
504:30
PK Blood
505:00
PK Blood
506:00
PK Blood
507:00
PK Blood
IP2
X
X
508:00
PK Blood
510:00
PK Blood
512:00
PK Blood
IP3
X
X


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 95 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
10.1.2
Derivation of pharmacokinetic parameters
BI 860585, exemestane and paclitaxel plasma concentrations will be plotted graphically 
versus time for all evaluable patients as listed in the plasma concentration-time tables for 
three analytes. For the presentation of the mean profiles, the arithmetic/geometric mean and 
the planned blood sampling times will be used.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. The data format for descriptive statistics of concentrations will be 
identical with the data format of the respective concentrations. For the calculation of 
pharmacokinetic parameters, only concentrations within the validated concentration range 
will be used. The descriptive statistics of pharmacokinetic parameters will be calculated using 
the individual values with the number of decimal places as provided by the evaluation 
program. Then, the individual values as well as the descriptive statistics will be reported with 
three significant digits in the CTR. The actual sampling times will be used. For pre-dose 
samples, the actual sampling time will be set to zero.  
If data allow, the following PK parameters will be calculated for all listed analytes during 
treatment Cycle 1:
 
 
 
 
 
For exemestane and BI 860585:

area under the plasma concentration-time curve of the analyte in plasma over the time 
interval of one day (at steady state) (AUC0-24(ss))


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 96 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

area under the plasma concentration-time curve over the time interval from zero 
extrapolated to infinity (AUC0-∞) (only for BI 860585 in Visit 1)

 
 

maximum measured concentration of the analyte in plasma (at steady state) (Cmax(ss))
 
 
 
 

time from dosing to maximum measured concentration of the analyte in plasma (at steady 
state) (tmax(ss))
 
 

terminal half-life of the analyte in plasma (at steady state) (t1/2(ss))
 
 
 
 
 
 
 
 
 
 
 
Further pharmacokinetic parameters may be calculated as appropriate.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 97 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 98 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
10.2
CLINICAL EVALUATION OF LIVER INJURY
10.2.1
Introduction
Alterations of liver laboratory 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: 
10.2.2
Procedures

Repeat the following lab tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours. If ALT and/or AST > 3 fold ULN ( or AST > 5 fold ULN for patients 
with impaired function at baseline) combined with an elevation of total bilirubin > 2 
fold ULN  or marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold 
ULN are confirmed, results of the laboratory parameters described below must be 
made available by the investigator to BI as soon as possible.
In addition, 

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;
and report these via the eCRF.
Clinical chemistry
alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 99 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
(Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E 
(Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle 
antibody (titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) 
antibody, Anti-mitochondrial antibody
<project dependent:> Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, 
IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), 
toxoplasmosis (IgG, IgM)>
Hormones, tumour marker
TSH
Haematology
Thrombocytes, eosinophils

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of patients by repeat testing of ALT, AST, and total bilirubin 
(with fractionation by total and direct) at least weekly until the laboratory ALT and / or 
AST abnormalities 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).
10.3
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG)
PERFORMANCE SCORE
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
Reference R01-0787.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 100 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
10.4
MODIFICATION OF DIET IN RENAL DISEASE FORMULA
The Modification of Diet in Renal Disease (MDRD) formula is commonly used to estimate 
GFR and is the recommended formula to calculate GFR in this trial.
GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African-
American)
where Scr is serum/plasma creatinine in mg/dL.
Renal function impairment will be classified in the following way:
• No renal function impairment: eGFR ≥90 mL/min/1.73 m2;
• Mild renal function impairment: eGFR <90 mL/min and GFR ≥60 mL/min/1.73 m2;
• Moderate renal function impairment: eGFR <60 ml/min and GFR ≥30 mL/min/1.73 m2.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 101 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
29 Apr 2014
EudraCT number
2013-000765-36
BI Trial number
1325.1
BI Investigational Product(s)
BI 860585
Title of protocol
An open label phase I dose finding study of BI 
860585 administered orally in a continuous 
dosing schedule as single agent and in
combination with exemestane or with paclitaxel 
in patients with various advanced and/or 
metastatic solid tumours
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB/IEC/Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
Clinical trial protocol synopsis - Methodology
Description of change
The text has been changed to: 
Uncontrolled, open label, multiple dose escalation 
followed by one or more expansion cohorts in 
each combination arm
Rationale for change
To reflect the inclusion of expansion cohorts.
Section to be changed
Clinical trial protocol synopsis – No. of patients  
Section 3.3
Section 7.6
Description of change
The total number of patients has been increased 
from 90 to 150.
Rationale for change
To reflect the inclusion of expansion cohorts.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 102 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Clinical trial protocol synopsis – No. of patients -
Each treatment
Description of change
The text has been changed to:
Arm B (BI 860585 + exemestane): approximately 
30 patients + approximately 30 patients in 
expansion cohorts
Arm C (BI 860585 + paclitaxel): approximately 
30 patients + approximately 30 patients in 
expansion cohorts
Rationale for change
To reflect the inclusion of expansion cohorts.
Section to be changed
Clinical trial protocol synopsis- Main criteria for 
inclusion
Description of change

The phrase “In addition, patients enrolled 
into the expansion part of the study must 
have measurable progressive disease” has 
been added.
Rationale for change
To reflect the inclusion of expansion cohorts.
Section to be changed
Clinical trial protocol synopsis – Criteria  for 
safety
Description of change
“Hypertriglyceridemia” has been added
Rationale for change
To be consistent with Section 1.2.1 .
Section to be changed
Flow chart header Cycle 1
Section 3.1 paragraph 19
Tables 10.1.1:1
Tables 10.1.1:2
Tables 10.1.1:3
Tables 10.1.1:4
Description of change
Addition of visit windows in Cycle 1.
Rationale for change
Describe the allowable window for
Visits.
Section to be changed
Flow chart Cycle 1
Flow chart Cycle 1 – Footnote 
Flow chart Cycle 2 and subsequent cycles
Flow chart Cycle 2- Footnote F
Section 3.1, paragraph 26
Section 6.2.1
Section 6.2.3


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 103 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Description of change
Addition of text to include optional FDG-PET, in 
addition to MRI/CT assessment, for patients in 
expansion cohorts.
Rationale for change
At any time during the patients participation in 
the trial, and according to investigator’s 
judgment,  tumour metabolic response may be 
explored in patient enrolled in the expansion 
cohorts.
Section to be changed
Flow chart footnote Cycle 1
Description of change
Addition of the following footnote: 
§ This visit can be done on the same day as 
C2V1, if an additional cycle is indicated
Rationale for change
To clarify that C1V5 and C2V1may be done on 
the same day.
Section to be changed
Flow chart footnote Cycle 1
Description of change
Addition of the following footnote: 
H. For patients in the expansion cohorts 
(optional): in addition to traditional imaging and 
in case the investigator and the sponsor find it 
appropriate, an FDG-PET may be done at any 
time during the patient’s participation in the trial, 
to evaluate tumour metabolic responses. An 
existing FDGPET, if obtained within 4 months 
prior to start of treatment, can be used as 
screening FDG-PET.
Rationale for change
Clarification
Section to be changed
Flow chart footnote Cycle 1
Description of change
I. For eGFR analysis at Day 2 and Day 23 , 24 
hours urine should be collected after BI 860585
administration (at Day 1 and Day 22), please refer 
to Section 5.2.3
Was changed to:
J. For eGFR analysis at Day 2 and Day 22, 24 
hours urine should be collected after BI 860585
administration (at Day 1 and Day 21), please refer 
to Section 5.2.3
Rationale for change
To anticipate collection of 24 hours urine for 
eGFR analysis with respect to collection of urine 
for PK on day 22 and 23 in ARM A ( 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 104 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Flow chart footnote Cycle 1
Description of change
J. A serum βHCG pregnancy test must be 
performed at screening in women of childbearing 
potential.
Was changed to:
K. A serum βHCG pregnancy test must be 
performed at screening in women of childbearing 
potential within 7 days of starting treatment.
Rationale for change
To be consistent with sections 5.2.3 and 6.2.1
Section to be changed
Flow chart footnote Cycle 1
Description of change
L. Please refer to Appendix 10.1.1 for a detailed 
description of pharmacokinetic 
 
sampling.
Was changed to:
M. For patients in the dose escalation and 
expansion parts of the study. Please refer to 
Appendix 10.1.1 for a detailed description of 
pharmacokinetic
Rationale for change
To clarify that PK sampling will also apply to 
expansion cohorts as per dose escalation cohorts 
in the corresponding treatment arms.
Section to be changed
Flow chart footnote Cycle 1
Description of change
M. In case of drug related Grade 3 or 4 toxicity, 
every effort should be made to collect PK
blood sample(s) together with ECG (ECG should 
always be performed BEFORE PK sampling); 
date and time of the sample(s) and of the most 
recent drug intake (before PK sample) need to be 
recorded for such sample(s).
Was changed to:
N. For all patients, in case of DLTs or drug 
related Grade 3 or 4 toxicity, every effort should 
be made to collect PK blood sample(s) together 
with ECG (ECG should always be performed 
BEFORE PK sampling); date and time of the 
sample(s) and of the most recent drug intake 
(before PK sample) need to be recorded for such
sample(s).
Rationale for change
Clarification


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 105 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Flow chart footnote Cycle 1
Description of change
N. One blank urine will be sampled prior to drug 
administration (BI 860585) on Visit 1 (at least 
two 2 mL aliquots), additionally urine will be 
collected over 24 hours: 0-4, 4-8 and 8-24 hours 
after study drugs administration at steady state 
(Days 22-23) in all cohorts from Arm A.
Was changed to:
O. In all cohorts from Arm 
 
: One blank urine will be sampled prior to 
drug administration (BI 860585) on Visit 1 (at 
least two 2 mL aliquots), additionally urine will 
be collected over 24 hours: 0-4, 4-8 and 8-24 
hours after study drugs administration at steady 
state (Days 22-23).
Rationale for change
 
 
 
 
 
 
 
Section to be changed
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 106 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
 
 
 
Rationale for change
 
 
 
 
 
 
 
 
Section to be changed
Flow chart Cycle 2 and subsequent cycles
Description of change
Addition of optional FDG-PET
Rationale for change
To evaluate tumour metabolic responses in patient 
enrolled in the expansion cohort, according to 
investigator’s judgment.
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 107 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Flow chart footnote Cycle 2 and subsequent 
cycles
Description of change
F. CT or MRI imaging: response assessment 
every 2 cycles starting at the end of Cycle 2; a 
scan at EOT visit is optional in case a scan was 
already done in the previous 4 weeks. 
Was changed to:
F. CT or MRI imaging: response assessment 
every 2 cycles starting at the end of Cycle 2; a 
scan at EOT visit is optional in case a scan was 
already done in the previous 4 weeks. For 
patients in the expansion cohorts, in addition 
to traditional imaging and in case the 
investigator and the sponsor find it 
appropriate, an FDG-PET may be done at any 
time during the patient’s participation in the 
trial, to evaluate tumour metabolic responses.
Rationale for change
To include optional evaluation of  tumour 
metabolic responses, according to investigator’s 
judgment, in patient enrolled in the expansion 
cohort.
Section to be changed
Flow chart footnote Cycle 2
Description of change
J. Only in case of drug related Grade 3 or 4 
toxicity, every effort should be made to collect a 
PK sample; date and time of the sample and of the 
most recent drug intake (before PK sample) need 
to be recorded for such samples  
Was changed to:
J. For all patients, in case of DLTs or drug 
related Grade 3 or 4 toxicity, every effort should 
be made to collect a PK sample; date and time of 
the sample and of the most recent drug intake 
(before PK sample) need to be recorded for such 
samples
Rationale for change
Clarification
Section to be changed
Flow chart footnote Cycle 2
Description of change
K. Drug intake should be after breakfast and as 
long as no different instructions are given
Was changed to:


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 108 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
Abbreviation
Description of change
Addition of the following abbreviations:         
FDG-PET, MDRD,RBD
Rationale for change
Update list
Section to be changed
Section 1.1 paragraph 10
Section 1.2 paragraphs, 1, 8 and 11
Section 2.3 paragraphs 5 and 6
Section 8.4.1
Section 9.2
Description of change
IB reference number deleted.
Rationale for change
To ensure that most current  IB is referred to.
Section to be changed
Section 2.2
Description of change
The following additional primary objective has 
been included:
Safety profile of BI 860585 in combination 
with exemestane and paclitaxel at the 
recommended dose(s) and schedule(s) [MTD 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 109 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
and/or relevant biological dose(s)] in patients 
with various tumour types (i.e. expansion 
cohorts)
Rationale for change
To define main objective for expansion cohorts.
Section to be changed
Section 2.2
Description of change
Investigate preliminary anti-tumour activity in all 
evaluable patients (please refer to Section 5.1.1
for a description of efficacy endpoints).
Was changed to:
Investigate preliminary anti-tumour activity in all 
evaluable and in all measurable patients (please 
refer to Section 5.1.1 for a description of efficacy 
endpoints).
Rationale for change
To define secondary objective for expansion 
cohorts.
Section to be changed
Section 2.3
Description of change
Adverse events as stated in Section 1.2.3 are 
expected and will be managed with adequate
monitoring and supportive care.
Was changed to:
Adverse events as stated in Section 1.2.1 of the 
protocol are expected and will be managed with 
adequate monitoring and supportive care.
Rationale for change
To specify correct reference section of clinical 
protocol.
Section to be changed
Section 3.1
Description of change
This study is a multicentre, open label Phase I 
dose escalation study using a 3+3 design. It is
designed to determine the MTDs of BI 860585 as 
a single agent and in combination with
exemestane or with paclitaxel in patients with 
advanced and/or metastatic solid tumours.
Was changed to:
This study is a multicentre, open label Phase I 
dose escalation study using a 3+3 design, 
followed by one or two expansion cohorts in 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 110 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
each combination arm.
The dose escalation part of the trial is designed 
to determine the MTDs of BI 860585 as a single 
agent and in combination with exemestane or 
with paclitaxel in patients with advanced and/or 
metastatic solid tumours.
Furthermore, as a result of data collected 
during the dose escalation part of the study, 
one or more doses [MTD and/or relevant 
biological dose(s)], shown to have a favourable 
safety, PK 
 profile, will be chosen and 
further investigated in one or two expansion 
cohorts, in each combination arm (Arm B and 
Arm C). 
This expansion part will further evaluate BI 
860585 in order to confirm the safety profile of 
the selected dose(s) of BI 860585 in 
combination with exemestane or with 
paclitaxel, and assess preliminary anti-tumor 
activity, PK 
 profiles, in patients with 
various tumour types. 
Ultimately this expansion part of the trial is 
aimed to determine a Recommended Phase II 
Dose (RP2D) for each treatment arm which is 
expected to be the most relevant biological 
dose (RBD) and not necessarily the MTD.  
Rationale for change
To update the trial design by including expansion 
cohorts in combination arms.
Section to be changed
Description of change
The study will be characterized by 3 distinct 
treatment arms running in parallel but not
starting enrolment simultaneously
Was changed to:
The dose escalation part of the study will be 
characterized by 3 distinct treatment arms running 
in parallel but not starting enrolment 
simultaneously
Rationale for change
To specify that the described procedure is related 
to the initial dose escalation phase of the study.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 111 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section to be changed
Section 3.1
Description of change
The following text was added for Arm A:
In principle no expansion cohort is foreseen for 
Arm A. However, once MTD is determined, 
should any patient with a specific tumour type 
(e.g. Pancreatic Neuroendocrine Tumour -
pNET) derive benefit during the dose 
escalation portion of the study and should the 
investigators ask to have patients with similar 
characteristics included in the trial (provided 
the study is still in the enrolling phase), a 
maximum of 12 patients might still be included 
in the MTD level on a case by case basis and 
after discussion with the sponsor.
Rationale for change
To clarify that no expansion cohort is foreseen in 
ARM A.  However an opportunity could be given 
to patients with a specific tumour, that showed to 
be responsive during the dose escalation phase, to 
receive treatment which might be beneficial. 
Section to be changed
Section 3.1
Description of change
The following text was added for ARM B and C:
Once MTD is reached one or two expansion 
cohorts of approximately 15 patients each, will 
be opened for enrollment. 
However enrollment in the expansion cohorts 
could be anticipated (before reaching MTD), 
after thorough discussion and agreement 
between the sponsor and the investigator, in 
order to explore an intermediate dose level 
displaying a favorable combination of safety, 
PK 
 profiles during the dose escalation. 
It could therefore be envisioned that one 
expansion cohort will be opened at MTD or 
one level below MTD, and in addition, there 
might be chances that an intermediate dose 
level displaying a favorable combination of 
safety, PK 
 profile might also be 
explored after thorough discussion and 
agreement between the sponsor and the 
investigator.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 112 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Rationale for change
To explain conduct of dose expansion phase.
Section to be changed
Figure 3.1:1
Description of change
To indicate that expansion cohorts will be 
included in combination arms and will be treated 
with MTD and/ or relevant biological dose(s).
Rationale for change
To update study design in accordance with overall 
design description.
Section to be changed
Section 3.1 paragraph 14
Description of change
The following text was added:
As mentioned above, approximately 30 
additional patients with measurable disease 
will be treated at the MTD and/or relevant 
biological dose(s), in one or two expansion 
cohorts, in each of the combination arms. This 
expansion part will evaluate anti-tumour 
activity in addition to the other current 
objectives (safety, pharmacokinetic 
 
profiles of BI 860585 in 
combination with exemestane and with 
paclitaxel).
Rationale for change
To be consistent with new study design.
Section to be changed
Section 3.1 paragraph 16
Section 4.1.1
Table 4.1.3:2
Table 10.1.1
Table 10.1.2
Description of change
BI 860585 will be administered approximately 30 
minutes after /within start of breakfast or meal.
Rationale for change
To give additional details on timing of food 
intake.
Section to be changed
Section 3.1
Description of change
For each treatment arm, and for each new dose 
level, the first patient will be observed for at
least 7 days of treatment in the first cycle before 
the next 2 patients may be included.
Moreover before opening enrollment of higher 
dose level cohorts all patients at an ongoing
dose level must have completed the first cycle (4 
weeks) treatment (BI 860585 with or


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 113 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
without exemestane or paclitaxel).
Was changed to
For each treatment arm, and for each new dose 
level, the first patient will be observed for at least 
7 days of treatment in the first cycle before the 
next 2 patients can start treatment. Moreover 
before opening treatment in higher dose level 
cohorts, all patients at an ongoing dose level must 
have completed the first cycle (4 weeks) 
treatment (BI 860585 with or without exemestane 
or paclitaxel).
The above mentioned criterion does not apply 
to the expansion cohorts since patients may be 
allowed to enter simultaneously.
Rationale for change
To clarify procedure and to specify that procedure 
will not apply to expansion cohorts.
Section to be changed
Section 3.1
Description of change
Patients eligible for further treatment will not start 
before the Day 28 procedures are completed at the 
end of Cycle 1. Starting from Cycle 2 onwards, a 
window of ± 3 days is allowed for the start of the 
next cycle. The visit on Day 28 and the visit of
Day 1 of the next cycle can be combined into one 
visit. 
Was changed to:
Patients eligible for further treatment in Cycle 2
will not start before the Day 28 (+1 day) 
procedures are completed at the end of Cycle 1. 
Starting from Cycle 2 onwards, a window of ± 3 
days is allowed for the start of the next cycle. The 
visit Visits procedure of on Day 28 and the visit
of Day 1 of the next cycle can be combined into 
one visit. 
Rationale for change
Clarification and for consistency with Flow chart 
Cycle 1.
Section to be changed
Section 3.1 paragraph 20
Table 4.1.3 :2
Table 4.1.3 :3
Table 4.1.3 :4


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 114 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Section 4.1.4.1 
Description of change
To specify that adverse events must be related to 
BI 860585.
Rationale for change
For consistency within the protocol. 
Section to be changed
Section 3.1 paragraph 21
Description of change
Patients will be replaced if they withdraw for a 
reason other than DLT before completing the first 
treatment cycle or miss more than one visit during 
their first treatment cycle (if the information that 
needs to be collected during this visit is not 
available and makes the patient non-evaluable for 
determining DLT).
Was changed to:
During the dose escalation part of the study, 
patients will be replaced if they withdraw for a 
reason other than DLT before completing the first 
treatment cycle or miss more than one visit during 
their first treatment cycle (if the information that 
needs to be collected during this visit is not 
available and makes the patient non-evaluable for 
determining DLT).
Rationale for change
To clarify that replacement of patients for the 
evaluation of DLT is foreseen only during the 
dose escalation phase.  
Section to be changed
Section 3.1 paragraph 22
Section 5.5.2 paragraph 2
Appendix 10.1.3 paragraph 1
Description of change
 
Rationale for change
For consistency within the protocol.
Section to be changed
Section 3.1  Paragraph 25
Description of change
For patients with measurable lesions, tumour 
assessment according to RECIST criteria version 
1.1 by CT or MRI will be performed at the 
investigator’s site. The same radiographic 
procedure must be used throughout the course of 
the study.
Was changed to:
For patients with measurable lesions and for all 
patients included in the expansion cohorts,


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 115 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
tumour assessment according to RECIST criteria 
version 1.1 by CT or MRI will be performed at 
the investigator’s site. The same radiographic 
procedure must be used throughout the course of 
the study.
Rationale for change
To underline that all patient in the expansion 
cohorts must have measurable disease as per 
inclusion criteria n. 9
Section to be changed
Section 3.1  
Description of change
The following paragraph was added:
Patients enrolled in the expansion part and 
who experience a DLT will undergo dose 
reduction in the same way as patients treated 
in the dose escalation part but the occurrence 
of a DLT will not lead to a change in MTD.
Rationale for change
To specify management of patient in the 
expansion cohort who experience DLTs.
Section to be changed
Section 3.1
Description of change
The following phrases were added:
In case of intra-patient dose escalations, every 
effort should be made to collect additional PK 
 plasma samples as indicated in 
Appendix 10.1.1:5. 
In case of DLTs or drug related Grade 3 or 4 
toxicity, every effort should also be made to 
collect a PK blood sample together with ECGs 
(triplicate). 
Rationale for change
To specify circumstances where additional PK 
samples may be collected during the trial.
Section to be changed
Section 3.1.1
Description of change
The text “Boehringer Ingelheim Clinical Trials 
Supply Unit” was deleted and replaced with 
“central depot”
Rationale for change
To accommodate changes in depots.
Section to be changed
Section 3.2
Description of change
The following paragraph was added:
Finally in order to provide an opportunity to 
better define the appropriate dose range and 
administration schedule of the RP2D, 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 116 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
expansion cohorts will further evaluate the 
safety profile of BI 860585 at the 
recommended dose(s) and schedule(s) as well 
as assess early signs of anti-tumour activity in 
patients with multiple tumour types in which 
treatment with BI 860585 in combination with 
exemestane or BI 860585 in combination with 
paclitaxel may give clinical benefit.  
Rationale for change
To reflect the objective of including expansion 
cohorts.
Section to be changed
Section 3.3.1
Description of change
The following phrase was added:
In addition, patients in the expansion cohorts 
must have measurable documented/proven 
progressive disease, according to RECIST 
criteria. 
Patients included in the escalation part are not 
eligible to enter the expansion part of the trial.
Rationale for change
To define  inclusion criteria for expansion cohort 
patients whereby patient must have measurable 
disease according to RECIST criteria version 1.1.
and cannot be patients participating in the dose 
escalation phase.
Section to be changed
Section 3.3.2
Description of change
The following inclusion criteria was added:
Additional inclusion criteria for expansion 
part:
9.Patients must have measurable progressive 
disease within the last 6 months 
documented/proven according to RECIST 
criteria version 1.1.
Rationale for change
In addition to other pre-existing criteria, patients 
enrolled in the expansion cohort must have 
measurable disease for standard evaluation of 
anti-tumour activity.
Section to be changed
Section 3.3.3


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 117 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Description of change
18. Treatment with cytotoxic anti-cancer-
therapies or standard chemotherapy,  
immunotherapy, radiotherapy, biological 
therapies, molecular targeted or other 
investigational drugs, within four weeks of the 
first treatment with the study medication (or 
within one week for non-cytotoxic drugs)
Was changed to:
18. Treatment with anti-cancer-therapies: 
cytotoxic or standard chemotherapy,  
immunotherapy, radiotherapy, biological 
therapies, molecular targeted or other 
investigational drugs, within four weeks of the 
first treatment with the study medication (or 
within one week for non-cytotoxic drugs)
Rationale for change
To be consistent with section 4.2.2.1
Section to be changed
Section 3.3.4.1
Description of change
There is a longer than 14-day treatment break due 
to any AE or other reasons. 
Was changed to:
There is a longer than 14-day treatment break due 
to any drug related AE or other medical reasons. 
If an interruption of more than 2 weeks is 
necessary and clinically justified, the patient 
may continue study treatment after discussion 
and agreement between the investigator and 
the sponsor.
Rationale for change
For consistency within protocol and to be able to 
take into consideration those patient that may 
need to undergo medical procedures/assessments 
that require more than 2 weeks interruption.
Section to be changed
Section 4.1.2
Description of change
For each treatment arm, and for each new dose 
level, the first patient entering the new dose level 
must have completed at least 7 days of treatment 
in the first cycle before the next 2 patients are 
entered into the same dose level cohort. At least 3 
patients will be treated at each dose level (cohort).
Moreover before opening enrollment of higher 
dose level cohorts all patients at an ongoing dose 
level must have completed the first cycle (4 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 118 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
weeks) treatment (BI 860585 with or without 
exemestane or paclitaxel).
Was changed to:
During dose escalation in each treatment arm, 
and for each new dose level, the first patient 
entering the new dose level must have completed 
at least 7 days of treatment in the first cycle 
before the next 2 patients can start treatment in
the same dose level cohort. At least 3 patients will 
be treated at each dose level (cohort).
Moreover before opening treatment in higher 
dose level cohorts all patients at an ongoing dose 
level must have completed the first cycle (4 
weeks) treatment (BI 860585 with or without 
exemestane or paclitaxel).
The above mentioned criterion does not apply 
to the expansion cohorts since patients may be 
allowed to enter simultaneously.
Rationale for change
To clarify procedure and to specify that procedure 
will not apply to expansion cohorts.
Section to be changed
Section 4.1.3
Description of change
The starting dose of BI 860585 for the 
combination arms will be determined during the 
dose escalations of BI 860585 single agent.
Was changed to:
The starting dose of BI 860585 for the escalating
combination arms will be determined during the 
dose escalations of BI 860585 single agent.
Rationale for change
To clarify that the procedure described refers to 
the dose escalation phase.
Section to be changed
Section 4.1.3 paragraph 4
Table 4.1.3:1 Title
Section 4.1.4.1  paragraph 1
Section 4.1.4.3 paragraph 3
Section 4.1.6 paragraph 1
Section 4.3 paragraph 2
Section 5.5.2.1 paragraph 2
Section 6.2.3.2 
Section 7.3.5
Description of change
Text has been re-phrased.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 119 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Rationale for change
For additional clarification of protocol specific 
aspects.
Section to be changed
Section 4.1.3
Description of change
The following phrase was also added:
During the expansion part of the trial, new and 
eligible patients with at least one measurable 
lesion by RECIST criteria 1.1 will receive the 
MTD and/or RBDs (relevant biological dose(s) 
of BI 860585 as determined with data from the 
dose escalation part of the study and after 
discussion and agreement between the sponsor 
and the investigators. 
Rationale for change
To clarify the doses that will be selected for 
expansion cohorts. 
Section to be changed
Section 4.1.4.1.1
Description of change
CTCAE Grade ≥3 AST/ALT:

AST and /or ALT > 5x ULN (if baseline 
value < 3x ULN) 
or

AST and /or ALT > 10x ULN (if baseline 
value 3-5x ULN); 
Was changed to:
CTCAE Grade ≥3 AST/ALT:

AST and /or ALT > 5x ULN (if baseline 
value < 3x ULN) 
or

AST and /or ALT > 10x ULN (if baseline 
value >3-5x ULN); 
Rationale for change
For consistency with exclusion criteria n.9
Section to be changed
Section 4.1.4.1.1
Description of change
The following phrase was added:
Any patient enrolled in the expansion part who 
experiences a DLT will undergo dose reduction 
in the same way as patients treated in the dose 
escalation part but the occurrence of a DLT 
will not lead to a change in MTD. However, 
any DLTs occurring in the expansion cohort 
will be considered in the evaluation of the 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 120 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
RP2D
Rationale for change
To clarify the management of DLTs in expansion 
cohorts and how this data will be considered with 
respect to MTD and RP2D determination.
Section to be changed
Section 4.2.1
Description of change
Episodes of hypercholesterolaemia should be 
managed with appropriate medical therapy and be 
monitored. Stomatitis should be managed with 
topical analgesic mouth treatments (e.g. 
benzocaine, butylaminobenzoate, tetracaine 
hydrochloride,) with or without topical 
corticosteroids (i.e. triamcinolone oral paste).
Was changed to:
Episodes of hypercholesterolaemia or 
hypertriglyceridemia should be managed with 
appropriate medical therapy and be monitored. 
Stomatitis and/or mucositis should be managed 
with topical analgesic mouth treatments (e.g. 
benzocaine, butylaminobenzoate, tetracaine 
hydrochloride,) with or without topical 
corticosteroids (i.e. triamcinolone oral paste).
Rationale for change
To be consistent with Section 1.2.1. 
Section to be changed
Section 5.1
Description of change
The primary aim of the trial is to establish the 
safety of the BI 860585 single agent, the safety of 
the combination of BI 860585 with exemestane or 
with paclitaxel in patients with various advanced 
and/or metastatic solid tumours, and to determine 
the MTD of the single agent treatment and the 
combination regimens. MTD will be measured
through DLT observed during the first treatment 
cycle. 
Was changed to:
There is no primary efficacy endpoint. The 
primary aim of the trial is to establish the safety 
of the BI 860585 single agent, the safety of the 
combination of BI 860585 with exemestane or 
with paclitaxel in patients with various advanced 
and/or metastatic solid tumours, and to determine 
the MTD of the single agent treatment and the 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 121 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
combination regimens. MTD will be measured 
through DLT observed during the first treatment 
cycle. 
In the expansion part, there is no primary 
efficacy endpoint, as the primary goal is the 
confirmation of safety with regard to the 
selected dose level(s) and treatment schedule 
(s) of BI 860585 in combination with 
exemestane or with paclitaxel.
Rationale for change
To clarify that there is no primary efficacy 
endpoint and to specify the primary endpoint for 
the expansion cohort.
Section to be changed
Section 5.2.1
Description of change
Any DLTs occurring after the start of the second 
cycle will be considered for the evaluation of the 
Recommended Phase II Dose (RP2D) of BI 
860585.  
Information about DLTs, AEs and other safety 
related will be collected and descriptively 
analysed for this purpose
Was changed to:
Any DLTs occurring after the start of the second 
cycle will be considered for the evaluation of the 
Recommended Phase II Dose (RP2D) of BI 
860585.
Any DLTs occurring in the expansion cohorts 
will be considered in the evaluation of the 
RP2D but will not lead to a change in MTD.
All information about DLTs, AEs and other 
safety related information occurring throughout 
the trial will be collected and descriptively 
analysed for this purpose
Rationale for change
To clarify that expansion cohorts safety data will 
contribute to definition of RP2D and that in 
general statistical analysis for safety data will be 
descriptive.
Section to be changed
Section 5.2.2.1
Description of change
The following additional adverse events of special 
interest have been added:
Hypertriglyceridemia


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 122 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Mucositis
Also
All CTCAE grades should be reported 
(including values obtained with home glucose 
monitoring device).
Rationale for change
To be consistent with section 1.2.1 and to clarify 
AESI CTCAE grades that should be reported.
Section to be changed
Section 5.2.3
Description of change
The following additional  biochemistry analysis
have been included:
total cholesterol, triglycerides
Rationale for change
To be consistent with Section 1.2.1 and 5.2.2.1.
Section to be changed
Section 5.2.3
Description of change
Biochemistry
Renal function will be monitored with GFR and 
serum creatinine and urea values and recorded in 
the eCRF. 
During Cycle 1, Creatinine clearance will be
measured through collection and analysis of 24-
hour urine at C1V1 and C1V4.
Was Changed to
Renal function will be monitored with GFR 
(MDRD formula) and serum creatinine and urea 
values and recorded in the eCRF. 
In addition, during Cycle 1, GFR will be 
estimated based on Creatinine clearance 
measured through collection and analysis of 24-
hour urine at C1V1 and C1V4.
Urine Examination
In case of abnormal findings, further evaluation 
should be performed and the findings 
documented. 
Was changed to:
In case of abnormal findings, these should be 
confirmed by an additional dipstick test 
followed by further investigations (e.g. 
microscopic examination, analysis of 24 hour 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 123 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
urine, creatinine measurements etc.) and 
findings documented.
Rationale for change
Clarification
Section to be changed
Section 5.3.3
Description of change
 
 
 
 
 
 
 
 
Rationale for change
Clarification
Section to be changed
Section 5.5.3.1
Section 5.5.3.2
Description of change
Authorized CRO indicated as a possible 
analytic site.
Rationale for change
To accommodate possible relocation of analytic 
site and prevent additional text amendment of 
protocol.
Section to be changed
Section 6.2
Description of change

PK profiles during Cycle 1 at Visits 1, 2, 3, 4 
and 5 (see Appendix 10.1.1). In case of drug 
related Grade 3 or 4 toxicity, every effort 
should be made to collect PK sample(s) 
together with ECGs. 
Was changed to

PK profiles during Cycle 1 at Visits 1, 2, 3, 4 
and 5 (see Appendix 10.1.1). In case of drug 
related Grade 3 or 4 toxicity, every effort 
should be made to collect additional PK 
sample(s) together with ECGs. 

In case of intra-patient dose escalation 
every effort should be made to collect 
additional PK sample(s) at the time points 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 124 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
indicated in Table 10.1.1:5. 
Rationale for change
To be consistent with Section 3.1.
Section to be changed
Section 6.2.2
Description of change
At the start of treatment, and during dose 
escalation, investigations and assessments will be 
performed as outlined in the Flow Chart and as 
per the description listed below:
Was changed to:   
At the start of treatment investigations and 
assessments will be performed as outlined in the 
Flow Chart and as per the description listed 
below:    
Rationale for change
To specify that visit schedule applies also to 
expansion phase.
Section to be changed
Section 6.2.2
Description of change
Safety lab parameters:
In Cycle 1 GFR analysis will be measured
through collection of 24-hour urine starting on 
Day 1 and Day 22.
Was changed to:
In Cycle 1 GFR analysis will be measured also
through collection of 24-hour urine starting on 
Day 1 and Day 21.
Rationale for change
To be consistent with Flow chart and section 
5.2.3.
Section to be changed
Section 7.1
Description of change
The following phrase was added:
Based on information from the dose escalation 
part of the study, approximately 60 additional 
patients with measurable disease will be 
treated at the MTD and/or relevant biological 
dose(s), in one or two expansion cohorts, in 
each of the combination arms.
In the expansion phase, the primary objective 
is to confirm the safety of the selected dose 
level; the secondary objectives are to explore 
the PK/PD profile and anti-tumour activity 
signal of BI 850585 in pre-selected patients.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 125 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
Rationale for change
To reflect new study design and patients numbers.
Section to be changed
Section 7.3.1
Description of change
The following phrase was added:
Expansion phase:
The primary analysis for the expansion phase 
of this study is to further explore DLTs, AEs 
and other safety related information to 
confirm the MTD and/ or relevant biological 
dose(s) determined in the dose finding phase.
Rationale for change
To reflect new study design
Section to be changed
Section 7.6
Description of change
The trial will be terminated as soon as the last 
patient has completed the last additional follow-
up visit documenting the disease progression  or 
the start of new treatment. In case patients would 
still be on treatment when the report of the trial is 
being performed, these patients will either be 
included in a follow-up trial or alternatively kept 
on treatment in this trial. In case the trial is ended 
by the sponsor when patients are still being 
treated with BI 860585, those patients will then 
be reported in a revised report and it will be noted 
in the original report that such a revised report 
will be written.
Was changed to:
The trial will be terminated as soon as the last 
patient entering the study has completed the last 
additional follow-up visit documenting the 
disease progression (clinical progression, 
progression according to RECIST version 1.1, 
death), start of new treatment or after 
receiving at least 4 cycles of BI 860585. In case 
patients would still be on treatment when the 
report of the trial is being performed, these 
patients will either be included in a follow-up trial 
or alternatively kept on treatment in this trial. 
These patients will then be reported in a revised 
report and it will be noted in the original report 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 126 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
that such a revised report will be written.
Rationale for change
To clarify time-point of final report.
Section to be changed
Section 9
Description of change
R14-1468, R14-1470 have been added as 
references.
Rationale for change
Update reference list.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 127 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
1
 
 
Section to be changed
Section 10.4
Description of change
MDRD formula indicated.
Rationale for change
To provide reference for section 5.2.3.
Section to be changed
Title page: TCM fax n.
Flow Chart Cycle 1  footnote U
Flow Chart Cycle 2 – footnote O
Abbreviations: MTD, SD, SOP, TCPK
Section 1.1 paragraph 5, 7and 8
Section 1.2.1 paragraph 7
Section 1.2.3 paragraph 2
Section 2.1 paragraph 4
Section 2.3 paragraphs 10 and 11
Section 3.1 paragraph 4, 5, 17 and 28
Section 3.1.1 paragraph 6
Section 3.3.3, criterium number 20
Section 3.3.4.3 – bullet point 3
Section  4.1.3 paragraph 9
Table 4.1.3 :1, 4th row
Section 4.1.4.1.1 –Non –Haematological Toxicity
Section 4.1.4.1.1 – last but one paragraph
Section 4.1.6 paragraph 3
Section 5.1.1
Section 5.2.1 Criteria defining a DLT
Section 5.6.2
Section 6.1 paragraph 3
Section 6.2.1 last row
Section 7.3.4 paragraph 2
Description of change
Typos
Rationale for change
Corrections
Number of global amendment
2


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 128 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Date of CTP revision
12 Feb 2015
EudraCT number
2013-000765-36
BI Trial number
1325.1
BI Investigational Product(s)
BI 860585
Title of protocol
An open label phase I dose finding study of BI 
860585 administered orally in a continuous 
dosing schedule as single agent and in 
combination with exemestane or with paclitaxel 
in patients with various advanced and/or 
metastatic solid tumours
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB/IEC/Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
Clinical trial protocol synopsis - Objectives
Description of change
The text 
 has been added
Rationale for change
For consistency within protocol.
Section to be changed
Clinical trial protocol synopsis – Methodology
Section 3.1
Description of change
The text “……one or more expansion cohorts in 
each combination arm” 
Was changed to:
“…… one or more expansion cohorts in each 
treatment arm”
Rationale for change
To reflect expansion cohort also in single agent 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 129 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
arm.
Section to be changed
Clinical trial protocol synopsis – No. of patients 
Section 3.1
Section 3.3
Section 7.6
Description of change
An additional 18 patients have been included in 
the sample size increasing the total number of 
patients from 150 to 168.
Rationale for change
To reflect the inclusion of expansion cohort in 
Arm A.
Section to be changed
Clinical trial protocol synopsis-
Section 2.2
Description of change
 
 
 
 
 
 
Section to be changed
Flowchart Cycle 1 
Table 10.1.1:1
Table 10.1.1:3
Table 10.1.1:4
Description of change
 
 
 
Section to be changed
Flowchart footnote Cycle 1
Description of change
 
 
 
  
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 130 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
Rationale for change
To be consistent with Appendix 10.1.
Section to be changed
Flowchart footnote Cycle 1
Description of change
Addition of the following footnote:
w. 
 
 
Rationale for change
Clarification
Section to be changed
Flowchart Cycle 1
Table 10.1.1:1
Table 10.1.1:3
Table 10.1.1:4
Description of change
 
 
 
Section to be changed
Flowchart footnote Cycle 1
Description of change
Addition of the following footnote: 
x. 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 131 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
 
 
 
 
 
Rationale for change
Clarification
Section to be changed
Flowchart footnote Cycle 2 and subsequent cycles
Description of change
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
Rationale for change
 
Section to be changed
Flowchart Cycle 1
Description of change
The following has been included:
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 132 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
Section to be changed
Flowchart Cycle 1
Description of change
The following additional footnote has also been 
included:  
y. For details please  refer to Section 5.3. 
Rationale for change
 
Section to be changed
Section 1.2.1
Section 2.3
Section 8.4.1
Section 9.2
Description of change
Inclusion of document number of Investigator’s 
Brochure: Doc. No: c02093461 .
Rationale for change
List of reference documents has been updated to 
include document number of Investigator’s 
Brochure and cross reference included within 
applicable protocol sections.
Section to be changed
Section 2.2
Description of change
The following text:
The safety profile of BI 860585 in combination 
with exemestane and paclitaxel will further be 
evaluated at the recommended dose(s) and 
schedule(s) [MTD and/or relevant biological 
dose(s)] in patients with various tumour types (i.e. 
expansion cohorts).
Was changed to:
The safety profile of BI 860585 will further be 
evaluated at the recommended dose(s) and 
schedule(s) [MTD and/or relevant biological 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 133 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
dose(s)] in patients with various tumour types (i.e. 
expansion cohorts).
Rationale for change
To reflect inclusion of expansion cohort in single 
agent treatment arm.
Section to be changed
Section 1.2.1
Section 2.3
Description of change
The following text has been added: An in vitro 
local tolerance study using human skin 
constructs classified BI 860585 (the succinate 
salt) as being irritant to the skin.
Rationale for change
An update was provided in the nonclinical 
Section 5.3 (Toxicology) of the Investigator’s 
brochure, mentioning the result of a worker 
safety-related in-vitro human skin irritation test, 
which predicted BI 860585 (as the succinate salt) 
as being irritant to the skin .
Section to be changed
Section 2.3
Section 4.2.
Description of change
The following text has been added: 
Cancer patients participating in BI 860585 
clinical trials should avoid direct exposure of 
the unprotected skin and eye to sunlight or 
equivalents for a period of one week after the 
last administration of BI 860585.
In addition:
Nisoldipine (a calcium channel blocker) and 
HMG CoA-reductase inhibitors (such as 
lovastatin, simvastatin, and atorvastatin), 
metabolized by CYP 3A4, are predicted as 
high risk for increased exposure. Their 
concomitant use during treatment with BI 
860585 should be avoided and replaced by an 
alternative drug. If their concomitant use 
cannot be avoided and no alternative is 
available then  the prescribed dose should be 
reduced by half with close monitoring for 
potential adverse reactions”. 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 134 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Rationale for change
To reflect new information from Investigator 
Brochure  update ( version n. 2) concerning 
additional toxicology information and  drug-
drug interaction risk assessment.
Section to be changed
Section 3.1 
Figure 3.1:1
Description of change
The following text :
In principle no expansion cohort is foreseen for
Arm A. However, once MTD is determined, 
should any patient with a specific tumour type 
(e.g. Pancreatic Neuroendocrine Tumour - pNET) 
derive benefit during the dose escalation
portion of the study and should the investigators 
ask to have patients with similar characteristics 
included in the trial (provided the study is still in 
the enrolling phase), a maximum of 12 patients 
might still be included in the MTD level on a case 
by case basis and after discussion with the 
sponsor”.
Was cancelled and  has been replaced with the 
following: 
Once MTD is determined, an expansion cohort 
of approximately 18 patients  will be included 
in the MTD level. 
Rationale for change
To reflect inclusion of expansion cohort in Arm A 
and update Figure accordingly.
Section to be changed
Section 3.1
Section 3.3.4.3
Description of change
The following indication has been included: 
Patients will be replaced if more than 7 doses 
of  exemestane or more than one dose of 
paclitaxel are missed during their first 
treatment cycle”.
Rationale for change
To provide guidance on patient replacement in 
case of interruption of exemastane or paclitaxel 
during Cycle 1.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 135 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
    
 
 
  
 
Section to be changed
Section 3.1
Description of change
The following text:


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 136 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
In addition, if considered appropriate by the 
investigator and the sponsor, patients in the 
expansion cohorts, may undergo FDG-PET 
assessment during their participation in
the trial, in order to evaluate their metabolic 
response to treatment. (R14-1468 , R14- 1470) .
Was changed to: 
In addition, if considered appropriate by the 
investigator and the sponsor, patients in the 
expansion cohorts, may undergo FDG-PET 
assessment at baseline and during their 
participation in the trial, in order to evaluate their 
metabolic response to treatment (see Flowchart)
(R14-1468 , R14-1470)
Rationale for change
To be consistent with flow chart.
Section to be changed
Section 3.1
Section 5.2.2.2
Description of change
The text:
All adverse events with onset within 28 days after 
the last administration of BI 860585 are
considered as on treatment.
Was changed to:
All adverse events with onset within 28 days after 
the last study drug administration are considered 
as on treatment.
Rationale for change
To indicate that treatment with study medication 
indicates any of the investigational drugs used in 
the study i.e BI 860585, paclitaxel or exemastane.  
Section to be changed
Section 3.1.1
Description of change
The following text:
 
 
 
 
Was changed to: 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 137 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
 
Section to be changed
Section 3.2
Description of change
The following text:
“…….anti-tumour activity in patients with 
multiple tumour types in which treatment with BI 
860585 in combination with exemestane or BI 
860585 in combination with paclitaxel may give 
clinical benefit”.
Was Changed to:
“……anti-tumour activity in patients with 
multiple tumour types in  whom treatment with 
BI 860585, in monotherapy or in combination 
with exemestane or in combination with 
paclitaxel, may give clinical benefit.  
Rationale for change
To reflect inclusion of expansion cohort in single 
agent treatment arm.
Section to be changed
Section 3.3.2
Section 3.3.3
Description of change
The following inclusion criteria: 
8. Patients carrying a tumour for whom 
treatment with either exemestane or paclitaxel 
would be considered appropriate.
Has been changed to:
8. Patients carrying a tumour for whom 
treatment with either exemestane or paclitaxel 
would be considered appropriate by the 
investigator.
The following exclusion criteria has been 
modified : 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 138 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
15. Patients with HIV/hepatitis/active infectious 
disease considered by the investigator to
be incompatible with the protocol;
Was changed to:
15.
Patients with known HIV/hepatitis/active 
infectious disease considered by the investigator 
to be incompatible with the protocol;
In addition,  the following inclusion criteria has 
been added:
10.Patients entering the expansion cohorts 
must also have:
-
Arm A: any advanced/metastatic solid 
tumour suitable for biopsy and must 
have provided informed consent for 
biopsy and biomarker analysis.
-
Arm B: any cytologically or 
histologically confirmed ER+ (estrogen 
receptor positive) advanced/metastatic 
solid tumours for which treatment with 
exemestane would be considered 
appropriate by the investigator.
-
Arm C: any advanced/metastatic solid 
tumour for which treatment with 
paclitaxel would be considered 
appropriate by the investigator.
Rationale for change
To clarify inclusion and exclusion criteria.  In 
addition, tumour types  to be included in the 
expansion cohorts have been specified. 
Section to be changed
Section 4.4.4.1.1
Description of change
The following text:
In case of BI 860585 treatment-related adverse 
events and/or DLT, study medication may
have to be discontinued temporarily.
Patients with DLT or treatment-related toxicities 
may continue therapy only after recovery
from the event to baseline or CTCAE Grade 1 and 
only with a reduced dose of BI 860585.
Was changed to:


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 139 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
In case of BI 860585 treatment-related adverse 
events study medication may have to be 
discontinued temporarily. In case of DLT study 
medication must be interrupted.
Patients with DLT or treatment-related toxicities 
may continue therapy only after recovery from 
the event to baseline or CTCAE Grade 1.  In case 
of DLT, therapy should continue only with a 
reduced dose of BI 860585.
Rationale for change
To clarify and for consistency within protocol.
Section to be changed
Table 4.1.4.1.1:1
Description of change
Title: Recommendations for dose modifications 
Was changed to:
Title: Recommendations for dose modifications 
of BI 860585 treatment related toxicities
Rationale for change
To clarify that recommendations on dose 
modifications are for BI 860585 related toxicities.
Section to be changed
Table 4.1.4.1.1:1
Description of change
The following text:
Haematological toxicity
CTCAE Grade 4 neutropenia
CTCAE Grade 3 neutropenia lasting ≥ 7 days;
CTCAE Grade ≥3 Febrile neutropenia; 
CTCAE Grade ≥ 3 documented infection with 
neutropenia
CTCAE Grade 3 thrombocytopenia lasting ≥ 7 days;
CTCAE Grade 4 thrombocytopenia; 
CTCAE Grade ≥ 3 anaemia
Non-Haematological toxicity
(Diarrhoea/Nausea/Vomiting )
CTCAE Grade ≥ 2 nausea and/or vomiting persisting
for 7 consecutive days despite antiemetic treatment/ 
hydration.
Non-Haematological toxicity
CTCAE Grade ≥ 3 non-haematological
toxicity( example stomatitis, rash, mucositis, 
pneumonitits, hyperglycaemia, hypercholesterolaemia)
Liver toxicity
CTCAE Grade ≥ 3 AST/ALT:
AST and /or ALT > 5x ULN (if baseline value < 
3x ULN)


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 140 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
                              or
AST and /or ALT > 10x ULN (if baseline value 
>3-5x ULN);
CTCAE Grade ≥ 2 total bilirubin:
       total bilirubin ≥ 2x ULN
Interrupt BI 860585 until AST and ALT ≤ 5x ULN 
and total bilirubin ≤ 1.5x ULN, start with BI 860585 at 
the dose level immediately below the
current dose.
Was changed to:
Haematological toxicity
CTCAE Grade 4 neutropenia lasting ≥ 7 days;
CTCAE Grade ≥ 3 documented infection with 
neutropenia; 
CTCAE Grade ≥3 febrile neutropenia; 
CTCAE Grade 3 thrombocytopenia associated 
with bleeding requiring transfusion; 
CTCAE Grade 4 thrombocytopenia; 
CTCAE Grade 4 anaemia
Non-Haematological toxicity
(Diarrhoea/Nausea/Vomiting )
CTCAE Grade 2 nausea and/or vomiting 
persisting for 7 consecutive days despite 
antiemetic treatment/ hydration
Non-Haematological toxicity
CTCAE Grade ≥ 3 non-haematological toxicity 
despite the use of adequate/maximal medical 
interventions and or prophylaxis as dictated by 
local institutional clinical practices or the 
judgment of the investigator (example 
stomatitis, rash, mucositis, pneumonitits, 
hypercholesterolaemia) 
Any Grade 3 hyperglycaemia that does not 
recover to Grade ≤ 1 within two weeks of 
adequate therapy
Liver toxicity
Drug-induced liver injury (DILI) as described 
in section 5.2.2.1


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 141 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
ALT ≤ 5x ULN (baseline) and total bilirubin ≤ 
1.5x ULN, start with BI 860585 at the dose level 
immediately below the current dose.
Rationale for change
To be consistent with  updated DLT definitions  
as well as simplify management of BI 860585 
dose modifications in case of liver toxicity/DILI. 
Section to be changed
Section 5.1
Description of change
The following text:
In the expansion part, there is no primary efficacy 
endpoint, as the primary goal is the confirmation 
of safety with regard to the selected dose level(s) 
and treatment schedule (s) of BI 860585 in 
combination with exemestane or with paclitaxel.
Was changed to:
In the expansion part, there is no primary efficacy 
endpoint, as the primary goal is the confirmation 
of safety with regard to the selected dose level(s) 
and treatment schedule (s) of BI 860585 in 
monotherapy and in combination with 
exemestane or with paclitaxel.
Rationale for change
To reflect inclusion of expansion cohort in single 
agent treatment arm.
Section to be changed
Section 5.2
Description of change
The following text:
The following will qualify as a dose limiting toxicity:

Any drug-related Grade ≥3 toxicity according to 
CTCAE version 4.03 not related to progressive 
disease occuring during the first cycle period (with 
exceptions and provisions noted below, 
hyperglycemia to be treated with metformin). 

Any drug-related toxicity not related to 
progressive disease that results in a greater than 14 
days delay in Cycle 2 Day 1 dosing will also be 
considered a DLT. 
Toxicity 
category
Criteria defining a DLT


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 142 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Haematologic

CTCAE Grade  4 neutropenia 

CTCAE Grade  3 neutropenia 
lasting ≥ 7 days

Febrile neutropenia CTCAE Grade 
≥ 3 

CTCAE Grade 3 thrombocytopenia 
lasting ≥ 7 days  

CTCAE Grade 4 thrombocytopenia 

CTCAE Grade ≥ 3 anaemia
Non 
hematologic

Any Grade ≥ 3 toxicities despite 
the use of adequate/maximal 
medical interventions and or 
prophylaxis as dictated by local 
institutional clinical practices or the 
judgment of the investigator

Any Grade 2 hyperglycaemia that 
does not recover to Grade ≤ 1 
within a week of adequate therapy 
Re-Treatment 
Delay

Any toxicities that result in a > 14 
days delay in Cycle 2 Day1 dosing
Was changed to.
The following will qualify as a dose limiting toxicity:
Related 
toxicity 
category
Criteria defining a DLT
Haematologic

CTCAE Grade  4 neutropenia 
lasting ≥ 7 days

CTCAE Grade ≥ 3 
documented infection with 
neutropenia

CTCAE Grade ≥ 3 febrile 
neutropenia 

CTCAE Grade 3 
thrombocytopenia associated 
with bleeding requiring 
transfusion

CTCAE Grade 4 
thrombocytopenia 

CTCAE Grade  4 anaemia
Non 
hematologic

Any Grade ≥ 3 non hematologic
toxicities despite the use of 
adequate/maximal medical 
interventions and or prophylaxis 
as dictated by local institutional 
clinical practices or the judgment 
of the investigator

Any Grade 3 hyperglycaemia 
that does not recover to Grade ≤ 
1 within two weeks of adequate 
therapy 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 143 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Re-Treatment 
Delay

Any toxicities that result in a > 
14 days delay in Cycle 2 Day1 
dosing
Rationale for change
DLT criteria have been modified.
Section to be changed
Section 5.2.2.1
Description of change
Adverse events - The following text was added:
An AE can therefore be any unfavourable and 
unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal 
product, whether or not considered related to the 
medicinal product.
Serious adverse event - The following text was 
added:
Life-threatening in this context refers to an event 
in which the patient was at risk of death at the 
time of the event; it does not refer to an event 
that hypothetically might have caused death if 
more severe.
Every new occurrence of cancer will be reported 
as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence 
of the cancer.
Causal relationship of adverse event - The
following text was added:
The causal relationship must be provided by the 
Investigator for all potential trial drugs, i.e. the 
BI trial drug and for all other trial drugs (such 
as any active comparator or placebo and for trial 
procedure). 
The reason for the decision on causal 
relationship needs to be provided in the (e)CRF 
and on the SAE form (if applicable).
Rationale for change
To reflect updated SOP CTP template.
Section to be changed
Section 5.2.2.1


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 144 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Description of change
The following text:
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.
If progressive disease occurs and is associated 
with symptoms or meets one of the seriousness 
criteria, the verbatim “Malignant neoplasm 
progression” should not be reported, instead the 
signs and symptoms of progressive disease will 
be reported as an adverse event or a serious AE (if 
applicable). The only exception to the above is in 
the event of death when attributed to progressive 
disease and where signs or symptoms are not 
available. In this situation it is acceptable to 
report the progression as the serious AE.
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.
Was changed to:
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 and SAE form (if 
applicable).
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 and SAE form 
(if applicable), if they are judged clinically 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 145 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
relevant by the investigator.
If such abnormalities already pre-exist prior 
trial inclusion they will be considered as baseline 
conditions.
Rationale for change
To reflect updated SOP CTP template.
Section to be changed
Section 5.2.2.1
Description of change
The following:
Hepatic injury is defined by the following 
alterations of liver parameters: 

For patients with normal liver function at 
baseline:
an elevation of AST and/or ALT ≥ 3 fold 
ULN combined with an elevation of total 
bilirubin ≥ 2 fold ULN measured in the 
same blood draw sample
Patients showing these lab abnormalities 
need to be followed up according to 
Appendix 10.2 of this CTP and the “DILI 
checklist” provided in ISF.

For patients with impaired function tests at 
baseline:
an elevation of AST and/or ALT ≥ 5 fold 
ULN combined with an elevation of 
bilirubin ≥ 2 fold ULN measured in the 
same blood draw sample.  Patients 
showing these lab abnormalities need to 
be followed up according to Appendix 
10.2 of this CTP and the "DILI checklist" 
provided in the ISF.
Was Changed to:
Hepatic injury is defined by the following 
alterations of liver parameters: 
For patients with normal liver function at 
baseline:

an elevation of AST and/or ALT ≥ 3 fold 
ULN combined with an elevation of total 
bilirubin ≥ 2 fold ULN measured in the same 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 146 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
blood draw sample and/or

Marked peak aminotransferase (ALT, 
and/or AST) elevations ≥10 fold ULN 
For patients with impaired function tests at 
baseline:

an elevation of AST and/or ALT ≥ 5 fold 
ULN combined with an elevation of bilirubin ≥ 2 
fold ULN measured in the same blood draw 
sample, and/or

Marked peak aminotransferase (ALT, 
and/or AST) elevations ≥10 fold ULN 
These lab findings constitute a hepatic injury 
alert and the patients showing these lab 
abnormalities need to be followed up according 
the "DILI checklist" provided in the ISF. In case 
of clinical symptoms of hepatic injury (icterus, 
unexplained encephalopathy, unexplained 
coagulopathy, right upper quadrant 
abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the 
investigator should make sure these 
parameters are analysed, if necessary in an 
unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist 
should be followed.
For patients experiencing a DILI/ potential 
DILI study medication should be interrupted 
and investigators should contact sponsor for 
guidance.
Rationale for change
To reflect updated SOP CTP template and 
Sponsor Guideline for Processing of Potential 
Drug-Induced Liver Injury in Clinical Trials.
Section to be changed
Section 5.2.2.2
Description of change
The following text: 
Investigators may report SAEs which occur to a 
subject after the follow-up period, if the 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 147 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
investigator becomes aware of them.
Was changed to:
After the last per protocol contact (i.e. after 
follow-up period) the investigator does not 
need to actively monitor patients for AEs. 
However, if the investigator becomes aware of 
SAEs or AESIs that occurred after the last per 
protocol contact, the SAEs and AESIs should 
be reported by the investigator to the sponsor 
if considered relevant by the investigator
Rationale for change
To reflect updated SOP CTP template.
Section to be changed
Section 5.2.2.2  
Description of change
The following text:
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. For follow-up information the 
same rules and timeline apply as for initial 
information.
Was changed to:
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. For follow-up information the 
same rules and timeline apply as for initial 
information.
In addition the following was added:
Screening failures: 
SAEs occurring in patients after having 
discontinued in the trial due to screening 
failures, i.e. after the screening period and who 
did not receive any trial medication, are to be 
reported if the Investigator considered the 
SAE related to the screening procedure. SAEs 
which occurred during the screening period 
are to be reported according to standard 
procedures.


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 148 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Rationale for change
To reflect updated SOP CTP template.
Section to be changed
Section 5.2.2.2
Description of change
The following text:
Drug exposure during pregnancy has to be 
immediately reported (within 24 hours or next 
business day whichever is shorter) to the defined 
unique entry point for SAE forms of the 
respective BI OPU (country-specific contact 
details will be provided in the ISF).
Was changed to:
Drug exposure during pregnancy has to be 
immediately reported (within 24 hours) to the 
defined unique entry point for SAE forms of the 
respective BI OPU (country-specific contact 
details will be provided in the ISF)
Rationale for change
To reflect updated SOP CTP template.
Section to be changed
Section 5.2.3
Description of change
The following have been added to assessment of 
safety laboratory parameters :
Fasting Glucose
Magnesium  
gamma glutamyl transferase (GGT).
Rationale for change
To specify that glucose measurements should be 
done during fasting and include additional 
analysis for monitoring of liver function and .
Section to be changed
Section 5.3.3
Description of change
The following text:
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 149 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Was replaced with:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 150 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
Section 5.6
Description of change
The following text :
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 151 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
Section 5.6.2
Description of change
The following test was added:


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 152 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 153 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
 
 
 
Section to be changed
Section 6.2.1
Description of change
 
 
 
 
Section to be changed
Section 6.2.1
Description of change
The following;
Evaluable disease, or at least one measurable 
lesion  according to RECIST criteria version 1.1
(R09-0262), including review of information to 
confirm progressive disease. 
Was change to;
Evaluable disease, or at least one measurable 
lesion (measurable lesions are mandatory for 
expansion cohorts) according to RECIST criteria 
version 1.1 (R09-0262), including review of 
information to confirm progressive disease. 
Rationale for change
To ensure consistency with inclusion criteria 9.
Section to be changed
Section 6.2.1
Description of change
The following has been added:
 
 
  
 
 
  


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 154 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
Section 6.2.4
Description of change
The following text:
The study is completed once the last patient of the 
study has experienced at least one of the 
following:
Has been treated for at least 4 cycles
Disease progression
Withdrawal from treatment due to a drug related 
adverse event
Fatal event


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 155 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
Lost to follow-up
Withdrawal of consent
Start of other anti-cancer treatment
Information about the planned time-point for final 
report analysis can be found in Section 7.6.
Was changed to:
The study will be analyzed and reported once 
the last patient of the study has experienced at 
least one of the following:

Has been treated for at least 4 cycles

Disease progression

Withdrawal from treatment due to a drug 
related adverse event 

Fatal event

Lost to follow-up

Withdrawal of consent

Start of other anti-cancer treatment
In case patients are still being treated with 
study medication when the final report of the
trial is being prepared, these patients will be 
kept on treatment in the trial  and  will then be 
reported in a revised report.  It will be noted in 
the original report that such a revised report 
will be written.
The trial will be terminated as soon as the last 
patient ending treatment has completed the 
first follow-up visit.
Rationale for change
To clarify time point for trial analysis and overall 
study termination.
Section to be changed
Section 7.1
Description of change
The following text:
Based on information from the dose escalation 
part of the
study, approximately 60 additional patients with 
measurable disease will be treated at
the MTD and/or relevant biological dose(s), in 
one or two expansion cohorts, in each of
the combination arms.
In the expansion phase, the primary objective is to 
confirm the safety of the selected


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 156 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
dose level; the secondary objectives are to explore 
the PK/PD profile and anti-tumour
activity signal of BI 850585 in pre-selected 
patients.
Was changed to:
Based on information from the dose escalation 
part of the study, an overall approximately 78
additional patients with measurable disease will 
be treated at the MTD and/or relevant biological 
dose(s), in one or two expansion cohorts, in each 
treatment arm. In the expansion phase, the safety 
of the selected dose level will further be 
evaluated; the secondary objectives are to 
explore the PK/PD profile, anti-tumour activity 
signal of BI 850585 in pre-selected patients
 
 
Rationale for change
To be consistent with trial design and objectives.
Section to be changed
Section 7.3.6
Description of change
The following text was added:
More details will be specified in the core 
TSAP.
Rationale for change
 
Section to be changed
Section 7.3.7
Description of change
The following text:
Not applicable to this study.
Was replaced with:
 
 
Section to be changed
Section 7.6
Description of change
The following text:
The trial will be terminated as soon as the last 
patient entering the study has completed the
last additional follow-up visit documenting the 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 157 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
disease progression (clinical progression,
progression according to RECIST version 1.1, 
death) or the ,start of new treatment or
after receiving at least 4 cycles of BI 860585. In 
case patients would still be on treatment
when the report of the trial is being performed, 
these patients will either be included in a
follow-up trial or alternatively kept on treatment 
in this trial. In case the trial is ended by the
sponsor when patients are still being treated with 
BI 860585, those These patients will then
be reported in a revised report and it will be noted 
in the original report that such a revised
report will be written.
Was changed to :
The trial will be terminated as soon as the last 
patient ending treatment has completed the 
first follow-up visit.  
Rationale for change
To clarify the time point of overall trial 
termination.
Section to be changed
Section 8.4.1
Description of change
The following has been added:
For exemestane or paclitaxel this is the SPC. 
The current versions of these reference 
documents are provided in the ISF. No AE are 
classified as listed for trial design or invasive 
procedures.
Rationale for change
To update as SOP CTP template, to include 
reference document for listedness of combination 
drugs.
Section to be changed
Table 10.1.1:1
Description of change
 
 
 
 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 158 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for change
 
 
Section to be changed
Table 10.1.1:3
Table 10.1.1:4
Description of change
The following additional samples and footnotes 
have been included:
 
 
 
 
nt 
regimen (last treatment before the study drug is 


Boehringer Ingelheim
13 Feb 2015
BI Trial No.: 1325.1
Doc. No.: c01837011-07
Trial Protocol
Page 159 of 159
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
Number of global amendment
2
 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01837011
7.0
clinical-trial-protocol-revision-02
An open label phase I dose finding study of BI 860585 administered orally in a
continuous dosing schedule as single agent and in combination with exemestane or
with paclitaxel in patients with various advanced and/or metastatic solid tumours.
Approval-Archive
13 Feb 2015 16:46 CET
Approval-Team Member Medicine
13 Feb 2015 16:55 CET
Author-Pharmacokinetics
13 Feb 2015 17:17 CET
Author-Trial Statistician
16 Feb 2015 08:11 CET
Approval-Therapeutic Area 
17 Feb 2015 08:50 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01837011
7.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02325889-03
BI Trial No.:
1325.1
Title:
An open label phase I dose finding study of BI 860585 administered 
orally in a continuous dosing schedule as single agent and in 
combination with exemestane or with paclitaxel in patients with 
various advanced and/or metastatic solid tumours
Including Protocol Amendment 2 (c01837011-07)
Investigational
Product(s):
BI 860585
Responsible trial 
statistician(s):
Phone: 
Fax:     
Date of statistical 
analysis plan:
17 AUG 2016 SIGNED
Version:
“Revised” 
Page 1 of 36
Proprietary confidential information
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 2 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINT(S)........................................................................................9
5.1
PRIMARY ENDPOINT(S) .................................................................................9
5.2
SECONDARY ENDPOINT(S) ...........................................................................9
5.2.1
Key secondary endpoint(s) .............................................................................9
5.2.2
Secondary endpoint(s).....................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................13
6.1
TREATMENT(S)...............................................................................................13
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................14
6.3
PATIENT SETS ANALYSED..........................................................................16
6.5
POOLING OF CENTRES ................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................17
7.
PLANNED ANALYSIS.......................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........19
7.4
PRIMARY ENDPOINT(S) ...............................................................................20
7.5
SECONDARY ENDPOINT(S) .........................................................................21
7.5.1
Key secondary endpoint(s) ...........................................................................21
7.5.2
(Other) Secondary endpoint(s).....................................................................21
7.8
SAFETY ANALYSIS.........................................................................................22
7.8.1
Adverse events ...............................................................................................22
7.8.2
Laboratory data.............................................................................................25
7.8.3
Vital signs.......................................................................................................26
7.8.4
ECG ................................................................................................................27
8.
REFERENCES.....................................................................................31


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 3 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE...............................................................................33


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 4 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF TABLES
Table 6.2: 1
Description of PVs ..........................................................................................14
Table 10: 1
History table ....................................................................................................34


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 5 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
BMI
Body Mass Index
BRPM
Blinded Report Planning Meeting
BSA
Body Surface Area
CR
Complete Response
CT
Concomitant Therapy
CTC
Common Terminology Criteria  
CTP
Clinical Trial Protocol
DBLM
Database Lock Meeting
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End of Active Treatment
EoT
End of Text
ES
Enrolled Set
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
LLT
Lowest Level Term
LVSI
Laboratory Values of Special Interest
MTD
Maximum Tolerated Dose
MedDRA
Medical Dictionary for Regulatory Activities


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 6 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Term
Definition / description
MQRM
Medical Quality Review Meeting
O*C
Oracle Clinical
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
PR
Partial Response
PT
Preferred Term
PV
Protocol Violation
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RPM
Report Planning Meeting
SCR
Screened Set
SD
Stable Disease
SDL
Subject Data Listing
StD
Standard Deviation
SOC
System Organ Class
TCM
Trial Clinical Monitor
TES
Treated and Evaluable Set
TOC
Table of Contents
TMW
Trial Medical Writer
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 7 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, the purpose of this document is 
to provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, and to include detailed procedures for executing the statistical 
analysis of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
The TSAP describes the analyses of this dose finding study.
In the following, study medication refers to BI 860585 in Arm A, to BI 860585 or 
exemestane in Arm B, and to BI 860585 or paclitaxel in Arm C. 
SAS® Version 9.4 (or higher) will be used for all analyses.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 8 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Due to stopping the project, the initially planned expansion cohorts are for the moment not 
planned to be recruited. Therefore, analyses for the expansion cohorts as stated in the CTP 
will not be described in this TSAP. All analyses on the dose finding part will be performed as 
planned, besides the derivation corrected in the following paragraph.
Duration of disease control (CR/PR/SD) has been defined in the CTP as time from first 
clinical benefit to progression or death (CTP Section 5). However, the correct derivation is 
different. In the analysis of this study, duration of disease control is defined from first 
treatment administration until the earliest of disease progression or death, amongst patients 
with disease control.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 9 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
ENDPOINT(S)
All endpoints are comprehensively defined in CTP Section 5.
5.1
PRIMARY ENDPOINT(S)
The primary objective of the trial is the determination of the maximum tolerated dose (MTD)
of BI 860585 monotherapy and in combination with either exemestane or paclitaxel based on
the number of patients with dose limiting toxicities (DLTs) during the MTD evaluation
period. 
MTD is defined as the highest dose studied for which the incidence of DLT is none out of 
three or less than 2 out of 6 patients. The MTD will be derived separately for patients in each
treatment arm. For the definition of DLT, see Section 5.2.1 of the CTP.
The MTD will be defined on the basis of DLT observed during the first 28 (28+1) in case the
last visit of the first cycle is done on the same day as the first visit of the second cycle) days
of treatment only excluding patients who were replaced during the MTD evaluation period.
The MTD evaluation period starts after the run-in phase (in case of combination arms) and 
with the first administration of study medication and ends after the first treatment cycle (28 
days).
Primary endpoints:

MTD in each treatment arm (based on number of DLTs in first course (28 days) of 
each treatment arm). 

Number of patients with DLTs in first course of each treatment arm.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)

Objective response rate (complete response (CR), partial response (PR) per RECIST 
criteria version 1.1): Objective response is defined as best overall response of CR or 
PR, where best overall response is determined according to RECIST1.1 recorded from 
date of first treatment administration until the earliest of disease progression, death, or 
last adequate tumour assessment before new anti-cancer therapy. Objective response 
rate is defined as the proportion of patients with CR or PR.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 10 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Disease control rate/clinical benefit rate (CR/PR/stable disease (SD), per RECIST 
criteria version 1.1): Disease control is defined as best overall response of CR or PR
or SD, where best overall response is defined according to RECIST 1.1 recorded from
date of first treatment administration until the earliest of disease progression, death or 
last adequate tumour assessment before new anti-cancer therapy. Disease control rate 
is defined as the proportion of patients with CR, PR, or SD.

Duration of objective response (CR/PR per RECIST) is derived for patients with 
objective response, defined as time from first objective response to the time of 
progression or death, whatever occurs first.
Derivation of duration of objective response:
For patients with objective response and with disease progression or death:

Duration of objective response [days] = date of outcome – date of first 
assessment indicating objective response + 1.
For patients with objective response and without disease progression or death:

Duration of objective response (censored) [days] = date of outcome – date 
of first assessment indicating objective response + 1.
Only radiological assessments after first assessment indicating objective response 
should be taken into consideration. For patients without disease progression or death, 
duration of OR will be censored on the date of the last radiological assessment before 
the data cut-off. In case patients initiated other anti-cancer therapies, the duration of 
OR will be censored on the date of the last radiological assessment before the start 
date of the other anti-cancer therapy. 

Duration of disease control (CR/PR/SD), defined as time from first treatment
administration until the earliest of disease progression or death, amongst patients with 
disease control.
Derivation of duration of disease control:
For patients with disease progression or death:

Duration of disease control [days] = date of outcome – date of first 
treatment administration + 1.
For patients without disease progression or death:

Duration of disease control (censored) [days] = date of outcome –
date of first treatment administration + 1.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 11 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
For patients without disease progression or death, duration of disease control will be 
censored on the date of the last radiological assessment before the data cut-off. In case 
patients initiated other anti-cancer therapies, the duration of DC will be censored on 
the date of the last radiological assessment before the start date of the other anti-
cancer therapy.

AUC0-24(ss), AUC0-∞, t1/2(ss), tmax(ss) and Cmax(ss) of BI 860585 administered as single 
agent and with combination agents. 
SD refers to confirmed SD, which means that the response evaluation should record SD twice 
after baseline. Non-CR/Non-PD for patients that only have non-target lesions at baseline will 
be merged to SD in the CTR.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 12 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 13 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
Treatments are not randomised. Data will be displayed by patient for each arm separately, 
and summarized by initial assigned dose level and arm. Additionally totals by arms will be 
shown. To justify the MTD determination, DLTs occurring during the MTD evaluation 
period will be presented separately from those occurring during the complete on-treatment 
period.
The three treatment arms will follow separate fixed dose-escalation designs with dose de-
escalation steps:

Arm A will be a 3+3 dose-escalation design (multiple ascending doses of BI 860585 
administered continuously in a 28-day cycle) in patients with unselected solid 
tumours who progressed before inclusion. 

Arm B will be a 3+3 dose-escalation design with BI 860585 being administered in 
multiple ascending doses in combination with fixed dose exemestane in patients with 
progressed metastatic disease and in whom the administration of exemestane may be 
considered as appropriate. This arm will only start recruiting once the combination
starting dose of BI 860585 has been fixed (see CTP Section 3.1). 

Arm C will be a 3+3 dose-escalation design with BI 860585 being administered in 
multiple ascending doses in combination with fixed dose paclitaxel at initial 75% of 
standard dose followed by standard combination dose, in patients with progressed 
metastatic disease in whom the administration of paclitaxel may be considered as 
appropriate. This arm will start recruiting only once the combination starting dose of 
BI 860585 has been fixed (same as Arm B). 
The on-treatment period is defined from the first administration of any trial medication until 
the end of the residual effect period (REP, 28 days).
The screening period ranges from the date of informed consent until the date of initial 
administration of any study medication.  
Follow-Up period starts with the end of the REP (date of last administration of trial 
medication +28 days + 1 day) and ends with the last per-protocol contact.
For the on-treatment period and the MTD evaluation period, the initial trial medication 
assigned at the beginning of the first treatment cycle will be used as the label of the analysing 
treatment.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 14 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.2
IMPORTANT PROTOCOL VIOLATIONS
Due to the fact that this is a Phase I study, no per protocol population is defined, however 
important protocol violations (IPVs) should be identified for patients in the treated set (any 
protocol violation which may affect safety or efficacy evaluation).
Data discrepancies and deviations from the CTP will be identified for all treated patients. 
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the medical quality review meetings (MQRMs), e.g. deviations in drug 
administration, in blood sampling etc. At these meetings, it will be decided whether the 
discrepant data can be used as they are or whether the data have to be corrected in the clinical 
database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
patients or if it can potentially influence the primary outcome measure(s) for the respective 
patients in a way that is neither negligible nor in accordance with the study objectives. This 
last category of important PV forms the basis for the decision of whether a patient does or 
does not belong to a specific analysis set. PVs that do not influence the patient's rights and 
safety or the evaluability of the patients for the main study objectives are called non-
important PVs. These are only considered when checking the trial quality in general. 
If any manual important PVs are identified, they are to be summarised into categories and 
will be captured in the MQRM/RPM minutes via an accompanying Excel spreadsheet 001-
MCS-50-413_RD-02 (7). The following table (Table 6.2: 1) contains the categories which are 
considered to be possible important protocol violations in this trial. 
Table 6.2: 1
Description of PVs
Category/
Code
Description
Comment/Example
Excluded from
A
Inclusion/Exclusion Criteria
A1
Criteria related to safety
A1.11
Patient has condition that may cause 
additional risk from study medication
EX 21 and 22
None
A1.21
Patient has laboratory assessments 
that may cause additional risk.
EX 6-10
None
A1.31
Patient is unable to comply with the 
protocol
EX 13
None
A1.41
Patient has condition that may 
interfere with evaluation of safety 
(and/or efficacy)
EX 1-3, EX 15, EX 18-20
None
A2
Criteria related to efficacy


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 15 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Category/
Code
Description
Comment/Example
Excluded from
A2.11
Patient does not have trial diagnosis 
or is not part of the target population
IN 1-4, IN 6, EX 1
None
B
Legal criteria
B11
Informed consent not available/not 
done
IN 5
All
B21
Informed consent after visit 1
IN 5
None
B31
Men or women who are sexually 
active and not using adequate 
contraception.
EX 12
None
B41
Pregnant or nursing female patient
EX 11
None
B51
Patient’s age < 18
IN 3
None
C
Administration of trial medication 
not in accordance with the protocol
C12
Administration of trial medication 
not in accordance with the protocol
Create listing, decision at 
MQRM/RPM
None
C22
Dose reduction scheme not according 
to protocol (Section 4.1.4)
Include two situations: no 
adjustment when required and 
adjustment when not required. A 
listing will be created and
decision made at MQRM/RPM.
None
C32
Unjustified intra-patient dose-
escalation
Create listing, decision at 
MQRM/RPM, see CTP Section 
4.1.4
None
C42
Withdrawal of patient not performed 
according to CTP
Create listing, decision at 
MQRM/RPM, see CTP Section 
3.3.4
None
C52
Discontinuation of trial drug not 
performed according to CTP
Create listing, decision at 
MQRM/RPM, see CTP Section 
3.3.4
None
C62
Overdose of BI 860585
Create listing, decision at 
MQRM/RPM
None
C72
Overdose of either exemestane or 
paclitaxel
Create listing, decision at 
MQRM/RPM
None
D
Restrictions
D12
Prohibited medication use during the 
on-treatment period.
Create listing, decision at 
MQRM/RPM
None
[1] IPV will be derived automatically
[2] IPV will be identified via individual review at MQRM/RPM/DBL


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 16 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.3
PATIENT SETS ANALYSED
Treated set (TS):
The treated set includes all patients who were administered at least one dose of any study 
medication (BI 860585, exemestane, or paclitaxel). This set will be used for all planned 
safety and efficacy analyses but not for the MTD determination according to the 3+3 
algorithm. 
Pharmacokinetic set (PKS):
This patient set includes all evaluable patients in the TS which provide at least one 
observation for at least one PK endpoint without important PVs relevant to the evaluation of 
PK. It is used for the statistical PK analysis.
Treated and evaluable set (TES):
The treated and evaluable set includes all patients who were administered at least one dose of 
trial medication and who are evaluable with respect to DLT in the MTD evaluation period. 
This patient set will be used for the MTD determination according to the 3+3 algorithm. 
Enrolled set (ES):
ES includes all patients who signed informed consent form and will be used to summarize 
patient disposition over all treatment arms.
 
No per protocol population will be used for analyses. However protocol violations will be 
described in the final report.
Patients who were treated, but replaced within the MTD evaluation period will be excluded 
from the determination of the MTD and will not be in the TES. Replacement of patients is not 
captured in the eCRF. The final list of replaced patients is supplied by the trial clinical 
monitor (TCM) no later than the last report planning meeting (RPM) before the data base 
lock.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 17 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (2)
Missing data and outliers of PK data are handled according to 001-MCS-36-472_RD-01 (3).
In general, missing data not discussed in this TSAP will not be imputed, unless required for 
the following analyses and definitions. Then the rules as described below apply.
1) Partial or missing start date of subsequent anti-cancer therapy
If the day of the start date of subsequent anti-cancer therapy is missing, then the 15th of the 
month will be imputed. If both, the day and the month of the start date of a subsequent anti-
cancer therapy are missing, then July 1st will be imputed. If the imputed start date is equal to 
or later than the date of death or the last contact date, then the earlier of date of death minus 1 
day and the date of last contact minus 1 day will be used. 
2) Definition of on-treatment period and actual treatment
Date of permanent discontinuation of last study medication: All reasonable efforts should be 
undertaken during the study to obtain the dates of permanent discontinuation of last study 
medication. However, if the date of the very last intake of study medication is missing, this 
will be imputed with the date of first BI 860585 intake in the last course +28 days. If the 
imputed date leads to a date that is later than the death date (date patient is last known to be 
alive), then the imputed date will be the date of death (date patient last known to be alive). If 
the imputed date leads to a date that is later than the snapshot date, then the imputed date will 
be the snapshot date.
3) Partial death dates
If a partial (year and month) death date is reported the date will be imputed with the end of 
the month for the analysis of duration of disease control and duration of objective response.
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general baseline is defined as the last time point immediately before the very first 
administration of trial medication. If there is no measurement before the very first 
administration of trial medication, no baseline will be derived. For ECOG performance 
status, body weight, vital signs and some safety lab parameters, baseline measurement could 
be on the same date as the very first administration of trial medication. If the time of the 
measurement is not collected or missing and the baseline measurement is done on the same 
day as the first administration of trial medication, it is assumed that the baseline measurement 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 18 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
was done before the administration. Baseline tumour assessments will be based on imaging 
performed no more than 28 days prior to the very first administration of trial medication.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 19 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
PLANNED ANALYSIS
In general, the display templates for End-of-Text (EoT) tables and figures should follow BI 
internal reference (6) as closely as possible and only a minimum number of custom-designed 
table shells will be specified if necessary.
For EoT tables, the set of summary statistics for continuous variable is: 
N/Mean/StD/Min/Median/Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum. 
For time-to-event analysis tables, the set of statistics is: number of patients [N(%)], Number 
of patients with event [N(%)], <Time to event> [months] followed by P25 (25th percentile), 
median, P75 (75th percentile), Number of patients censored [N(%)]. If not specified otherwise, 
the duration as well as the time to event will be displayed in months and a final decision will 
be made at the last RPM.
Tabulations of frequencies for categorical data will include all possible categories (even if 
with no count and also the missing category if there is missing data) and will display the 
number of observations in a category as well as the percentage (%) relative to the number of 
treated patients in the respective treatment group (all patients in the respective treatment 
group in the respective patient set whether they have non-missing values or not). Percentages 
will be rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values. 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 (%)]” will be displayed only for the 
main category.
If a table presents only categorical data, ”[N (%)]” will be displayed in the column header 
only.
A “Total” column displaying totals over all arms will not be included in summary tables for 
post-baseline data. Only totals for each arm separately will be shown.
Abbreviations (e.g., Wors.) or acronyms (e.g., PD) should not be displayed in tables and 
Subject Data Listings (SDLs) without any explanation. They will be either spelled out or 
explained in footnotes.
The conversions among days, weeks, months and years should follow:
• Weeks = days ÷ 7
• Months = 12 × days ÷ 365.25
• Years = days ÷ 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Standard descriptive analysis and summary tables will be presented for all patients in the
treated set by treatment group.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 20 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Disposition of patients
Standard descriptive analysis of disposition will be provided.
If applicable, the number of patients who will continue treatment after database lock will be
reported in the disposition table.
Important protocol violation
A table or listing of patients with important protocol violations will be created.
Demographics and baseline characteristics
Standard descriptive analysis of demographics and baseline characteristics will be provided.
 
 
 
 
 
 
 
 
 
 
7.4
PRIMARY ENDPOINT(S)
The primary endpoints of this trial are the MTD and the number of patients with DLTs during 
the MTD evaluation period.
The primary analysis is for the determination of MTD. The purpose of the analysis is to 
summarize and document the data that led to the selection of MTD.
A summary of the number of patients with DLTs in the MTD evaluation period and overall 
on the on-treatment-period will be given by initial treatment. Only patients in the TES will be 
used for MTD determination.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 21 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
A listing of patients with DLTs by initial treatment will include: Type of DLT (preferred term 
(PT)), CTCAE grade of AEs, Onset and Duration of DLTs [days], Patients recovered 
[yes/no], Actual dose of BI 860585 at onset of the AE [mg].
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
(Other) Secondary endpoint(s)
Early efficacy signals of BI 860585 as single agent or in combination with exemestane or 
paclitaxel will be explored as secondary endpoints. 
Objective response rate and disease control rate:
Objective response rate and disease control rate according to RECIST criteria version 1.1 will 
be analysed descriptively for all treated patients.
Duration of Objective Response:
Duration of objective response will be listed for patients achieving objective response (CR or 
PR according to RECIST). Median duration of objective response will be calculated based on 
the Kaplan-Meier method.
Duration of disease control:
Duration of disease control will be listed for patients achieving disease control (CR, PR or 
SD according to RECIST). Median duration of clinical benefit will be calculated based on the 
Kaplan-Meier method.
Overall response:
As objective response is defined as the best overall response of PR and CR, overall response 
needs to be determined. This is defined as: 

If the overall response is progressive disease, the earliest date of multiple assessments 
(target lesion, non-target lesion, new lesion) will be taken,

If the overall response is CR, PR, SD, no change, or not evaluable, the latest of 
multiple assessment dates will be taken, i.e. in the case of CR, PR, SD, no change, or 
not evaluable the latest of multiple dates will be used.
PK Parameters:
Plasma concentrations of BI 860585, exemestane, and paclitaxel will be plotted against time. 
The calculation of the pharmacokinetic parameters as well as the descriptive analysis of the 
concentration values and the descriptive and comparative analysis of the pharmacokinetic 
parameters will be based on the methods outlined in Section 7.3.5 of the CTP as well as in 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 22 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-36-472_RD-01 (3). Tables and figures for concentrations values and PK 
parameters will be created according to the reference document ’Graphs and Tables for 
Clinical Pharmacokinetic Noncompartmental Analyses’ (001-MCS-36-472_RD-02 (5)).
 
7.8
SAFETY ANALYSIS
All safety analyses besides the MTD determination according to the 3+3 algorithm will be 
performed on the treated set. 
MTD determination will be performed on the TES. Patients who were replaced within 28 
days after first administration of BI 860585 monotherapy or in combination with exemestane 
or with paclitaxel will be excluded from the TES however they are part of the safety analysis
on the treated set. Replaced patients will be listed with the reason for replacement.
7.8.1
Adverse events
The analyses of adverse events (AEs) will be descriptive in nature. All analyses will be based
on the number of patients with AEs (not the number of AEs).
According to BI standards, multiple overlapping or adjacent AE occurrences of the same AE 
are collapsed into one AE event if all AE attributes are identical. These AE attributes are: 
lowest level term (LLT), intensity, action taken, therapy required, seriousness, reason for 
seriousness, relationship, outcome, and AE of special interest (AESI).
The analyses will be based on BI standards. Adverse events will be coded with the most 
recent version of MedDRA. The severity of AEs will be scaled according to CTCAE version 
4.03 (R10-4848).
The analyses of adverse events will be based on the concept of treatment-emergent adverse 
events, where a treatment emergent AE has an onset in the analyzing treatment period. 
Adverse events will be distinguished for the period in which the patients are under study drug 
(on-treatment) as well as for screening, and post-study. Adverse events will be displayed by 
the initial dose of BI 860585 monotherapy or in combination with exemestane or with 
paclitaxel administered on the first day of treatment with study medication. In addition, a 
listing will be provided, detailing the actual dose of BI 860585 monotherapy or in 
combination with exemestane or with paclitaxel administered on the day when the adverse 
event starts.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 23 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Sorting order: In tables presenting PTs only, PTs will be sorted by descending frequency in 
the respective arm. In tables presenting system organ classes (SOCs) and PTs, SOCs will be 
sorted alphabetically and PTs (within SOC) by descending frequency of the respective arm.
Reporting of CTCAE grades in tables: AEs with a given CTCAE definition will be displayed 
in tables showing AEs by worst CTCAE grade. AEs with missing CTCAE grade will be in 
the category “All grades”.
Displaying of CTCAE grades in AE tables (Section 15) will be “All grades”, “Grade 1/2” and 
“Grade 3/4/5”. A separate table will show AEs leading to death. In the appendix (Section 16), 
the categorization “All grades”, “Grade 1”, “Grade 2”, “Grade 3”, ”Grade 4” and “Grade 5”
will be used.
Listings of adverse events will be displayed by patients. Adverse events will be reported with
start and end date (calendar date) rather than with start day and end day as calculated from
the first day of treatment with study medication.
Incidence and severity of adverse events
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and of serious AEs (SAE) will be reported by severity according to CTCAE grades.
Other significant adverse events
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
or permanent discontinuation of study medication (BI 860585, exemestane, or paclitaxel). 
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.
Drug-related adverse events
The frequency of patients with drug-related AEs will be tabulated.
Adverse events leading to dose reduction
AEs leading to dose reduction of BI 860585 and AEs leading to dose reduction of paclitaxel
will be tabulated. This includes patients with AEs leading to dose reduction of BI 860585 
after increasing the dose. 
Adverse events leading to discontinuation of study medication
AEs leading to discontinuation of any study medication will be reported.
AEs leading to discontinuation of BI 860585, AEs leading to discontinuation of exemestane, 
and AEs leading to discontinuation of paclitaxel will be reported separately for the respective 
arms.
Serious adverse events
The frequency of patients with SAEs will be tabulated.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 24 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Adverse events leading to death
AEs leading to death during the on-treatment period will be tabulated. Reported fatal AEs
that occurred in the post-study phase will be displayed.
Adverse events of special interest (AESI)
Adverse events of special interest (AESI) as defined in the protocol and collected on the 
eCRF will be analysed.
Dose-limiting toxicities (DLTs) 
A summary of the number of patients with DLTs within the MTD evaluation period and in 
the whole on-treatment period will be given.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 25 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI
standards (4). The same on-treatment periods as considered for the analysis of adverse events
will be applied for laboratory values. 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 v4.03. 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 and from worst 
to last laboratory value during the on-treatment phase.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 26 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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”.
Possible clinically significant abnormal laboratory values are defined as those laboratory
values that are of CTCAE Grade ≥2 and show an increase from baseline value by at least one
CTCAE grade. For those parameters for which no CTCAE has been defined, BI standard
definition will be used to determine possible clinical significance. Frequency of patients with
possible clinically significant abnormal laboratory values will be provided whenever
applicable. If no baseline value is available but the patient has a post-baseline laboratory
value of CTCAE Grade ≥2 an increase from baseline will be assumed, i.e. the laboratory
value considered as possible clinically significant.
Generally, in case only one direction of worsening (high or low laboratory values) is 
specified in the CTCAE document, there is no need to examine the other direction. Therefore 
for calculating the change in CTCAE grade from baseline / pre-dose level, patients with a 
CTCAE grade of "-9" (no CTCAE grade defined) will be treated as a CTCAE grade 0 for all 
analyses. In laboratory listings, the CTCAE grade will be displayed as "-9".
For Uric Acid, Glomerular filtration rate (GFR) and Hypokalemia, the CTCAE grade cannot 
always be assigned by the laboratory parameter itself as two different CTCAE grades have 
the same laboratory constellation, but are distinguished by additional clinical parameter. In 
this case a CTCAE grade of "-1" will be assigned initially. Patients with a CTCAE grade of "-
1" will be treated as
-
Grade 1 for Uric Acid
-
Grade 3 for GFR
-
Grade 1 for Hypokalemia 
for all analyses. In laboratory listings, the CTCAE grade will be displayed as "-1".
Laboratory values of special interest (LVSI)
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 ALT and/or
AST > 3ULN with total bilirubin ≥ 2ULN and ALKP < 2ULN. 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 presented separately.
Tabulations of hepatic enzyme elevations and liver laboratory values will be done according
to the FDA Drug Induced Liver Injury (DILI) guidance [P09-12413].
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 27 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.4
ECG
Newly emergent abnormalities will be recorded and analysed as adverse events.
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 28 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 29 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 30 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
 
 
 
 
 
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 31 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
REFERENCES
1
001-MCG-160_RD-01: "TSAP annotations", current version; IDEA for
CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON.
3
001-MCS-36-472_RD-01: "Noncompartmental 
Pharmacokinetic/Pharmacodynamic Analyses of Clinical Studies", 
current version; IDEA for CON.
4
001-MCG-157: "Display and Analysis of Laboratory Data", current 
version, IDEA for CON.
5
001-MCS-36-472_RD-02: “Graphs and Tables for Clinical 
Pharmacokinetic and Pharmacodynamic Noncompartmental Analyses”, 
current version; IDEA for CON
6
001-MCG-159_RD-03: "Standard table shells for inferential and 
descriptive End-of-Text tables (EoT-Catalogue)", current version; IDEA 
for
CON.
7
001-MCS-50-413_RD-02: “Important Manual Protocol Violations 
Spreadsheet”, current version; IDEA for CON
P09-12413
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER), 2009.
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). Website 
evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06 
14_QuickReference_8.5x11.pd f (2010)


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 32 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 33 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP:


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 34 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
03-Feb-14
None
This is the final TSAP without any 
modification
Revised
17-Aug-16
Title 
Page
2
3
4
5
6.1
6.2
6.3
6.6
Protocol amendment included
Name of trial statistician and phone 
number adapted
Updated list of abbreviations
SAS Version changed to Version 9.4
Definition of study medication included
Analysis of expansion cohorts 
cancelled, derivation of duration of 
disease control adapted
Detailed description of endpoints with 
censoring rules, MTD evaluation 
period, and other variables added
Statement that DLTs during MTD 
evaluation period will be presented 
separately added
Changed to reflect CTP Amendment 
No. 2
Clarification that SD refers to 
confirmed SD, definition of confirmed 
SD added
Clarification that Non-CR/Non-PD 
should be merged to SD
 
Definition of label of analysing 
treatment that will be used
Adaption of definition of IPVs (C6 and 
C7 added, footnotes added)
Clarification of patient sets, added 
definition of treated and evaluable set, 
of enrolled set
Added specifications for missing data


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 35 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
6.7
7
7.4
7.5
7.8
(partial or missing start dates of 
subsequent anti-cancer therapy and 
definition of on-treatment and actual 
treatment, 
Handling of partial death dates added
Statement added that baseline 
measurement is assumed to be prior to 
administration if on the same day
Standard about time to event analyses 
included
Clarification of “total” columns in 
tables
 
 
Updated to reflect changes in patient 
analysis sets
Deletion of logistic regression analysis 
of conditional probabilities of 
observing a DLT in the MTD 
evaluation period given the dose
Clarification of analysis of duration of 
disease control, added definition of 
overall response
 
Alignment of patient sets
Adaption to reflect current 
SOPs/Guidelines
Version of CTCAE added
Handling of AEs with missing CTCAE 
grade changed
Paragraphs on analysis of DLTs, of 
SAEs, of drug-related AEs, 
 


Boehringer Ingelheim
TSAP for BI Trial No: 1325.1
Page 36 of 36
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
8
Paragraph on AEs leading to 
discontinuation and to dose reduction
of study medication adapted
Analysis of AEs leading to dose 
reduction of paclitaxel added
Definition of potential Hy’s law cases 
corrected
Handling of CTCAE -9 and -1 added
 
 
 
 
Updated list of references