Conditions: Prostatic Neoplasms, Castration-Resistant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
The overall aim of the trial is to investigate the safety and anti-tumour activity of an experimental drug BI 836845 taken together with the prostate cancer drug, enzalutamide, compared to enzalutamide given alone, in castrate resistant prostate cancer (CRPC) patients that have previously been treated and failed on docetaxel and abiraterone treatments. Initially, a tolerability and safety phase (phase Ib escalation) will be performed to confirm the maximum tolerated dose (MTD), or recommended doses of both BI 836845 and enzalutamide that can be taken together.

Once the MTD, or recommended phase II dose, have been determined an expansion cohort will also be explored (phase Ib expansion) in CRPC patients already taking enzalutamide and have a rise in prostate serum antigen (PSA) levels. Patients may not have received prior docetaxel or abiraterone. Patients in this cohort will receive the MTD, or recommended phase II dose, of BI 836845 and enzalutamide determined in the phase Ib escalation phase.

The randomised trial (phase II) will be an open label, parallel group study design in a 1:1 ratio to which patients will receive either BI 836845 plus enzalutamide (Arm A) at the MTD/recommended doses, or enzalutamide alone (Arm B).

In all parts of the trial safety, anti-tumour activity will be assessed, in addition to circulating tumour cells (CTC), prostate serum antigen (PSA) response and progression, and determination of Overall Survival (OS).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 836845 intervention 2: Enzalutamide intervention 3: Enzalutamide
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02304008-15
EudraCT No.:
BI Trial No.:               
2013-004011-41
1280.8
BI Investigational
Product(s):
BI 836845
Title:
A Phase Ib/II, Multicentre, Open Label, Randomised Study of BI 836845 
in Combination with Enzalutamide, versus Enzalutamide alone, in 
Metastatic Castration-Resistant Prostate Cancer (CRPC) Following 
Disease Progression on Docetaxel-Based Chemotherapy and Abiraterone
Clinical Phase:
Ib/II
Trial Clinical 
Monitor:
Tel:
Co-ordinating 
Investigator:
Tel:
Status:
Final Protocol (Revised Protocol based on global amendment 11)
Version and Date:
Version:
12
Date: 06 Jun 2022
Page 1 of 241
Proprietary confidential information. 
! 2022 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


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06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15
Trial Protocol Version 12
Page 2 of 241
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 836845
Protocol date:
Trial number:
Revision date:
06 Jun 2022
08 May 2014
1280.8
Title of trial:
A Phase Ib/II, Multicentre, Open Label, Randomised Study of BI 836845 in 
Combination With Enzalutamide, versus Enzalutamide alone, in Metastatic 
Castration-Resistant Prostate Cancer (CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
Co-ordinating 
Investigator:
Tel:
Trial site(s):
30 or more
Clinical phase:
Ib/II
Objective(s):
Primary Objectives:
Phase Ib dose escalation: Determine the safety and tolerability of BI 836845 in 
combination with enzalutamide following progression on docetaxel-based 
chemotherapy and abiraterone 
Phase Ib expansion cohort: Evaluate the anti-tumour activity of BI 836845 and 
enzalutamide in patients naive to taxane-based chemotherapy and abiraterone
Phase II: Evaluate the anti-tumour activity of between the two treatment arms of BI 
836845 in combination with enzalutamide versus enzalutamide alone following 
progression on docetaxel-based chemotherapy and abiraterone 
Secondary Objectives for Phase Ib and Phase II:
∀
Prostate serum antigen (PSA) response/progression; changes in circulating 
tumour cells (CTC)
∀
Overall survival (Phase II only)


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BI Trial No.: 1280.8
Doc. No.: c02304008-15
Trial Protocol Version 12
Page 3 of 241
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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
BI 836845
Protocol date:
Trial number:
Revision date:
06 Jun 2022
08 May 2014
1280.8
Methodology:
Open label, multicentre study in three parts:
Phase Ib – Single arm, dose escalation of BI 836845 plus enzalutamide
Phase Ib - Single arm expansion cohort of BI 836845 plus enzalutamide
Phase II –  Two arm, randomised, parallel design
Arm A- BI 836845 plus enzalutamide 
Arm B – enzalutamide
No. of patients: 
total entered:
Approximately 120 patients (all parts of the study)
each treatment:
Phase Ib:
Approximately 9-12 patient tolerability and safety phase (Escalation)
Approximately 25 patients exploratory expansion cohort (Expansion Cohort)
Phase II:
40 patients Arm A 
40 patients Arm B
Diagnosis :
Metastatic Castration-Resistant Prostate Cancer (CRPC)
Main criteria
for inclusion:
Escalation cohort and randomised phase II: Patients with diagnosed and 
histologically, or cytologically, confirmed metastatic CRPC that have received and 
progressed after docetaxel-based chemotherapy and abiraterone treatment
Expansion cohort only: Patients with diagnosed and histologically, or cytologically, 
confirmed metastatic CRPC that are receiving enzalutamide and are showing a rise in 
PSA level. Patients not to have received taxane-based chemotherapy or abiraterone.
Test product(s):
BI 836845
dose:
Starting dose 750 mg (dose reduction to 500 mg and dose escalation to 1000 mg)
administered weekly
mode of admin.:
Intravenously over 1 hour
Comparator products:
Enzalutamide
dose:
Starting dose 160 mg per day (dose reduction to 120 mg and 80 mg)
mode of admin.:
Oral
Duration of treatment: Intravenous weekly infusion of BI836845, and/or oral daily enzalutamide, with 
repeated cycles in absence of clinical disease progression or undue toxicities


Boehringer Ingelheim
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15
Trial Protocol Version 12
Page 4 of 241
Proprietary confidential information. ! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A
Name of active ingredient:
BI 836845
Protocol date:
Trial number:
Revision date:
06 Jun 2022
08 May 2014
1280.8
Criteria for efficacy,
pharmacokinetics
pharmacodynamics & 
pharmacogenomics:
Phase Ib Expansion Cohort
Primary Endpoint:
∀
PSA response 
Secondary Endpoints: 
∀
Radiological progression free survival (PFS) based on investigator 
assessment
∀
Changes in circulating tumour cells (CTC) response – CTC reduction 
Phase II Randomised Trial
Primary Endpoint : 
∀
Radiological progression free survival (PFS) based on investigator 
assessment
Secondary Endpoints:
∀
Radiological progression free survival (PFS) based on central review
∀
Overall survival
∀
Time to PSA progression
∀
Maximum decline in PSA 
∀
Percentage change in PSA at week 12
∀
PSA response
∀
Changes in circulating tumour cells (CTC) response – CTC reduction 


Boehringer Ingelheim
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15
Trial Protocol Version 12
Page 5 of 241
Proprietary confidential information. ! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A
Name of active ingredient:
BI 836845
Protocol date:
Trial number:
Revision date:
06 Jun 2022
08 May 2014
1280.8
Criteria for safety:
Phase Ib Escalation
Primary Endpoint  
∀
Number of patients with Dose Limiting Toxicities 
∀
Maximum Tolerated Dose (MTD) of BI 836845 
Statistical methods:
Cox proportional hazards analyses, log rank tests and other descriptive statistical 
analyses.


Boehringer Ingelheim                                                                                                                           
                                                     
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
Page 6 of 241
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FLOW CHART # PHASE IB ESCALATION / EXPANSION COHORT (FOR ALL PATIENTS UNTIL APPROVAL 
OF PROTOCOL VERSION 10)
Study period
Screening
Treatment 1
EOT2
FU13
Add. 
FU3
Cycle 1
Cycle 2
Cycle 3/4 onwards
Visits (V)
V1
V2
V3
V4
V1
V2
V3
V4
V1
V2
V3
V4
EOT
FU1
FU
Days (D)
-28 to -1
D1
D8
±1
D15
±1
D22
±1
D1
±1
D8
±1
D15 
±1
D22 
±1
D1
±1
D8 
±1
D15 
±1
D22 
±1
EOT 
+42 
(+7)
Informed consent4
X
Demographics
X
Medical history
X
Inclusion/exclusion criteria
X
X
Physical exam7
X
X
X
X
X
X21
Height
X
Body weight
X
X
X
X
X
X
Vital signs8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG 12-lead –triplicate9
X
X
X
X
X
X
X
X
X
X
X
ECHO or MUGA (LVEF)
X
ECOG performance status
X
X
X
X
X
X
Safety lab11
X12
X12
X
X
X
X12
X
X
X
X12
X
X
X
X12
X
Circulating tumour cells (CTC) 15
X
X
X15
X
PSA blood sampling16
X
X
X16
X
Tumour assessment / bone scans19
X
X19
X20
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X22
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense enzalutamide23
X
X
X
X
X
X
X
X
X
X
X
X
Diary card issue (expansion cohort)24
X
X
Drug administration: Enzalutamide 
Once daily continuous dosing
Drug administration: Infusion BI 836845 
X
X
X
X
X
X
X
X
X
X
X
X


Boehringer Ingelheim                                                                                                                           
                                                     
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
Page 7 of 241
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Compliance check of enzalutamide 
X25
X
X
X
X
X25
X
X
X
X
Termination of trial medication
X
Patient status
X
X
Patient completion26
X
X
*
For patients discontinuing BI 836845 permanently – From cycle 4 onwards patients that have discontinued BI 836845, but remain on enzalutamide, will only be required to visit on Day 1 
of each cycle.
1.
Treatment cycles: each treatment cycle consists of 28 days.
2.
EOT: end of treatment visit; within 7 calendar days after permanent termination of trial drug(s). If permanent discontinuation of study drug falls on a scheduled visit, examinations as defined 
for EOT should be performed instead of the examinations of the scheduled visit.
3.
FU: Follow-up visit: 42 days (+7) after permanent discontinuation of trial medication. 
Additional FU: Patients who have not progressed and not started further anti-cancer therapy at first FU should have additional follow-up visits at scheduled tumour assessments until 
progression /start of further anti-cancer therapy. Only tumour assessments, AEs and concomitant medication to be reviewed, no other assessments required.
4.
Written informed consent must be obtained before any trial specific screening assessments are performed.
7.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental and neurological status.
8.
Vital signs: includes respiration rate (after two minutes supine rest), pulse, temperature, and blood pressure. On dosing days, at any time before drug administration.
9.
12-lead ECG: 12-Lead resting digital electrocardiogram (ECG) are recorded digitally and in triplicate. ECGs will be performed at: Screening, Cycle 1 on Day 1, Day 8 and Day 15 ; Cycle  2
on Day 8 and Day 15; Cycle 3 on Day 1, Day 8, Day 15; Day 1 of Cycles 6, 9, 12 and every 12 weeks thereafter; also at EOT and first FUP. See Appendix 10.6 for schedule.
ECGs to be taken: Pre-dose (-20 min. to -5 min. before administration of BI 836845 and/or enzalutamide) and immediately after the end of infusion of BI 836845 (up to 15 minutes after end
of infusion). ECGs to be taken prior to PK sample time-points where applicable.
11. Safety labs: haematology, coagulation, biochemistry, electrolytes, urinalysis by dipstick before dosing. See section 5.2.5 for details.
12. Fasting glucose and HbA1C only at screening and Day 1 of each cycle and EOT.
15. CTC blood sampling prior to study drug administration at C1D1, C2D1, C3D1, C5D1, C7D1 and every 12 weeks thereafter, e.g. C10D1, C13D1 onwards and EOT. See section 5.1.2.3 and 
Appendix 10.6 for schedule.
16. PSA blood sampling at screening, C1D1 and from C3 D1 and Day 1 of every cycle thereafter.
 


Boehringer Ingelheim                                                                                                                           
                                                     
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Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
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19. Tumour assessment: CT or MRI imaging of the chest, abdomen and pelvis at screening and prior to the start C3D1 onwards (see below) according to modified RECIST criteria (version 1.1)
see appendix 10.4. If clinically indicated, imaging of any other known or suspected sites of disease using an appropriate method (CT scan and MRI) should be performed. After study entry, 
all lesions identified during the screening should be followed up at all specified imaging time points. The same radiographic procedure must be used throughout the study. See section 5.1.2.1
A bone scan should be performed at screening and prior to the start C3D1 and onwards according to schedule below. 
Tumour assessment and bone scan will be performed at the following time points until progression/start of further anti-cancer therapy (assessments may be performed up to 7 days prior to 
the scheduled assessment date):
∀
At screening: all patients will have a  CT or MRI and bone scan at screening, unless valid results are available from a scan performed within 28 days prior to start of study 
treatment, as part of routine clinical practice
∀
Week 8 (49-56 days after start of study treatment)
∀
Week 16 (105-112 days after start of study treatment)
∀
Week 24 (161-168 days after start of study treatment)
∀
Every 12 weeks thereafter (i.e., during week 35-36 (245-252 days after start of study treatment), during week 47-48 (329-336 days after start of study treatment), etc…)
In the event of an interruption/delay to treatment the tumour assessment schedule should not be changed.  
20. All patients should have a tumour assessment/bone scan at EOT visit regardless of the reason for discontinuation, unless the last evaluation was performed within 4 weeks of EOT
21. Optional physical examination.
22. If not recovered at EOT, or new AE, or drug related death.
23. Dispensing of enzalutamide at every weekly visit. However for those patients which discontinue BI 836845 permanently, from cycle 4 onwards, enzalutamide will be dispensed only on Day 1 
of each cycle, e.g. C4D1, C5D1 onwards.
24. Diary card issued only in expansion cohort at the time of informed consent and at C1 Day 22. Diary card to be completed for 7 days in screening period prior to C1 Day-1 (Day-7 to Day-2), 
and for 7 days prior to C2 Day 1 (C1 Day 23 to Day 28).
25. For expansion cohort only at these visits: Review of diary card and compliance check of enzalutamide taken during screening period prior to C1 Day -1 and prior to C2D1
26. For more details on patient completion, see section 6.1.3.5
Optional fresh tumour biopsy – see footnote 5.


Boehringer Ingelheim                                                                                                                           
                                                     
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
Page 9 of 241
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FLOW CHART # PHASE IB ESCALATION / EXPANSION COHORT (FOR ALL PATIENTS AFTER 
APPROVAL OF PROTOCOL VERSION 10)
Study period
Cycle 3/4 onwards1
Visits (V)
V1
V2
V3
V4
EOT2
FU13
Days (D)
D1
±1
D8 
±1
D15 
±1
D22 
±1
EOT +42 
(+7)
Tumour assessment / bone scans8
X
X
X
Safety Lab7
X
X
X
Adverse event
X
X
X
X
X
X4
Dispense enzalutamide6
X
Drug administration: Infusion BI 836845 
X
X
X
X
Drug administration: Enzalutamide
Continuous daily dosing
Compliance check of enzalutamide 
X
X
Termination of trial medication
X
Patient status
X
Patient completion5
X
1.
   Treatment cycles: each treatment cycle consists of 28 days.
2.
EOT: end of treatment visit; within 7 calendar days after permanent termination of trial drug(s). If permanent discontinuation of study drug falls on a scheduled visit, examinations as 
defined for EOT should be performed instead of the examinations of the scheduled visit.
3.
FU: Follow-up visit: 42 days (+7) after permanent discontinuation of trial medication. 
4.
If not recovered at EOT, or new AE, or drug related death. After FU1 visit any AEs considered related to BI836845 must still be reported.
5.
For more details on patient completion, see section 6.1.3.5
6.
Enzalutamide may be dispensed either weekly or at the start of each cycle.
7.
Safety labs: haematology, biochemistry, electrolytes, before dosing. See section 5.2.5 for details.
8.
Tumour assessment: CT or MRI imaging of the chest, abdomen and pelvis according to modified RECIST criteria (version 1.1). If clinically indicated, imaging of any other known or 
suspected sites of disease using an appropriate method (CT scan or MRI) should be performed. After study entry, all lesions identified during the screening should be followed up at all 
specified imaging time points. The same radiographic procedure must be used throughout the study. See section 5.1.2.  A bone scan should be performed according to schedule below. 
Tumour assessment and bone scans will be performed at the following time points until progression/start of further anti-cancer therapy (assessments may be performed up to 7 days prior 
to the scheduled assessment date):
∀
Week 24 (161-168 days after randomisation)
∀
Every 12 weeks thereafter (i.e., during week 35-36 (245-252 days after randomisation), during week 47-48 (329-336 days after randomisation), etc…)
In the event of an interruption/delay to treatment the tumour assessment schedule should not be changed.
All patients should have a tumour assessment/bone scan at EOT visit regardless of the reason for discontinuation, unless the last evaluation was performed within 4 weeks of EOT.


Boehringer Ingelheim                                                                                                                           
                                                     
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
Page 10 of 241
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FLOW CHART # PHASE IB ESCALATION / EXPANSION COHORT (FOR ALL PATIENTS AFTER 
APPROVAL OF PROTOCOL VERSION 12)
Study period
Cycle 3/4 onwards1
Visits (V)
V1
V2
V3
V4
EOT2
FU13
Days (D)
D1
±1
D8 
±1
D15 
±1
D22 
±1
EOT +42 
(+7)
Tumour assessment / bone scans8
X
X
X
Safety Lab7
X
X
X
Adverse event
X
X
X
X
X
X4
Dispense enzalutamide6
X
Drug administration: Infusion BI 836845 
X
X
X
X
Drug administration: Enzalutamide
Continuous daily dosing
Compliance check of enzalutamide 
X
X
Termination of trial medication
X
Patient status
X
Patient completion5
X
1.
Treatment cycles: each treatment cycle consists of 28 days.
2.
EOT: end of treatment visit; within 7 calendar days after permanent termination of trial drug(s). If permanent discontinuation of study drug falls on a scheduled visit, examinations as 
defined for EOT should be performed instead of the examinations of the scheduled visit.
3.
FU: Follow-up visit: 42 days (+7) after permanent discontinuation of trial medication. 
4.
If not recovered at EOT, or new AE, or drug related death. After FU1 visit any AEs considered related to BI836845 must still be reported.
5.
For more details on patient completion, see section 6.1.3.5
6.
Enzalutamide may be dispensed either weekly or at the start of each cycle. 
7.
Safety labs: haematology, biochemistry, electrolytes, before dosing. See section 5.2.5 for details.
8.
Tumour assessment: CT or MRI imaging of the chest, abdomen and pelvis according to modified RECIST criteria (version 1.1). If clinically indicated, imaging of any other known or 
suspected sites of disease using an appropriate method (CT scan or MRI) should be performed. After study entry, all lesions identified during the screening should be followed up at all 
specified imaging time points. The same radiographic procedure must be used throughout the study. See section 5.1.2.  A bone scan should be performed according to schedule below. 
Tumour assessment and bone scans will be performed at the following time points until progression/start of further anti-cancer therapy (assessments may be performed up to 7 days prior 
to the scheduled assessment date):
∀
Week 24 (161-168 days after randomisation)
∀
Every 12 weeks thereafter (i.e., during week 35-36 (245-252 days after randomisation), during week 47-48 (329-336 days after randomisation), etc…)
∀
Standard of care after implementation of Protocol Version 12
In the event of an interruption/delay to treatment the tumour assessment schedule should not be changed.
All patients should have a tumour assessment/bone scan at EOT visit regardless of the reason for discontinuation, unless the last evaluation was performed within 4 weeks of EOT.


Boehringer Ingelheim                                                                                                                           
                                                     
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
Page 11 of 241
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FLOW CHART # PHASE II RANDOMISED TRIAL (FOR ALL PATIENTS UNTIL APPROVAL OF PROTOCOL 
VERSION 10) 
Study period
Screening
Treatment 1
EOT2
FU3
OP4
Cycle 1
Cycle 2
Cycle 3/4 onwards
Visits (V)*
V1
V2
V3
V4
V1
V2
V3
V4
V1
V2
V3
V4
EOT
FU
OP
Days (D)
-28 to -1
D1
D8
±1
D15
±1
D22
±1
D1
±1
D8
±1
D15
±1
D22
±1
D1
±1
D8
±1
D15
±1
D22
±1
EOT 
+42 
(+7)
Informed consent5
X
Demographics
X
Medical history
X
Inclusion/exclusion criteria
X
X
Randomisation27
X
Physical exam8
X
X
X
X
X
X22
Height
X
Body weight
X
X
X
X
X
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG 12-lead - triplicate 10
X
X
X
X
X
X
X
X
X
X
X
ECHO or MUGA (LVEF)
X
ECOG performance status
X
X
X
X
X
X
Safety lab12
X13
X13
X
X
X
X13
X
X
X
X13
X
X
X
X13
X
Circulating tumour cells (CTC)16
X
X
X16
X
PSA blood sampling17
X
X
X17
X
Tumour assessment / bone scans20
X
X20
X21
Adverse event
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X23
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Arm A & B: Dispense enzalutamide24
X
X
X
X
X
X
X
X
X
X
X
X
Arm A & B Drug administration: Enzalutamide
Once daily continuous dosing
Arm A Drug administration: Infusion BI 836845 
X
X
X
X
X
X
X
X
X
X
X
X
Compliance check of enzalutamide
X
X
X
X
X
X
X
X
X


Boehringer Ingelheim                                                                                                                           
                                                     
06 Jun 2022
BI Trial No.: 1280.8
Doc. No.: c02304008-15                                                                       Trial Protocol Version 12
Page 12 of 241
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Termination of trial medication
X
Patient status
X
X
Patient completion25
X
X
*
From cycle 4 onwards patients on enzalutamide (Arm B) and those patients that have discontinued BI 836845, but remain on enzalutamide (Arm A), will only be required to visit on day 
1 of each cycle.
1.
Treatment cycles: each treatment cycle consists of 28 days 
2.
EOT: end of treatment visit; within 7 calendar days after permanent termination of trial drug(s). If permanent discontinuation of study drug falls on a scheduled visit, examinations as 
defined for EOT should be performed instead of the examinations of the scheduled visit
3.
FU: Follow-up visit; 42 days (+7) after permanent discontinuation of trial medication.  
Additional FU: Patients who have not progressed and not started further anti-cancer therapy at first FU should have additional follow-up visits at scheduled tumour assessments until 
progression /start of further anti-cancer therapy. Only tumour assessments, AEs and concomitant medication to be reviewed, no other assessments required.
4.
OP: Observational phase; every 90 days (∃15) after last FU, patients will be followed for survival every three months until patient death. Survival information can be obtained via phone 
contact
5.
Written informed consent must be obtained before any trial specific screening assessments are performed
8.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental and neurological status. 
9.
Vital signs: includes respiration rate respiration rate (after two minutes supine rest), pulse, temperature, and blood pressure. On dosing days, at any time before drug administration.
10. 12-lead ECG: 12-Lead resting digital electrocardiogram (ECG) are recorded digitally and in triplicate. ECGs will be performed at: Screening, Cycle 1 on Day 1, Day 8 and Day 15; 
Cycle 2 on Day 8 and Day 15; Cycle 3 on Day 1, Day 8 and Day 15. Day 1 of Cycles 6, 9, 12 and every 12 weeks thereafter; also EOT and first FUP. See Appendix 10.6 for schedule.
ECGs to be taken: Pre-dose (-20 min. to -5 min. before administration of BI 836845 and/or enzalutamide) and immediately after the end of infusion of BI 836845 (up to 15 minutes after
end of infusion), or one hour after the administration of enzalutamide. ECGs to be taken prior to PK sample time-points where applicable.
12. Safety labs: haematology, coagulation, biochemistry, electrolytes, urinalysis by dipstick before dosing. See section 5.2.5 for details.
13. Fasting glucose and HbA1C only at screening and Day 1 of each cycle and EOT.
5.1.2.3 and Appendix 10.6 for schedule.
17. PSA blood sampling at screening, C1D1 and from C3 D1 and at Day 1 of every cycle thereafter.
 


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20. Tumour assessment: CT or MRI imaging of the chest, abdomen and pelvis at screening and prior to start C3D1 onwards (see below) according to modified RECIST criteria (version 1.1). 
If clinically indicated, imaging of any other known or suspected sites of disease using an appropriate method (CT scan or MRI) should be performed. After study entry, all lesions 
identified during the screening should be followed up at all specified imaging time points. The same radiographic procedure must be used throughout the study. See section 5.1.2.1
A bone scan should be performed at screening, prior to the start C3D1and onwards according to schedule below. 
Tumour assessment and bone scans will be performed at the following time points until progression/start of further anti-cancer therapy (assessments may be performed up to 7 days prior 
to the scheduled assessment date):
∀
At screening: all patients will have a  CT or MRI and bone scan at screening, unless valid results are available from a scan performed within 28 days prior to start of study 
treatment, as part of routine clinical practice
∀
Week 8 (49-56 days after randomisation)
∀
Week 16 (105-112 days after randomisation)
∀
Week 24 (161-168 days after randomisation)
∀
Every 12 weeks thereafter (i.e., during week 35-36 (245-252 days after randomisation), during week 47-48 (329-336 days after randomisation), etc…)
In the event of an interruption/delay to treatment the tumour assessment schedule should not be changed.
21. All patients should have a tumour assessment/bone scan at EOT visit regardless of the reason for discontinuation, unless the last evaluation was performed within 4 weeks of EOT.
22. Optional physical examination.
23. If not recovered at EOT, or new AE, or drug related death.
24. Dispensing of enzalutamide at every weekly visit. However for patients in Arm B and those patients in Arm A which discontinue BI 836845 permanently, from cycle 4 onwards,
enzalutamide will be dispensed only on Day 1 of each cycle, e.g. C4D1, C5D1 onwards.
25. For more details on patient completion, see section 6.1.3.5
 
27. The randomization may take place up to 3 days prior to C1D1 if site procedures require advance randomization to accommodate the logistics of dispensing study medication to patients. 
Sites that use this option must include a copy of site policy/written justification in the ISF and submit a copy to the sponsor. If randomization is performed prior to C1D1, the subsequent 
visits must be scheduled with reference to C1D1.


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FLOW CHART # PHASE II RANDOMISED TRIAL (FOR ALL PATIENTS AFTER APPROVAL OF PROTOCOL 
VERSION 10)
Study period
Cycle 3/4 onwards1
Visits (V)
V1
V2
V3
V4
EOT2
FU13
Days (D)
D1
±1
D8 
±1
D15 
±1
D22 
±1
EOT +42 
(+7)
Tumour assessment / bone scans8
X
X
X
Safety lab7
X
X
X
Adverse event
X
X
X
X
X
X4
Dispense enzalutamide6
X
Drug administration: Infusion BI 836845 
X
X
X
X
Drug administration: Enzalutamide
Continuous daily dosing
Compliance check of enzalutamide 
X
X
Termination of trial medication
X
Patient status
X
Patient completion5
X
1.
Treatment cycles: each treatment cycle consists of 28 days.
2.
EOT: end of treatment visit; within 7 calendar days after permanent termination of trial drug(s). If permanent discontinuation of study drug falls on a scheduled visit, examinations as 
defined for EOT should be performed instead of the examinations of the scheduled visit.
3.
FU: Follow-up visit: 42 days (+7) after permanent discontinuation of trial medication. 
4.
If not recovered at EOT, or new AE, or drug related death. After FU1 visit any AEs considered related to BI836845 must still be reported.
5.
For more details on patient completion, see section 6.1.3.5
6.
Enzalutamide may be dispensed either weekly or at the start of each cycle. 
7.
Safety labs: haematology, biochemistry, electrolytes, before dosing. See section 5.2.5 for details
8.
Tumour assessment: CT or MRI imaging of the chest, abdomen and pelvis according to modified RECIST criteria (version 1.1). If clinically indicated, imaging of any other known or 
suspected sites of disease using an appropriate method (CT scan or MRI) should be performed. After study entry, all lesions identified during the screening should be followed up at all 
specified imaging time points. The same radiographic procedure must be used throughout the study. See section 5.1.2.  A bone scan should be performed according to schedule below. 
Tumour assessment and bone scans will be performed at the following time points until progression/start of further anti-cancer therapy (assessments may be performed up to 7 days prior 
to the scheduled assessment date):
∀
Week 24 (161-168 days after randomisation)
∀
Every 12 weeks thereafter (i.e., during week 35-36 (245-252 days after randomisation), during week 47-48 (329-336 days after randomisation), etc…)
In the event of an interruption/delay to treatment the tumour assessment schedule should not be changed.
All patients should have a tumour assessment/bone scan at EOT visit regardless of the reason for discontinuation, unless the last evaluation was performed within 4 weeks of EOT.


Boehringer Ingelheim                                                                                                                           
                                                     
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FLOW CHART # PHASE II RANDOMISED TRIAL (FOR ALL PATIENTS AFTER APPROVAL OF PROTOCOL 
VERSION 12)
Study period
Cycle 3/4 onwards1
Visits (V)
V1
V2
V3
V4
EOT2
FU13
Days (D)
D1
±1
D8 
±1
D15 
±1
D22 
±1
EOT +42 
(+7)
Tumour assessment / bone scans8
X
X
X
Safety lab7
X
X
X
Adverse event
X
X
X
X
X
X4
Dispense enzalutamide6
X
Drug administration: Infusion BI 836845 
X
X
X
X
Drug administration: Enzalutamide
Continuous daily dosing
Compliance check of enzalutamide 
X
X
Termination of trial medication
X
Patient status
X
Patient completion5
X
1.
Treatment cycles: each treatment cycle consists of 28 days.
2.
EOT: end of treatment visit; within 7 calendar days after permanent termination of trial drug(s). If permanent discontinuation of study drug falls on a scheduled visit, examinations as 
defined for EOT should be performed instead of the examinations of the scheduled visit.
3.
FU: Follow-up visit: 42 days (+7) after permanent discontinuation of trial medication. 
4.
If not recovered at EOT, or new AE, or drug related death. After FU1 visit any AEs considered related to BI836845 must still be reported.
5.
For more details on patient completion, see section 6.1.3.5
6.
Enzalutamide may be dispensed either weekly or at the start of each cycle. 
7.
Safety labs: haematology, biochemistry, electrolytes, before dosing. See section 5.2.5 for details
8.
Tumour assessment: CT or MRI imaging of the chest, abdomen and pelvis according to modified RECIST criteria (version 1.1). If clinically indicated, imaging of any other known or 
suspected sites of disease using an appropriate method (CT scan or MRI) should be performed. After study entry, all lesions identified during the screening should be followed up at all 
specified imaging time points. The same radiographic procedure must be used throughout the study. See section 5.1.2.  A bone scan should be performed according to schedule below. 
Tumour assessment and bone scans will be performed at the following time points until progression/start of further anti-cancer therapy (assessments may be performed up to 7 days prior 
to the scheduled assessment date):
∀
Week 24 (161-168 days after randomisation)
∀
Every 12 weeks thereafter (i.e., during week 35-36 (245-252 days after randomisation), during week 47-48 (329-336 days after randomisation), etc…)
∀
Standard of care after implementation of Protocol Version 12
In the event of an interruption/delay to treatment the tumour assessment schedule should not be changed.
All patients should have a tumour assessment/bone scan at EOT visit regardless of the reason for discontinuation, unless the last evaluation was performed within 4 weeks of EOT.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART # PHASE IB ESCALATION / EXPANSION 
COHORT (FOR ALL PATIENTS UNTIL APPROVAL OF 
PROTOCOL VERSION 10) ......................................................................6
FLOW CHART # PHASE IB ESCALATION / EXPANSION 
COHORT (FOR ALL PATIENTS AFTER APPROVAL OF 
PROTOCOL VERSION 10) ......................................................................9
FLOW CHART # PHASE IB ESCALATION / EXPANSION 
COHORT (FOR ALL PATIENTS AFTER APPROVAL OF 
PROTOCOL VERSION 12) ................................................................... 10
FLOW CHART # PHASE II RANDOMISED TRIAL (FOR ALL 
PATIENTS UNTIL APPROVAL OF PROTOCOL 
VERSION 10) ........................................................................................... 11
FLOW CHART # PHASE II RANDOMISED TRIAL (FOR ALL 
PATIENTS AFTER APPROVAL OF PROTOCOL 
VERSION 10) ........................................................................................... 14
FLOW CHART # PHASE II RANDOMISED TRIAL (FOR ALL 
PATIENTS AFTER APPROVAL OF PROTOCOL 
VERSION 12) ........................................................................................... 15
TABLE OF CONTENTS ................................................................................ 16
ABBREVIATIONS.......................................................................................... 21
1.
INTRODUCTION.................................................................................... 23
1.1
MEDICAL BACKGROUND............................................................................23
1.2
DRUG PROFILE...............................................................................................24
1.2.1
BI 836845 ...............................................................................................24
1.2.2
Enzalutamide.........................................................................................26
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 28
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................28
2.2
TRIAL OBJECTIVES.......................................................................................29
2.3
BENEFIT - RISK ASSESSMENT ...................................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 33
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................33
3.1.1
Administrative structure of the trial...................................................36
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................37
3.3
SELECTION OF TRIAL POPULATION ......................................................38


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3.3.1
Main diagnosis for study entry............................................................39
3.3.2
Inclusion criteria...................................................................................39
3.3.3
Exclusion criteria ..................................................................................40
3.3.4
Removal of patients from therapy or assessments.............................42
3.3.4.1
Removal of individual patients................................................42
3.3.4.2
Discontinuation of the trial by the sponsor..............................43
3.3.5
Replacement of patients .......................................................................44
4.
TREATMENTS........................................................................................ 45
4.1
TREATMENTS TO BE ADMINISTERED....................................................45
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................45
4.1.2
Method of assigning patients to treatment groups ............................46
4.1.3
Selection of doses in the trial................................................................46
4.1.3.1 BI 836845.................................................................................46
4.1.3.2 Enzalutamide............................................................................47
4.1.3.3
Determination of the dose of BI 836845 in combination with 
enzalutamide ............................................................................47
4.1.3.4 Exploratory expansion cohort ....................................................48
4.1.4
Drug assignment and administration of doses for each patient .......48
4.1.4.1
Phase Ib tolerability/safety and dose finding phase.................48
4.1.4.2
BI 836845 (Phase Ib and Phase II - Arm A)............................49
4.1.4.3
Enzalutamide (Phase Ib and Phase II- Arm A and B) ............49
4.1.4.4 Temporary treatment interruption and dose reduction for BI 
836845 and  enzalutamide during phase Ib and phase II.........50
4.1.4.5
Additional cycles of treatment.................................................52
4.1.4.6
Preparation of BI 836845.........................................................52
4.1.5
Blinding and procedures for unblinding ............................................52
4.1.5.1
Blinding....................................................................................52
4.1.5.2
Procedures for emergency unblinding .....................................52
4.1.6
Packaging, labelling, and re-supply ....................................................52
4.1.7
Storage conditions.................................................................................53
4.1.8
Drug accountability ..............................................................................53
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................54
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................54
4.2.1.1
Management of infusion reactions...........................................55
4.2.1.2
Management of potential hyperglycaemia...............................56
4.2.2
Restrictions............................................................................................56
4.2.2.1
Restrictions regarding concomitant treatment .........................56
4.2.2.2
Restrictions on diet and life style.............................................57
4.3
TREATMENT COMPLIANCE.......................................................................58
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 59
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................59
5.1.1
Endpoint(s) of efficacy (anti-tumour activity)....................................59


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5.1.1.1
Phase Ib Expansion Cohort.....................................................59
5.1.1.2
Phase II Randomised Trial......................................................59
5.1.2
Assessment of efficacy (anti-tumour activity) ....................................60
5.1.2.1
Assessment of tumours and bone............................................60
5.1.2.2
Assessment of PSA.................................................................62
5.1.2.3 Circulating tumour cell (CTC) assessments ............................62
5.1.3
Central Imaging ....................................................................................63
5.2
SAFETY..............................................................................................................63
5.2.1
Endpoint(s) of safety.............................................................................63
5.2.2
Assessment of adverse events...............................................................64
5.2.2.1
Definitions of adverse events...................................................64
5.2.2.2
Adverse event collection and reporting ...................................66
5.2.3
Dose Limiting Toxicity (DLT) definitions...........................................69
5.2.4
Maximum Tolerated Dose (MTD) and Recommended Phase II 
Dose (RP2D) ..........................................................................................70
5.2.5
Assessment of safety laboratory parameters......................................70
5.2.6
Electrocardiogram................................................................................72
5.2.6.1
ECG Recording – Phase Ib and Phase II .................................72
5.2.6.2 ECG evaluation........................................................................73
5.2.7
Left ventricular ejection fraction ........................................................73
5.2.8
Assessment of vital signs and physical examination..........................73
5.2.9
Demographics and medical history.....................................................73
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................78


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6.
INVESTIGATIONAL PLAN.................................................................. 85
6.1
VISIT SCHEDULE............................................................................................85
6.1.1
Screening Visit: -28 to day -1...............................................................85
6.1.2
Treatment Visits....................................................................................85
6.1.3
Follow Up Period and Trial Completion ............................................86
6.1.3.1
End of treatment visit (EOT) ...................................................86
6.1.3.2
Residual effect period (REP) ...................................................87
6.1.3.3
Follow-up period......................................................................87
6.1.3.4
Observation period...................................................................87
6.1.3.5
Patient completion ...................................................................88
6.1.3.6
End of whole trial.....................................................................88
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................88
6.2.1
Screening period....................................................................................88
6.2.2
Treatment period ..................................................................................89
6.2.3
End of trial and follow-up period........................................................93
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 96
7.1
STATISTICAL DESIGN – MODEL ...............................................................96
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................96
7.3
PLANNED ANALYSES....................................................................................96
7.3.1
Primary analyses...................................................................................96
7.3.2
Secondary analyses ...............................................................................97
7.3.3
Safety analyses.......................................................................................97
7.3.4
Interim analyses ....................................................................................98
7.4
HANDLING OF MISSING DATA ..................................................................99
7.5
RANDOMISATION ........................................................................................100
7.6
DETERMINATION OF SAMPLE SIZE ......................................................100
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS .............................................................................................. 104
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ........................................................................................................104
8.2
DATA QUALITY ASSURANCE ...................................................................104
8.3
RECORDS........................................................................................................105
8.3.1
Source documents ...............................................................................105
8.3.2
Direct access to source data and documents.....................................105


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8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS............................................................................................................105
8.4.1
Listedness.............................................................................................105
8.4.2
Expedited reporting to health authorities and IECs/IRBs..............105
8.5
STATEMENT OF CONFIDENTIALITY.....................................................106
8.6
COMPLETION OF TRIAL............................................................................106
9.
REFERENCES....................................................................................... 107
9.1
PUBLISHED REFERENCES.........................................................................107
9.2
UNPUBLISHED REFERENCES...................................................................112
10. APPENDICES ........................................................................................ 113
10.1
COCKCROFT-GAULT FORMULA ............................................................113
10.2
ECOG PERFORMANCE STATUS...............................................................114
10.3
EXAMPLES OF CYP 3A4 AND CYP2C8 INHIBITORS, INDUCERS 
AND CYP3A4 SUBSTRATES........................................................................115
10.3.1 Examples of CYP3A4 substrates........................................................115
10.3.2 Strong and moderate CYP3A4 and CYP2C8 inhibitors and 
inducers................................................................................................115
10.4
TUMOUR RESPONSE ASSESSMENT ACCORDING TO MODIFIED 
RECIST 1.1.......................................................................................................117
10.5
COMMON TERMINOLGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE)...........................................................................................................119
10.7
EXAMPLES OF BONE SCAN PROGRESSIONS USING PROSTATE 
CANCER CLINICAL TRIALS WORKING GROUP GUIDELINES 
(PCWG2) ..........................................................................................................142
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 143


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ABBREVIATIONS
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
AR
Androgen Receptor 
BI
Boehringer Ingelheim
CI
Confidence Interval
CML
Local Clinical Monitor 
COVID-19
Coronavirus 2019
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CRPC
Castrate Resistant Prostate Cancer
CTC
CTCAE
Circulating Tumour Cells
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EOT
End Of Treatment
EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
HPC
Human Pharmacology Centre
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IGF
Insulin Growth Factor
IGF-1R
Insulin Growth Factor 1 Receptor
IGF-1
Insulin Growth Factor 1
IGF-2
Insulin Growth Factor 2
IGFBP
Insulin Growth Factor Binding Protein
INR
International Normalised Ratio 
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System


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LHRH
Luteinizing Hormone Releasing Hormone 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MST
Medical Subteam
MTD
Maximum Tolerated Dose
OPU
Operative Unit
p.o.
per os (oral)
PCC
Protocol Challenge Committee
PD
Pharmacodynamics
PFS
Progression Free Survival
PSA
Prostate-Specific Antigen
PTT
Partial Thromboplastin Time
q.d.
quaque die (once a day)
REC
Research Ethics Committee
RECIST
Response Criteria In Solid Tumours
REP
Residual Effect Period
RBD
Relevant Biological Dose
RP2D
SAE
Recommended Phase II Dose
Serious Adverse Event
s.c.
subcutaneous
SCAR’s
Severe cutaneous adverse reactions
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMM
Team Member Medicine
TMW
Trial Medical Writer
TRAMP
Transgenic adenocarcinoma of mouse prostate
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
VEGF
Vascular Epidermal Growth Factor


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of 
cancer-related deaths among men in developed countries (R11-0764). Androgen-deprivation 
therapy is, and has been, the gold standard of care for advanced or metastatic prostate cancer 
for decades. Although more than 90% of prostate cancer patients initially respond to 
androgen deprivation therapy, most tumours become refractory and eventually reoccur as 
castration-resistant prostate cancer (CRPC), for which there are limited treatment options 
with only modest survival benefit.
A significant amount of data has been accumulated suggesting that the insulin-like growth 
factor (IGF) system plays an important role in prostate cancer initiation and progression.  The 
IGF axis is composed of 2 peptide growth factors (IGF-1 and -2), 2 transmembrane receptors 
(IGF-1R and -2R), 6 IGF-binding proteins (IGFBP-1 to -6), and IGFBP proteases. IGFs are 
synthesized primarily in the liver and have effects on protein and carbohydrate metabolism 
but also regulate cellular processes of proliferation, differentiation, angiogenesis and 
apoptosis (R13-0728). These later attributes have resulted in the IGF axis being associated 
with a critical role in the development of a variety of malignancies including prostate cancer 
(R10-6695, R13-0992, R13-0723, R13-0724, R13-0729). IGF-1R is a transmembrane 
receptor tyrosine kinase that is widely expressed in human tissues. Binding of IGF ligands 
induces conformational changes of IGF-IR and activation of its intrinsic intracellular tyrosine 
kinase activity. The activated receptor induces recruitment of the insulin receptor substrates 
(IRS) 1 and 2, which in turn activates the mitogen-activated protein kinase (MAPK) and the 
phosphoinositide 3-kinase (PI3K)/Akt intracellular signaling pathways, leading to cellular 
proliferation and apoptosis inhibition (R13-0725 , R13-0726). 
Elevated levels of serum IGF-1 have been associated with an increased risk of prostate cancer 
in meta-regression analysis (R07-4212, R13-0727) (R13-0730), and high plasma IGF-1 and 
low IGFBP-3 has been associated with more advanced stages of prostate cancer (R13-0731, 
R13-0732). In human primary prostate cancers, IGF-1R, IGF-1, and -2 have all been reported 
to have increased expression compared with normal prostate tissue (R13-0982 , R13-0993, 
R13-0994) and is also increased in advanced and metastatic disease (R13-0659, R13-0018). 
IGF-1 and IGF-1R are increased with progression to castration-resistance in vivo (R13-0660). 
In the TRAMP model (transgenic adenocarcinoma of mouse prostate), prostate cancer 
incidence is substantially reduced in IGF-1–deficient mice, whereas organ-specific 
overexpression of IGF-1R increased prostate neoplasia (R13-0705). In other preclinical 
studies, the IGF axis appears to be up-regulated in bone metastases (R13-0704) and IGF-1 
has been shown to accelerate tumour growth (R13-0703), promote migration through 
PI3K/AKT (R13-0995), and be involved with angiogenesis through VEGF (R13-0707).
Enzalutamide is an androgen receptor inhibitor that targets multiple steps in the androgen 
receptor signalling pathway in the tumour cell; namely inhibition of nuclear translocation of 
the androgen receptor, DNA binding, and co-activator recruitment and has no known 
agonistic effect.
A phase 3, double-blind, placebo-controlled trial (the AFFIRM trial) with enzalutamide,  
stratified 1199 men with CRPC after chemotherapy according to the Eastern Cooperative 


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Oncology Group (ECOG) performance-status score and pain intensity. Patients were 
randomised in a 2:1 ratio to receive oral enzalutamide at a dose of 160 mg per day (800 
patients) or placebo (399 patients). The primary end point was overall survival.
The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet 
reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo 
group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; 
P<0.001). The superiority of enzalutamide over placebo was shown with respect to all 
secondary end points: the proportion of patients with a reduction in the prostate-specific 
antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate 
(29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to 
PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-
free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first 
skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Hence 
enzalutamide significantly prolonged the survival of men with metastatic castration-resistant 
prostate cancer after chemotherapy (R13-1229).
These data were more recently confirmed in the PREVAIL trial (R15-1307) investigating 
Enzalutamide in metastatic prostate cancer before chemotherapy: Enzalutamide significantly 
decreased the risk of radiographic progression and death and delayed the initiation of 
chemotherapy. 
The present trial shall investigate the safety and efficacy of enzalutamide taken in 
combination with BI 836845, an IGF ligand blocking agent directed towards IGF-1 and IGF-
2, in CRPC patients.
1.2
DRUG PROFILE
1.2.1
BI 836845
BI 836845 is a humanised IgG1 monoclonal antibody that binds to and neutralises the 
function of IGF-1 and IGF-2. 
The growth of multiple cancer cell lines derived from different cancer types was inhibited by 
BI 836845 alone or in combination with other anti-cancer drugs in preclinical models. BI 
836845 has a potent inhibitory effect on the IGF-1R phosphorylation potential (IGF 
bioactivity) of human plasma ex vivo. Due to its cross-reactivity to rat and Cynomolgus 
monkey IGF-1 and IGF-2, the pharmacodynamic effect of BI 836845 on IGF bioactivity in 
both these species was demonstrated by a clear and potent reduction in plasma IGF 
bioactivity for all doses tested.
Repeat-dose toxicity studies with once weekly intravenous administration of BI 836845 for 
13 weeks in Cynomolgus monkeys and for 13 or 26 weeks in rats revealed a variety of dose 
related and essentially reversible effects. The treatment related changes included the body as 
a whole (growth retardation) in both species and liver functions, the haematolymphatic 
system, kidneys, bone, teeth, and ovaries in rats only. Most, if not all, observed effects were 
attributable to the pharmacodynamic potential of BI 836845, i.e. reflecting the neutralization 
of specific growth factors in these species during a phase of rapid body growth. 


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Consequently, signs of general growth retardation, e.g. reduced body weight gain and body 
size were apparent in both species examined. The effects on the haematolymphatic system 
and liver function seen in the rat studies were considered to be of no toxicological relevance. 
For more details please refer to the most recent update of the investigator brochure (IB, 
c01690707).
Two Phase I studies with BI 836845 monotherapy are ongoing in patients with advanced 
solid tumours to determine the safety, maximum tolerated dose and/ or relevant biological 
dose, pharmacokinetics (PK) and PK/pharmacodynamic (PD) correlation, applying either a 
weekly dosing schedule in study 1280.1 (U11-3025) or a once every three weeks dosing 
schedule in study 1280.2 (U10-2994) during escalation phase; study 1280.2 has since 
changed to a weekly dosing phase in the expansion phase.
As of the database cut-off date of the IB (U10-2830) of 10 July 2013, 81 subjects have 
received BI 836845 across the two phase I trials (U11-3025 and U10-2994). Overall in these 
studies, BI 836845 was well-tolerated. The type and pattern of adverse events (AEs) observed 
to date have generally been mild to moderate (CTCAE Grade 1 and 2) and consistent with the 
underlying neoplastic conditions of patients enrolled in the trials. The most frequently 
reported AEs reported across both studies (any cause) were general disorders, especially 
fatigue, as well as gastrointestinal disorders (nausea, vomiting and diarrhoea). Specifically, 
there were no laboratory findings that would indicate kidney damage in patients, as 
previously observed in the 13-week study in rats (U10-2830).
Of the 81 subjects treated until the cut-off date, only one experienced a drug-related serious 
adverse event (SAE). One further patient experienced a dose-limiting toxicity (DLT).
Four subjects discontinued treatment due to non-drug related AEs. Infusion-related reactions 
were not observed. Metabolic AEs involving perturbed glucose homeostasis, among the most 
common toxicities documented for IGF-1R-targeting monoclonal antibodies and small 
molecule tyrosine kinase inhibitors, were observed at relatively low frequencies. Two out of 
81 subjects reported transient hyperglycemia: one patient (CTCAE Grade 2) in study 1280.1 
and one patient (CTCAE Grade 3) in 1280.2, see the most recent edition of the IB for full 
details (U10-2830).
Preliminary tumour response data is available for the subjects treated in both the first in-man 
studies; however the results are insufficient to reliably assess the anti-tumour activity of BI 
836845 as monotherapy. There were 12 (25.0%) patients with confirmed stable disease in 
study 1280.1 and four patients (12.1%) with confirmed stable disease in study 1280.2. Two 
patients had confirmed partial responses in study 1280.1: a patient with nasopharyngeal 
carcinoma and a patient with peripheral primitive neuroectodermal tumour, a member of the 
Ewing’s family of tumours.
Preliminary PK interim data from the dose escalation part of both trials indicate that 
maximum plasma concentrations of BI 836845 are reached at the end of the infusion or 
shortly thereafter. After reaching the peak, plasma concentrations showed an at least biphasic 
decay with a terminal half-life of about 6 days. The estimated volume of distribution was 
about 5.8 L (approx. two times the plasma volume) and the total plasma clearance was about 
0.5 mL/min. The incidence of anti-drug antibodies (ADA) was approximately 19% in 1280.1 
and 30% in 1280.2. Overall, the ADA-response was weak, dose-independent and in many 
cases transient and had no impact on PK or PD.


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No deviations from dose-proportional pharmacokinetics have been observed in the dose 
range analysed (10-1050 mg q1w in 1280.1 and 10-3600 mg q3w in 1280.2). Steady state 
plasma concentrations of BI 836845 were achieved after 5-7 weeks. Repeated weekly dosing 
resulted in about 1.5 fold accumulation of BI 836845 plasma concentration at steady state, 
while only limited accumulation was observed after repeated infusions every three weeks. 
It is known that humanised IgGs like BI 836845 are mainly cleared by catabolism. This 
mechanism of clearance is not shared or overlapping with the clearance mechanism for small 
molecules. Thus, BI 836845 is not predicted to directly affect the hepatic, renal, or biliary 
elimination of small molecules. Furthermore, BI 836845 is not targeting cytokines, and mAbs 
targeting upstream IGFs have not been related to modulation of CYP450 isozymes or drug 
transporters (P13-02270). Hence, the potential of BI 836845 to alter the pharmacokinetics of 
co-medication is considered low. 
1.2.2
Enzalutamide
Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen 
receptor signalling pathway. The chemical name is 4-{3-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-
methylbenzamide. The molecular weight is 464.44 and molecular formula is 
C21H16F4N4O2S. Enzalutamide is a white crystalline non-hygroscopic solid. It is practically 
insoluble in water.
Enzalutamide has been shown to competitively inhibit androgen binding to androgen
receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A 
major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to 
enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer
cells in vitro, and decreased tumour volume in a mouse prostate cancer xenograft model.
Following oral administration (160 mg daily) in patients with metastatic castration-resistant 
prostate cancer, the median time to reach maximum plasma concentrations (Cmax) is 1 hour 
(range 0.5 to 3 hours). At steady state, the plasma mean Cmax values for enzalutamide and 
N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), 
respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 
μg/mL (30% CV), respectively.  With daily dosing enzalutamide steady state is achieved by 
Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily 
fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 
1.25). At steady state, enzalutamide showed approximately dose proportional 
pharmacokinetics over the daily dose range of 30 to 360 mg. The plasma pharmacokinetics is 
adequately described by a linear two-compartment model with first-order absorption.
In vitro, CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based 
on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active 
metabolite (N-desmethyl enzalutamide). Enzalutamide is primarily eliminated by hepatic 
metabolism. The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral 
dose is 5.8 days (range 2.8 to 10.2 days) (R13-5391).  Please also refer to the current 
summary of product characteristics (SPC) from eMC website.


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Second Primary Malignancies
Cases of second primary malignancies have been reported in patients treated with 
enzalutamide in clinical studies. In phase 3 clinical studies, the most frequently reported 
events in enzalutamide treated patients, and greater than placebo, were bladder cancer (0.3%), 
adenocarcinoma of the colon (0.2%), transitional cell carcinoma (0.2%) and bladder 
transitional cell carcinoma (0.1%).  Patients should be advised to promptly seek the attention 
of their physician if they notice signs of gastrointestinal bleeding, macroscopic haematuria, or 
other symptoms such as dysuria or urinary urgency develop during treatment with 
enzalutamide.
Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or 
face, tongue, lip, or pharyngeal oedema, have been observed with enzalutamide. Severe 
cutaneous adverse reactions (SCARs) have been reported with enzalutamide. At the time of 
prescription patients should be advised of the signs and symptoms and monitored closely for 
skin reactions.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Among men in the United States, prostate cancer accounts for more than 200,000 new cancer 
cases and 32,000 deaths annually. Although androgen deprivation therapy yields transient 
efficacy, most patients with metastatic prostate cancer eventually die of their disease. These 
aspects underscore the critical need to articulate both genetic underpinnings and novel 
therapeutic targets in prostate cancer.  During disease progression, CRPC increasingly 
utilizes salvage pathways to evade therapeutic attempts to block growth. Multiple 
mechanisms that may drive progression involve the androgen-receptor (AR) pathway, 
including AR activation via crosstalk of signal transduction pathways such as the IGF axis.
An increasing body of evidence has linked activation of the IGF axis with castrate-resistant 
progression of prostate cancer including via ligand-independent activation of the androgen 
receptor (R13-0706) and increases in IGF-1 (R13-0660), IGF-1R (R13-0018), IGFBP-2 
(R13-0756), and IGFBP-5 (R13-0757). Preclinical studies have supported this approach using 
a variety of IGF pathway inhibitors (R10-5690, R13-0758, R13-0759). In both castrate-
sensitive and –resistant prostate cancer models, activity has been observed with the IGF-1R–
specific monoclonal antibody cixutumumab (formerly IMC-A12), which induced tumour cell 
apoptosis, cell-cycle arrest, and down regulation of ligand-independent, androgen-regulated 
gene expression (R13-0016, R13-0658, R13-0657).A recently completed phase 2 clinical trial 
with figitumumab (formerly CP-751,871), an IgG2 IGF-1R antibody inhibitor that blocks 
IGF-1 binding and promotes receptor internalization, in patients with localized prostate 
cancer showed a decrease in serum levels of prostate specific antigen (PSA) (R13-0656). 
Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant 
prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.
A recent non-clinical study (unpublished in-house study) of enzalutamide (MDV-3100), plus 
BI 836845, was conducted to test the anti-proliferation effects in vitro by 2D cell 
proliferation assay of the combination, when compared to single agent activity. Three of the 
prostate cell lines tested showed single agent responses with enzalutamide and BI 836845 and 
resulted in limited inhibition of cell proliferation; however the combination effect in the same 
cell lines was complete inhibition of cell proliferation. Overall, the results indicate that the 
presence of androgen receptor and IGF-1R, in addition to the expression of PTEN and wild-
type PIK3CA, characterises prostate cancer cells that showed complete inhibition of cell 
proliferation in the presence of the combination of enzalutamide and BI 836845 in vitro.
The progression to CRPC correlates with gain-of-function of the AR and activation of AKT. 
However, as single agents, AR or AKT inhibitors result in a reciprocal feedback loop (R14-
0873). The existence of bidirectional cross-talk between the IGF-1R/PI3K/AKT pathway and 
the AR axis has been proposed (R14-0873) and there is ample evidence for the interaction of 
IGF signaling and the androgen receptor in prostate cancer progression (R14-0855; R14-
0854). Specifically, IGF-1R signaling to activate PI3K/AKT pathway has been proposed to 
be one of the mechanisms to transactivate the AR in the absence of androgen and progression 
to androgen-independent diseases (R14-0855; R14-0851; R14-0852). For instance, Schayek 
et al. showed that re-expression of wild-type AR in an AR-negative metastatic prostate cancer 
cell line M12 led to significant increase in IGF-1R expression. However, when they 


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expressed two AR mutants that were compromised in the ability to bind to androgens or co-
regulators, no effect on IGF-1R expression was seen. The authors thus concluded that 
androgens regulate IGF-1R expression through a genomic pathway. To further support this 
conclusion, they further showed that AR can directly bind to IGF-1R promoter region. These 
data, along with recent evidence indicating that the combination of an AKT inhibitor with an 
antiandrogen, results in prolonged disease stabilization in a model of CRPC, provide further 
evidence for the strategy of targeting the AR and the IGF-1R/PI3K/AKT signaling axis (R14-
0873; P14-02928). Taken collectively, these studies suggest that co-targeting the IGF and AR 
pathways with BI 836845 and enzalutamide may offer synergistic therapeutic benefits for 
prostate cancer.
The above information taken together, demonstrates that targeting the IGF axis is an 
attractive concept as a treatment for prostate cancer.
The present trial shall therefore investigate the safety and anti-tumour activity of 
enzalutamide in combination with BI 836845, compared to enzalutamide given alone, in 
CRPC patients previously treated and failed on docetaxel and abiraterone treatment. Patients 
recruited to this trial may, or may not, have received and failed prior cabazitaxel treatment, in 
any setting.
An expansion cohort, during the phase Ib study, will also be pursued at the maximum 
tolerated dose (MTD), and/or recommended phase II dose (RP2D), in patients that are 
already undergoing treatment with enzalutamide and showing a measured rise in PSA whist 
on enzalutamide according to standard criteria (R13-1642). Patients may not have received 
prior taxane therapy or abiraterone
Overall, this trial is intended to prove the clinical proof of concept for the proposed 
combination of enzalutamide and BI 836845. The data of this randomised II trial will be used 
as the basis for the clinical assumptions for the phase III pivotal trial in an area of high unmet 
medical need.
2.2
TRIAL OBJECTIVES
The primary objectives of the trial are to:
∀
Determine the safety and tolerability profile of BI 836845 in combination with 
enzalutamide following progression on docetaxel-based chemotherapy and 
abiraterone (phase Ib escalation).
∀
Evaluate the anti-tumour activity of BI 836845 in combination with enzalutamide in 
patients naïve to taxane-based chemotherapy and abiraterone (phase Ib expansion 
cohort).
∀
Evaluate the anti-tumour activity between the two treatment arms of BI 836845 in 
combination with enzalutamide versus enzalutamide alone following progression on 
docetaxel-based chemotherapy and abiraterone (phase II), 


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∀
The secondary objectives of the trial are the determination of PSA response and 
progression in combination with anti-tumour activity; changes in circulating tumour 
cells (CTC); plus the determination of overall survival (only in the phase II part of the 
trial).
 
 the incidence and intensity of adverse events according to 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 dated 14 June 2010 
(R10-4848); ECG evaluation correlated with PK assessment. 
 
All patients in the trial have sufficient data to adequately answer the primary and secondary 
objectives of the trial. After approval of protocol version 10, the data collected in the clinical 
trial database will be limited to data required to ensure the safety of the patient, and to support 
safety reporting to authorities. Patient visits and assessments will continue per the revised Flow 
Chart. At the end of the clinical trial, the new reduced data collected will be locked and the 
data will be summarised in a CTR revision.
2.3
BENEFIT - RISK ASSESSMENT
Monotherapy studies performed to date with BI 836845 in patients with various malignant 
tumours has shown the drug to be well tolerated, with only mild to moderate drug related 
adverse events reported of CTCAE Grade 1 and 2 (U10-2830). Published data from IGF-1R 
antagonist therapies report serious adverse events such as hyperglycemias and deaths related 
to metabolic and cardiac adverse events have been reported (P12-08900). Thus, although 
BI 836845 has a different mechanism of action i.e. inhibition of the ligand rather than 
inhibition of the receptor, with the potential to have a different side effect profile, parametch
for glucose metabolism, other metabolic parameters, renal function, other adverse events, 
including full ECG analysis of the QT interval, will be carefully supervised and evaluated in 
the present trial.
BI 836845 is a humanised antibody given intravenously. Infusion reactions and immune 
responses cannot be excluded; and have been reported. Any infusion reactions that occur will 
be carefully evaluated and appropriate preventive and/or corrective action implemented. 
Immune response monitoring and analysis will be assessed continually throughout treatment
and into the follow-up period.
The collection of tumour biopsy in this trial will only be performed if there is a low risk of 
complication and as little discomfort to the patient as possible. Risks and complications 
associated with biopsy are usually small; however they can cause pain or bruising at the 
biopsy site, bleeding, infection, and reaction to local anaesthetic. Very rarely the bleeding 
may be significant and require surgery.  As a consequence, so as to minimise potential risks 
associated with the tumour biopsy, restrictions have been stipulated in this study: patients 
must have controlled haematology parameters and platelet counts, and the use of concomitant 
anti-platelet and anti-coagulation therapy prior to biopsy has been restricted. Patients with a 


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history of a hereditary bleeding disorder, or clinically relevant major bleeding event will be 
excluded from giving a biopsy.
Data from literature suggest that inhibition of the IGF pathway by monotherapy with either 
IGF receptor inhibitors or inhibitors of the IGF ligands may only exert moderate efficacy, 
thus the combination of an IGF inhibitor drug with other drugs already established in the 
treatment of prostate cancer, may confer an advantage.
Patients eligible for participation in the randomised phase II part of the trial will receive 
either BI 836845 in combination with enzalutamide, or enzalutamide alone. The side effects
of enzalutamide are well known and described in the respective SPC. The most common 
adverse reactions with enzalutamide (≥ 5%) are asthenia/fatigue, back pain, diarrhoea, 
arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory 
infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord 
compression and cauda equina syndrome, haematuria, paresthesia, anxiety, and hypertension. 
All adverse reaction will be carefully monitored throughout the course of the trial. The 
addition of BI 836845 to the standard enzalutamide therapy is not expected to substantially 
worsen or contribute to the toxicity profile of enzalutamide; however, the tolerability and 
safety phase of the study will confirm the safety of the combination and determine a 
recommended dose before proceeding to the randomised trial. Renal and hepatic function as 
well as other safety parameters will be carefully examined before each new treatment course.
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.
The phase Ib escalation and expansion parts of the study will be continuously supervised and 
monitored by the BI study team and investigators (steering committee), as described in 
section 3.1.1. An internal Boehringer Ingelheim (BI) data monitoring committee (DMC) will 
be nominated and be responsible for the continuous supervision of the safety of the patients 
included in the phase II randomised trial. 
Patients are expected to benefit from the established and registered enzalutamide treatment. 
The addition of BI 836845 to enzalutamide is hoped to provide additional benefit to patients
that include: improved disease control, increased survival and quality of life over the standard 
therapy alone.
Based on the pharmacological mechanism and existing non-clinical and clinical data, there is 
currently no reason to believe that xentuzumab, either as monotherapy or in combination with 
enzalutamide therapy, will increase the occurrence or worsen the outcomes of a COVID-19 
infection. In the target population of patients with metastatic castration resistant prostate cancer 
and progression on docetaxel-based chemotherapy and abiraterone, the benefit-risk assessment 
for xentuzumab remains positive also in the presence of a COVID-19 outbreak. 
The decision on whether to continue study drugs if a patient develops COVID-19 will be left 
to the investigator’s benefit/risk assessment on a case-by-case basis. Based on laboratory data 
and any adverse event that may occur, the clinical trial protocol includes guidance for 
continuation, interruption, dose reduction, and discontinuation of study drugs.


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The 1280-0022 phase II placebo-controlled, randomized trial recently completed primary 
endpoint analysis and showed no added benefit of xentuzumab compared to placebo, in 
patients with everolimus and exemestane backbone therapy, when treating trial participants 
with metastatic breast cancer, HR+, HER2- and non-visceral disease. No new safety signals 
were observed with the addition of xentuzumab to the everolimus and exemestane 
combination.
In consideration of these top line results of 1280-0022, as of 19 October 2021, Boehringer 
Ingelheim recommended to immediately discontinue all xentuzumab treatments. Sites were 
also recommended to discontinue associated assessments, including central laboratory 
sampling. Boehringer Ingelheim also terminated all oncology development of xentuzumab.
Relative to benefit-risk for any patient continuing on enzalutamide treatment:  The recent 
SmPC label for enzalutamide identified two new risks/warnings:
1. Second primary malignancies:  Cases of second primary malignancies have been 
reported in patients treated with enzalutamide in clinical studies. In phase 3 clinical 
studies, the most frequently reported events in enzalutamide treated patients, and 
greater than placebo, were bladder cancer (0.3%), adenocarcinoma of the colon 
(0.2%), transitional cell carcinoma (0.2%) and bladder transitional cell carcinoma 
(0.1%).  Patients should be advised to promptly seek the attention of their physician if 
they notice signs of gastrointestinal bleeding, macroscopic haematuria, or other 
symptoms such as dysuria or urinary urgency develop during treatment with 
enzalutamide.
2. Severe cutaneous adverse reactions(SCARs):  Hypersensitivity reactions manifested 
by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal 
oedema, have been observed with enzalutamide. Severe cutaneous adverse reactions 
(SCARs) have been reported with enzalutamide. At the time of prescription patients 
should be advised of the signs and symptoms and monitored closely for skin 
reactions.
However, in spite of these rare recently identified serious side effects (low risk of secondary 
malignancies and of severe cutaneous adverse reactions) of enzalutamide noted above, given 
the proven survival benefit of enzalutamide in CRPC patients in the Affirm study (noted 
above in section 1.1), the continued use of enzalutamide in patients having apparent benefit 
remains positive in terms of benefit-risk.  However, investigators should use their discretion 
in weighing all benefits and risks in deciding to continue patients on enzalutamide.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This phase Ib, and phase II randomised open label trial, will be conducted to explore the anti-
tumour activity and safety profile of the combination treatment of BI 836845 and
enzalutamide (Arm A), compared to enzalutamide alone (Arm B) in patients with CRPC.  A 
tolerability and safety phase Ib will initially be performed to determine the MTD, and/or 
recommended phase II dose (RP2D) of BI 836845 in combination with enzalutamide for the 
phase Ib expansion cohort and phase II randomised trial, see figure 3.1:1. In addition, any
safety issues will also be assessed before commencement of the expansion cohort and
randomised trial.
BI 836845 will be administered weekly in 28 day cycles of treatment, as per the Flow Chart, 
by a one hour intravenous infusion. Enzalutamide will be administered daily by continuous 
oral dosing during each treatment cycle.
Phase Ib
Phase II
Figure 3.1: 1
Illustration of study design
N=40
N = 40
Randomised Trial
Patients with CRPC
ECOG 0-1
Post docetaxel & 
abiraterone
Measurable 
Disease
PD
Enzalutamide
BI 836845
+
Enzalutamide
N = 80
Randomised 1:1
R
A
N
D
O
M
I
S
E
ARM A
ARM B
PD
Tolerability/Safety
3+3 Escalation
Patients with CRPC
ECOG 0-2
Post docetaxel & 
abiraterone
Measurable 
disease
Exploratory 
Expansion Cohort
Patients with CRPC
ECOG 0-1
Failing on 
enzalutamide 
( PSA)
Pre taxane-based 
therapy
No prior 
abiraterone   
________
Approximately 25 
pts treated with BI 
836845 +
9-12 pts
treated with BI 
836845 +
enzalutamide


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Phase Ib – Tolerability and safety / expansion cohort:
A 3+3 design tolerability and safety phase (escalation) will initially be performed with a 
single escalation step in order to determine the MTD, and/or recommended phase II doses,
and the safety profile of BI 836845 in combination with enzalutamide. Approximately 9-12
patients may be assessed to determine the MTD and/or the recommended phase II dose
(RP2D). Patients in phase Ib escalation will not be randomised into phase II and will not be 
included in the final efficacy (anti-tumour activity) analysis of the study; however these 
patients will continue treatment until disease progression, undue toxicities, or discontinuation 
for any other reason, see section 3.3.4 for details. 
An exploratory expansion cohort will be pursued in approximately 25 enrolled patients to 
ensure 21 evaluable patients at the MTD, and/or recommended phase II dose (RP2D)
determined in the escalation part of phase Ib described above. A patient is considered 
evaluable if data for the assessment of the primary endpoint is available. Patients recruited to 
this cohort will be on ongoing enzalutamide therapy and be beginning to show a rise in PSA
(as described in section 3.3.2 inclusion #19) on this treatment at the time of consent for the
expansion cohort of the study. These patients will continue to receive enzalutamide from the 
first day of treatment on the study combined with BI 836845. Patients in this expansion 
cohort will continue treatment until disease progression, undue toxicities, or discontinuation 
for any other reason, see section 3.3.4 for details. 
Phase II – Randomised phase II:
In phase II, 80 patients will be randomised in a 1:1 ratio to receive treatment with either BI 
836845 plus enzalutamide (Arm A) at the MTD, and/or the recommended phase II dose
(RP2D) determined in phase Ib escalation, or enzalutamide alone (Arm B), in an open label, 
parallel group study design. Patients will continue treatment until disease progression, undue 
toxicities, or discontinuation for any other reason, see section 3.3.4 for details. 
After discontinuation of all trial drugs and completion of the final follow up visit, see section 
6.1.3, patients will be followed up further (every 90 days after the last follow up visit) for 
survival status in an observation period (until approval of protocol version 10 after which no 
further survival status will be collected).


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Phase I and Phase II:
Patients will be enrolled onto the study at the time of signing the informed consent and will 
conclude participation in the treatment phase of the study once the end of treatment (EOT) 
and last follow-up visit has been performed. If withdrawal from the study falls on a scheduled 
visit then that visit will be considered the EOT and all EOT assessments will be performed. 
For the collection of adverse events, these will be collected from the signing of the informed 
consent (pre-treatment). Patients will still be considered as “on-treatment” from first study 
drug administration until 42 days after the last study drug infusion of BI 836845 and/or the 
last dose of enzalutamide (i.e. at the planned time of the first follow-up visit), whichever is 
the last drug to be taken by the patient.
Prior to approval of protocol version 10, patients that withdraw from treatment and do not 
have progressive disease, or have not started another anti-cancer therapy, will continue with 
limited follow-up visits at scheduled tumour assessments, until start of progressive disease, or 
start of other anti-cancer therapy. Patients, after protocol version 10 is approved will only 
require FU1 at least 42 days after the last study drug infusion of BI 836845 and/or the last 
dose of enzalutamide.
Soft tissue tumour assessment by imaging according to modified Response Evaluation 
Criteria for Solid Tumours (RECIST) version 1.1 (R09-0262 and appendix 10.4), as well as 
bone scans according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) (R13-
1642 and section 5.1.2.1), at baseline, every two cycles until week 24 and then every three 
cycles thereafter as per the Flow Chart.  Assessment of response will be performed at the 
investigator site and will be sufficient for the decision to allow a patient to continue on 
treatment in the study. Patients should be kept on trial until radiographic, and/or bone scan 
progression and/or symptomatic progression, which may include PSA progression. Patients 
should not be discontinued due to rising PSA alone. During phase II an independent analysis 
of response will also be performed by a central imaging unit CRO (see section 5.1.3); 
however this CRO will not be used to make treatment decisions.
PSA collection
 
CTC collection will be performed throughout phase Ib and phase II as per the time-points 
specified in the relevant Flow Chart and Appendix 10.6.
The study will be performed by investigators specialised in the treatment of advanced solid 
cancers, especially CRPC, and experienced in phase I/II oncology trials. The sites will have 
available all equipment necessary for dealing with any serious side-effects and potential 
emergencies.


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI). BI will appoint a Trial Clinical Monitor, 
responsible for coordinating the activities required in order to manage the trial in accordance 
with applicable regulations and internal standard operating procedures (SOPs), directing the 
clinical trial team in the preparation, conduct, and reporting of the trial, order the materials as 
needed for the trial, ensures appropriate training and information of local clinical monitors 
(CMLs), clinical research associates (CRAs), and investigators of participating countries.
Data management and statistical evaluation will be performed by BI according to BI SOPs. 
For these activities, a Trial Data Manager and a Trial Statistician will be appointed. Tasks 
and functions assigned in order to organise, manage, and evaluate the trial will be defined 
according to BI SOPs. Special tasks may be contracted to a CRO. A list of responsible 
persons will be given in the Clinical Trial Master File (CTMF) document. In each local BI-
organisation (OPU) participating in this study, a local clinical monitor (CML) will be 
appointed responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI OPU. On-site monitoring will be performed by Boehringer Ingelheim or a CRO 
appointed by Boehringer Ingelheim.
A Co-ordinating Investigator will be nominated to coordinate investigators at different sites 
participating in this multicentre trial and to sign the clinical trial report. Documents on 
participating (Principal) investigators and other important participants, especially their 
curricula vitae, will be filed in the Clinical Trial Master File (CTMF).
Evaluation of the imaging findings and response assessment will be performed at the 
investigational site. Independent review will be performed by a central imaging unit CRO in 
the phase II randomised trial.
The trial drugs (where required) will be provided by BI or a CRO appointed by BI. The trial 
drugs will be stored according to the required storage conditions.
During phase Ib dose escalation phase of the study, regular teleconference will be held 
between the investigators and BI study team for review of safety data, decisions over dose
escalation, discussions of on-going patients, and discussion of operational aspects. Relevant 
safety, laboratory, and efficacy data should be reviewed by on-site monitoring and, if 
possible, recorded in the eCRF before the teleconference. During the regular teleconferences 
with the investigators and BI study team, the next higher dose level will be determined from 
the progress of existing patients at the current dose level and in consideration of available 
safety, toxicity and PK-PD data. Any potential patients for the trial will also be discussed. 
The decision to conclude dose escalation should be agreed by the investigators and BI study 
team. The decision to commence the expansion cohort and phase II will be discussed between 
the investigators and BI study team. All teleconference details will be documented 
accordingly and reviewed by all investigators. Approval of the entry of a new patient into any 
cohort will be confirmed, and documented, in a fax or e-mail between the CML and the 
investigator/site.


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During phase Ib dose expansion phase of the study, regular teleconferences will be held 
between the investigators and BI study team for review of safety data, discussions of on-
going patients, and discussion of operational aspects. Relevant safety, laboratory, and 
efficacy data should be reviewed by on-site monitoring and, if possible, recorded in the eCRF 
before the teleconference. Any potential patients for the trial will also be discussed. 
An internal DMC for the phase II study will be appointed by BI which will represent an
independent group of experts at BI who, collectively, have expertise in the evaluation of 
efficacy and safety and data quality and in the conduct and monitoring of clinical trials. The 
DMC’s responsibility will be the continuous assessment of the trial data to ensure overall 
safety in the patients treated, monitor the quality and provide the trial team with advice about 
the conduct of the trial and the integrity of the data in the phase II randomised trial. Details of 
the DMC responsibilities and frequency of data review will be described in the DMC charter.
All trial relevant documentation will be stored in BI’s CTMF document according to BI 
SOPs. Trial relevant documentation which has to be at the trial site will be filed in the 
investigator site file (ISF) at the investigator site. The ISF document will be kept in print-out 
version at the sites as required by local regulation and BI SOP. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
BI 836845 is currently being investigated as monotherapy in two phase I trials (U11-3025, 
U10-2994) in various malignant tumour indications. A relevant biological dose (RBD) of 
BI 836845 has been determined as the recommended dose for monotherapy and will be the 
basis for determining the dose that can be used safely in combination with other therapies. 
Given the good tolerability and safety profile of BI 836845 it is expected that the addition of 
enzalutamide at the labelled dose might be combined safely. 
Thus, the phase Ib dose confirmation part of this trial aims to determine the MTD, and/or 
recommended phase II dose, of BI 836845 to be used in combination with enzalutamide for 
the treatment of metastatic CRPC is deemed a sufficient safety analysis before 
commencement to the expansion cohort and phase II randomised trial. This design allows for 
a simple transition from the safety and tolerability dose-finding phase Ib, to the randomised 
phase II proof of concept trial, thereby preventing delays in the development of BI 836845 in 
CRPC.
The initial tolerability and safety phase Ib of the trial (escalation) will be performed to 
determine the MTD and/or recommended phase II dose (RP2D) and any safety issues of 
combining enzalutamide and BI 836845 before commencement of the randomised trial and 
the exploratory expansion cohort. The traditional 3+3 design remains the prevailing method 
for conducting phase I cancer clinical trials. The main advantages of the 3+3 design are that it 
is simple to implement and considered safe for patients. In addition, the accrual of three 
patients per dose level will provide additional information regarding the pharmacokinetic 
inter-patient variability. The 3+3 rule-based design will allow for the assignment of patients 
to chosen dose levels according to specified rules, or DLTs, based on actual observations of 
target events noted from the clinical data. The MTD will be determined using the DLT 
criteria specified in this protocol, see section 5.2.3.


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The exploratory expansion cohort is to be conducted in patients that are already undergoing 
treatment with enzalutamide and are beginning to show a rise in PSA level according to 
standard criteria (R13-1642). Patients may not have received prior taxane chemotherapy or
abiraterone treatment for inclusion into this part of the study. The results of the expansion 
cohort will not affect the continuation of the randomised phase II trial. Further data 
concerning safety, QT assessment and drug-drug interactions will also be collected 
throughout this cohort.
The phase II trial will be performed according to an open-label, randomised design. Blinding 
is not considered ethical, or necessary. The determination of radiological disease progression 
will be assessed by the investigational site and as recommended by modified RECIST 1.1 
(R09-0262), and Prostate Cancer Clinical Trials Working Group Criteria (PCWG2) (R13-
1642) as per Appendix 10.4 and Section 5.1.2.1, to assess whether a patient should remain on 
trial. However, an independent central imaging unit will be used to analyse and confirm 
progression free survival endpoint in the phase II trial in a blinded manner. Internal review by 
the trial team will also be blinded.
All patients will receive the standard enzalutamide regimen that is registered and 
recommended by the manufacturer during the phase Ib escalation, expansion cohort, and the 
phase II randomised trial, regardless of the treatment arm to which they are randomised.
The main objective of the trial is to test and support the hypothesis that BI 836845 will 
improve clinical outcome when combined with enzalutamide in patients with advanced 
and/or metastatic CRPC. 
3.3
SELECTION OF TRIAL POPULATION
A total of up to approximately 120 patients may be recruited into the study.  Approximately 
9-12 patients will be entered into the phase Ib tolerability and safety phase of the study 
(escalation part) to ensure the safety of the combination therapy and determine the MTD 
and/or recommended phase II dose (RP2D). For the exploratory expansion cohort
approximately 25 patients will be treated with BI 836845 at the MTD, and/or recommended
phase II dose (RP2D) in combination with enzalutamide.
In phase II of the study, 80 patients will be randomised onto one of the two study arms, with 
40 patients randomised to each arm (Arm A=40, Arm B=40).  
The Phase Ib escalation part of the study will be performed in 4 or more centres. The Phase 
Ib expansion part of the study will be performed in 8 or more centres. The Phase II of the 
study will be performed in 25-30 centres globally.
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.


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3.3.1
Main diagnosis for study entry
Patients to be included in this trial must have diagnosed and histologically, or cytologically,
confirmed metastatic CRPC.
For the phase Ib dose escalation cohort and phase II cohort patients must have received and 
progressed after docetaxel-based chemotherapy and abiraterone treatment in any setting. 
Patients may, or may not, have received and failed prior cabazitaxel treatment, in any setting.
For the exploratory expansion cohort patients will have received enzalutamide and be 
beginning to show a rise in PSA level according to standard criteria (R13-1642), and as per 
section 3.3.2 (inclusion criterion #19), prior to entry into the trial. Patients must not have 
received prior docetaxel, cabazitaxel or abiraterone treatment, in any setting.
3.3.2
Inclusion criteria
1. The patient has histologically, or cytologically, confirmed adenocarcinoma of the 
prostate. 
2. Male patient aged ≥ 18 years old.
3. Patients with radiographic evidence of metastatic prostate cancer (stage M1 or D2). 
Distant metastases evaluable by radionuclide bone scan, CT scan, or MRI within 28 
days before the start of study treatment.
4. Patients with a PSA ≥ 5 ng/mL. 
5. Patients with prior surgical or chemical castration with a serum testosterone of <50 
ng/mL. If the method of castration is luteinizing hormone releasing level hormone 
(LHRH) agonists, the patient must be willing to continue the use of LHRH agonists 
during protocol treatment. 
6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. 
7. Cardiac left ventricular function with resting ejection fraction ≥50% as determined by 
ECHO or MUGA.
8. Absolute neutrophil count (ANC) ≥1500/uL.
9. Haemoglobin ≥9 g/dL.
10. Platelets ≥100,000/uL. 
11. Bilirubin ≤ 1.5 times the upper limit of normal (ULN).
12. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 times the ULN
(or ≤ 5 times the ULN if liver metastases are present). 
13. Creatinine ≤ 1.5 x ULN.
14. International normalized ratio (INR) ≤ 2 and a partial thromboplastin time (PTT) ≤ 5 
seconds above the ULN (unless on oral anticoagulant therapy). Patients receiving full-


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dose anticoagulation therapy are eligible provided they meet all other criteria, are on a 
stable dose of oral anticoagulant or low molecular weight heparin (except warfarin or 
coumarin-like anticoagulants, which are not permitted). 
15. Fasting plasma glucose < 8.9 mmol/L (< 160 mg/dL) and HbA1c < 8.0%.
Inclusion criteria only for patients entering phase Ib dose escalation and phase II:
16. Patients who have disease progression during, or after, receiving docetaxel and have 
had at least 12 weeks of treatment  and in the opinion of the investigator are unlikely 
to derive significant benefit from additional docetaxel-based therapy, or were 
intolerant to therapy with this agent.
17. Patients who have disease progression during, or after, receiving abiraterone treatment 
in any setting.
18. Patients must have progressive disease defined as at least one of the following:
a.
Progressive measurable disease: using conventional solid tumour criteria 
RECIST 1.1.
b. Bone scan progression: at least two new lesions on bone scan, plus a rising 
PSA as described in c below.
c.
Increasing PSA level: at least two consecutive rising PSA values over a 
reference value (PSA #1) taken at least 1 week apart. A third PSA (PSA #3) is 
required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required 
to be greater than PSA #2.   
Inclusion criterion #19 only for patients entering phase Ib expansion cohort:
19. Patients must be receiving continuous enzalutamide treatment and show a rise in PSA
level: at least two consecutive rising PSA values over a reference value (PSA #1) 
taken at least 1 week apart. A third PSA (PSA #3) is required to be greater than PSA 
#2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2. 
20. Archive tumour tissue is available prior to recruitment for pharmacogenomic tests.
3.3.3
Exclusion criteria
1. Exclusion criterion 1 is not applicable for patients enrolled after protocol version 3 (or 
subsequent versions) are approved.
2. Exclusion criterion 2 is not applicable for patients enrolled after protocol version 3 (or 
subsequent versions) are approved.
3. Prior therapy with agents targeting IGF and/or IGFR pathway.
4. Patients that have been treated with any of the following within 4 weeks of starting 
trial treatment: chemotherapy, immunotherapy, biological therapies, molecular 
targeted therapy, hormone therapy (except LHRH agonists and LHRH antagonists), 


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radiotherapy (except in case of localized radiotherapy for analgesic purpose or for 
lytic lesions at risk of fracture which can then be completed within 2 weeks prior to 
study treatment).
5. Use of any investigational drug within 4 weeks before start of trial treatment or 
concomitantly with this trial.
6. Patients that have been treated with strong CYP2C8 inhibitors, CYP2C8 inducers,
within 2 weeks of starting the trial treatment.
7. QTcF prolongation > 450 ms or QT prolongation deemed clinically relevant by the 
investigator (e.g., congenital long QT syndrome). The QTcF will be calculated as the 
mean of the 3 ECGs taken at screening.
8. Patients with small cell or neuroendocrine tumours.
9. Patients with known or suspected leptomeningeal metastases.
10. Uncontrolled or poorly controlled hypertension.
11. Exclusion criterion 11 is not applicable for patients enrolled after protocol version 5 
(or subsequent versions) are approved.
12. Known human immunodeficiency virus infection or acquired immunodeficiency 
syndrome-related illness.
13. Patients with epilepsy, seizures, or predisposing factors for seizure as judged by the 
investigator.
14. Patients unable to comply with the protocol as judged by the investigator.
15. Active alcohol or active drug abuse as judged by the investigator.
16. A history of allergy to human monoclonal antibodies.
17. Patients who are sexually active and unwilling to use a medically acceptable method 
of contraception, e.g. condom plus spermicide use for participating males,  plus
another form of birth control such as implants, injectables, combined oral 
contraceptives, intrauterine devices for female partners, during the trial and for at least 
three months after end of active therapy. Men unwilling to agree to not donate sperm 
while on trial drug and up to 6 months following the last dose of trial drug.
Exclusion criteria only for patients entering phase Ib dose escalation and phase II:
18. Patients that have received prior enzalutamide in any setting will not be eligible.
Exclusion criterion only for patients entering phase Ib expansion cohort:
19. Patients that have received prior taxane-based chemotherapy or abiraterone in any 
setting will not be eligible for the expansion cohort.
Additional exclusion criterion for patients undergoing tumour biopsy:


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20. For patients that are to undergo the tumour biopsy, a history of a hereditary bleeding 
disorder, or clinically relevant major bleeding event in the past 6 months, as judged by 
the investigator.
After approval of protocol version 3 (or subsequent versions) the additional following 
exclusion criteria apply:
For all patients:
21. Previous or concomitant malignancies at any other site with the exception of the 
following: 
a.) benign basal cell carcinoma
b.) benign low grade transitional cell carcinoma of the bladder
c.) other effectively treated malignancy that has been in remission for 
more than 5 years and is considered to be cured
Only for patients entering phase Ib dose escalation and phase II cohorts:
22. Patients who have received more than 2 prior non-docetaxel-containing cytotoxic 
chemotherapy regimens for Metastatic Castration-Resistant Prostate Cancer 
(mCRPC). 
23. Patients who have received a taxane based treatment or abiraterone, within 4 weeks 
before start of study treatment.
After approval of protocol version 6 (or subsequent versions) the additional
following exclusion criteria apply:
Onlyfor patients entering phase Ib dose expansion cohort:
24. Patients that are in immediate need of chemotherapy (e.g. for visceral disease, or 
intractable pain) should be excluded.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient must discontinue therapy with the trial drug(s) in case the following apply: 
1. The patient withdraws consent to further study treatment 
2. The patient develops unequivocal disease progression, supported by radiological evidence 
where possible.
3. An individual patient violates eligibility criteria which would affect the safety of the 
patient and/or the patient fails to comply with the protocol (after discussion between the 
sponsor and the investigator)


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4. The patient is receiving forbidden concomitant therapy affecting the safety of the patient 
according to the judgment of the investigator (refer to section 4.2)
5. The patient is no longer able to participate for other medical reasons (e.g. surgery, 
adverse events, or other diseases)
6. The patient meets one of the criteria that require permanent discontinuation of trial drug 
or dose reductions beyond those specified in section 4.1.4.4
7.  Investigator and patient (following discussion) consider it in the patient’s best interest to 
remove the patient from BI 836845 following results of the phase II trial.
8.  The trial is terminated for any of the reasons listed in section 3.3.4.2 ”Discontinuation of 
the trial by the sponsor”.
Patients who discontinue or withdraw prior to entering the active treatment phase will be 
entered in the trial database and will be reported. The data for patients who discontinued or 
withdrew from the trial after entering the active treatment phase must be documented and the 
reason for withdrawal must be recorded in the eCRF. These data must be included in the trial 
database and must be reported.
If an individual patient withdraws consent for further participation in the trial including 
withdrawal to be followed up, the patient will be asked to have an end of trial investigation 
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 done for this patient. 
However, the investigator will be allowed to report the date and reason of death in case of
public registry, or the investigator becomes aware of the date and/or reason for death.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial or any other administrative reasons.
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial.
4. Discontinuation of the clinical development program with BI 836845 in CRPC.
As described in section 2.3 Benefit-risk assessment, topline results of 1280-0022 showed 
no added benefit of xentuzumab compared to placebo when treating participants with 
metastatic breast cancer. Consequently, the clinical development of xentuzumab (BI 
836845) was discontinued by Boehringer Ingelheim in oncology generally, including in 
CRPC.  Due to the worsening in benefit-risk and the discontinuation of the clinical 
development program with BI 836845 in CRPC, the trial will proceed towards 
termination based on the following 3 steps:
a. For xentuzumab-treated patients, the xentuzumab treatment will not extend past the 
drug expiration date (May 2023) of the last planned GMP manufacturing batch of IMP 
xentuzumab (provided that all patients are on xentuzumab for at least 2 years, and they 


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are tolerating the drug without tumor progression). Patients that will discontinue 
xentuzumab can still be eligible for continued treatment with enzalutamide (standard of 
care in this setting) provided they are tolerating the drug without tumor progression.
b. When all patients have discontinued xentuzumab treatment, if any patient on 
enzalutamide is able to continue taking this approved medication off study, then, at the 
request of the sponsor, the patient may end such treatment as part of the trial and 
discontinue study participation (if both the Investigator and patient agree).
c. After all patients end treatment with all study drugs (xentuzumab and enzalutamide), 
the trial will be terminated.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of patients 
For phase Ib escalation:
Patients will be replaced for determination of the primary endpoint (MTD) in cases of:
∀
Patient’s withdrawal during the first cycle of treatment for reasons other than DLT, e.g. 
patient no longer wishes to participate, or lost to follow up during first cycle.
∀
Patients who do not experience DLT, but miss more than one dose of BI 836845 during 
the first cycle of treatment. 
∀
Patients who do not experience DLT, but miss 3 or more consecutive doses of 
enzalutamide during the first cycle of treatment.
∀
Patients who miss one complete cycle at any time beyond the first cycle of treatment may 
be replaced after discussion between the sponsor and the investigator.
∀
Patients who are non-evaluable with respect to DLT.
∀
Patients with CTCAE grade ≥3 allergic reaction/hypersensitivity to the study drug(s) 
within the first cycle will be replaced.
Patients that have been replaced might continue treatment in the trial should criteria in section 
4.1.4.4 apply; however these patients will not be considered for analysis of the primary 
endpoint of this part.
For phase Ib expansion cohort:
Patients who withdraw after assignment but before start of therapy will be replaced.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator product(s)
Substance:
BI 836845 humanised monoclonal antibody
Pharmaceutical form:
Liquid formulation
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml of BI 836845 supplied in 20 ml vials. Appropriate dose 
of BI 836845 will be diluted in physiological sodium chloride 
solution (0.9%).
Duration of use:
One hour at the start of each week (Day 1, 8, 15 and 22) of a 28
day cycle of treatment until disease progression or undue toxicities. 
Infusion duration may be extended to over one hour in case of 
infusion reaction or adverse events.
Route of administration: Intravenous
Starting dose:
750 mg (possible dose adjustments to 500 mg and 1000 mg) total 
dose by one hour i.v. infusion 
Additional information:
Starting dose may be adjusted during phase Ib tolerability/safety 
and dose finding phase
Substance:
Enzalutamide (Xtandi®)
Pharmaceutical form:
Liquid-filled soft gelatin capsule or film-coated tablets
Source:
Unit strength:
40 mg or 80mg
Duration of use:
Daily dose during each 28 day cycle of treatment
Route of administration: Oral
Starting dose:
160 mg (possible dose adjustments to 120 mg and 80 mg) daily as 
per SPC
Additional information:
None 


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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 
written informed consent are eligible for participation in the study.
Patients entering Phase Ib:
∀
At least 9-12 eligible patients will be entered into the safety and tolerability phase Ib, 
dose escalation part of the study and receive BI 836845 plus enzalutamide. Patients 
will be entered in a 3+3 design with a single dose escalation, dependent on DLTs 
observed.  
∀
Approximately 25 patients will be entered into the exploratory expansion cohort at the 
MTD and/or recommended phase II dose (RP2D) determined from the above safety
and tolerability phase.
Patients entering Phase II will be randomised at the first visit of Cycle 1 in a 1:1 ratio to 
either:
∀
Arm A and receive BI 836845 plus enzalutamide, or 
∀
Arm B and receive enzalutamide alone
Treatment assignment in the randomised trial will be by means of a third-party phone /web-
based randomisation during the screening phase. This will involve the use of an interactive 
response technology (IRT i.e. Interactive Voice Response System [IVRS]/Interactive Web 
Response System [IWRS]). To facilitate the use of the IRT, the investigator will receive an 
IRT worksheet for each patient with the complete IRT dialogue and all necessary instructions 
for using the IRT.
4.1.3
Selection of doses in the trial
4.1.3.1 BI 836845
The dose level and frequency of BI 836845 was determined following phase I dose escalation 
studies in both a weekly (U11-3025) and 3-weekly dosing scheme (U10-2994).  Minimal 
protocol defined DLTs were observed and no MTD was reached in either study; however a 
relevant biological dose was determined.
A dose of BI 836845 is considered biologically relevant, when concentrations of free IGF-1 
and free IGF-2 are considerably reduced over time. Free IGF-1 and free IGF-2 plasma 
concentrations are not measured in studies 1280.1 and 1280.2. Therefore a semi-mechanistic
PK/PD model was developed describing the time-dependent kinetics of and the interaction 
between BI 836845 and the different PD biomarkers (i.e. IGF-1, IGF-2, and IGFBP3) over 
time. Simulations using this model indicate that a weekly dosing of 1000 mg BI 836845 
reduces free IGF-1 concentration by more than 90% and in addition free IGF-2 by 64 % at 
trough steady-state relative to pre-treatment; this is considered a relevant biological effect. 
Therefore, a weekly dose of 1000 mg BI 836845 is considered a suitable dose.


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The exact dose of BI 836845 to be used in the expansion cohort and combination treatment 
arm of the phase II study will be determined during the phase Ib tolerability and safety phase,
(phase Ib escalation phase) see section 4.1.3.3.
4.1.3.2 Enzalutamide
The recommended dose of enzalutamide, as per the SPC, is 160 mg (four 40 mg capsules, 
four 40mg tablets or two 80mg tablets) administered orally once daily and can be taken with 
or without food (for dosing instructions on PK sampling visits see below).
4.1.3.3
Determination of the dose of BI 836845 in combination with enzalutamide
The phase Ib tolerability and safety phase (phase Ib escalation cohort) will be performed to 
determine the MTD, recommended phase II dose (RP2D) of BI 836845 in combination with 
enzalutamide using a 3+3 design in order to confirm the recommended dose to be used in the
phase II randomised trial and exploratory expansion cohort.
Dosing with BI 836845 will be as follows:
∀
The starting dose of BI 836845 will be 750 mg (75%) total dose plus 160 mg (100%) 
daily dose of enzalutamide.  
o
If 0 out of 3 patients experience a DLT enter 3 patients at highest dose of BI 
836845
o
If 1 out of 3 patients experience a DLT enter 3 more patients at starting dose 
of BI 836845. 

If 0 of 3 of these additional patients experience a DLT move to highest 
dose of BI 836845. 

If ≥ 1 out of 3 of these additional patients experience a DLT trial is 
stopped. 
o
If ≥ 2 out of 3 patients experience a DLT trial is stopped.
∀
The highest dose of BI 836845 will be 1000 mg (100%) total dose plus 160 mg 
(100%) daily dose of enzalutamide.
o
If ≤1 out of 3 patients experience a DLT enter 3 additional patients at 
highest dose of BI 836845.
o
If ≥ 2 out of 3 patients experience a DLT:

If only 3 patients are entered at starting dose of BI 836845 enter 
additional 3 patients at starting dose of BI 836845

If 6 patients are already recruited in starting dose regimen recruitment 
into escalation part of trial is complete.


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The MTD will be defined as the dose level at which one or less DLT is observed in six 
patients during the first cycle of treatment of each patient (28 days). See section 5.2.4
Non-evaluable patients for DLT will be replaced. 
The decision on dose escalation and determination of next dose, the MTD, and/or 
recommended phase II dose (the exploratory expansion cohort will also use the same dose as 
Phase II) will be determined after discussion with the trial team comprising of at least one BI 
Clinical Monitor, BI project physician (TMM) and Coordinating Investigator, or designee, 
and taking into account patient safety.
4.1.3.4 Exploratory expansion cohort
For the exploratory expansion cohort patients will have received prior enzalutamide, but no 
prior abiraterone for CRPC, and while on enzalutamide show a rise in PSA according to 
standard criteria (R13-1642), and section 3.3.2 (inclusion criterion #19), before entry into the 
trial. Patients may not have received any prior taxane-based chemotherapy before entering 
this cohort. Approximately 25 patients will be treated with the combination therapy of BI 
836845 and enzalutamide at the MTD and/or recommended phase II dose (RP2D).  This 
expansion cohort will allow for further safety, tolerability and PK assessments (including 
investigation of potential drug-drug interaction), in addition to the evaluation of anti-tumour 
activity.
The current enzalutamide treatment taken prior to the trial must be continued after 
patient informed consent and throughout the screening period and up to the day before
the dosing with BI 836845. A compliance check of enzalutamide taken prior to the first day 
of study treatment should be performed to ensure consistent dosing up to the point of entry 
into the study, see section 4.3.
Safety will be continually assessed and reported accordingly for all repeated cycles of 
treatment for all patients throughout the phase Ib escalation and at the MTD and/or 
recommended phase II dose (RP2D).
4.1.4
Drug assignment and administration of doses for each patient
4.1.4.1
Phase Ib tolerability/safety and dose finding phase
Initially, three patients will be treated at the starting dose regimen (75% BI 836845 and 100% 
enzalutamide). Dose escalation will be performed according to the rules outlined in Section 
4.1.3.3. Dose escalation and entry of patients into the highest dose regimen will begin only 
after accrual of the required minimum number of patients has been achieved and all patients 
in the cohort have completed cycle 1 (28 days) of treatment. Patients who are not treated to 
the end of the first cycle for any reasons other than DLT will be replaced, as per section 3.3.5. 
MTD is the highest dose at which no more than one of 6 patients experiences DLT within the 
initial treatment cycle. Six patients must be treated at the MTD, or recommended phase II
dose (RP2D) before commencement of the phase Ib exploratory expansion cohort and phase
II.  


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Prior to inclusion of any new patient, the investigator must confirm the correct dose with the 
BI Clinical Monitor by means of a fax registration form. If a patient develops a DLT, 
treatment must be paused and a dose reduction must occur as per the details described in 
section 4.1.4.4. 
BI 836845 vials will be allocated by the IRT system at each weekly visit before study drug 
administration.
4.1.4.2
BI 836845 (Phase Ib and Phase II - Arm A)
BI 836845 will be given intravenously as a single dose over approximately one hour (60 
minutes), with repeated weekly administration on day 1, 8, 15 and 22 of every 28 day cycle 
of treatment in phase Ib and Arm A in phase II.
BI 836845 will be administered in the exploratory expansion cohort and phase II Arm A, at 
the MTD and/or recommended phase II dose (RP2D) level determined during phase Ib
tolerability and safety (escalation).
Infusion reactions that might occur during infusion with BI 836845, e.g. pyrexia, chills, 
rigors, dyspnoea, urticaria, bronchospasm, hypotension, hypertension, may be managed by
reducing the infusion rate and administering prophylactic antihistamines for subsequent 
dosing. Severe reactions may require immediate and permanent discontinuation of infusion. 
A one hour observation period is recommended following each infusion for the first 3 cycles 
of treatment and at least a 15 minute observation period is recommended following 
subsequent infusions. See section 4.2.1.1.
Infusion reactions will not be reported on the standard AE page but will be reported on a 
separate page specifically for infusion reactions in the CRF.
BI 836845 vials will be allocated by the IRT system at every weekly visit.
4.1.4.3
Enzalutamide (Phase Ib and Phase II- Arm A and B)
On the days of infusion, the enzalutamide dose (160mg daily) should be taken in the clinic 
immediately after the start of the infusion of BI 836845. On all other days patients must take 
the recommended enzalutamide dose of 160 mg daily, as per the SPC at the same time of day 
and preferably in the morning.
On the days of PK sampling, enzalutamide must be taken in the clinic, and not at home.
For countries where enzalutamide is supplied, enzalutamide packs will be allocated by the 
IRT system for every weekly visit and/or the start of every cycle dependent on the part of the 
trial to which the patients are entered. The supply will cover either a full week (7 days), or a 
full cycle (28 days), of treatment. Back-up packs will be provided. Replacement packs will 
also be available for supplies that might be lost by the patient, or where there might be a 
delay in the first visit of a cycle.
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to 
ensure patient’s safety. Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue the trial treatment and trial medication may be 
shipped to the patient’s home if acceptable according to local law and regulations. The 


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shipment should occur via a courier approved by the sponsor in order to ensure correct 
conditions of shipment.
4.1.4.4 Temporary treatment interruption and dose reduction for BI 836845 and 
enzalutamide during phase Ib and phase II
Drug-related DLTs or those adverse events requiring dose adjustment, will be managed by a 
pause in treatment followed by a subsequent dose reduction of the relevant medication
according to tables 4.1.4.4:1 and 4.1.4.4:2. In phase Ib escalation, BI 836845 and 
enzalutamide must be paused when a drug-related DLT occurs regardless of the cycle of 
treatment. In the phase Ib exploratory expansion cohort and phase II, the causal drug(s) 
should be paused regardless of the cycle of treatment. In both phase Ib and phase II, the 
patient will be kept on study until both BI 836845 and enzalutamide are permanently stopped
and the patient is discontinued.
Table 4.1.4.4: 1 Dose interruption/reduction scheme by AE type and CTCAE Grade (Phase I 
and II)
AE Type and CTC Grade
Action
∀
AST or ALT > 5x ULN (for 
baseline AST/ALT ≤ ULN) or > 
(baseline value + 4x ULN) (for 
baseline AST/ALT > ULN)
∀
CTCAE Grade 3 or 4 toxicity
∀
CTCAE Grade 2 infusion reaction 
despite adequate pre-medication.
∀
CTCAE Grade 2 nausea and/or 
vomiting persisting for 7 or more 
days despite antiemetic treatment.
∀
Any other study drug related 
toxicity at any time point during 
the study considered significant 
enough to be qualified as AE 
requiring dose reduction in the 
opinion of the investigators and 
confirmed by the safety review 
with the BI clinical monitor
In phase Ib escalation both treatments should 
be paused. In phase Ib expansion and Phase II 
only causal treatment should be paused.
BI 836845 treatment may resume when 
patient has recovered to grade ≤1 or baseline. 
Baseline is defined as the CTCAE grade at 
the start of treatment. Resume treatment at 
reduced dose according to table 4.1.4.4:2
If patient has not recovered to Grade ≤1 or 
baseline within 28 days study treatment must 
be permanently discontinued*
Enzalutamide treatment should be withheld 
for one week or until symptoms improve to ≤ 
Grade 2, then resumed at the same or a 
reduced dose if warranted, as per the SPC. 
Resume treatment at reduced dose according 
to table 4.1.4.4:2
If patient has not recovered to ≤ Grade 2 or 
baseline within 28 days, enzalutamide must 
be permanently discontinued*
Dose reductions will only apply to individual 
patients. Doses of BI 836845 and/or 
enzalutamide may be reduced independently
of one another. Once the treatment dose has 


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Table 4.1.4.4: 1 Dose interruption/reduction scheme by AE type and CTCAE Grade (Phase I 
and II) (continued)
AE Type and CTC Grade
Action
been reduced, an increase back up to the 
previous dose will not be permitted.
Seizure (any grade)
Patients who develop seizure must stop 
enzalutamide; however they will be 
permitted to continue BI 836845 (in the 
combination treatment) if deemed 
appropriate by the investigator and if 
criteria of removal from trial are not met.
Any unrelated AEs
The study drug(s) may be interrupted for 
up to 28 days, but no dose reduction 
should occur unless indicated in the 
current drug label/SPC of enzalutamide. 
Otherwise, the decision to continue with 
the study treatment will be made by the 
BI Clinical Monitor in agreement with 
the investigator.
*In the event that the patient is deriving obvious clinical benefit to the judgement of the 
investigator, e.g. stable disease or an objective response further treatment with the study drug 
will be decided only after agreement between the investigator and the BI clinical monitor
Dose reduction of BI 836845 and/or enzalutamide:
Either treatment may be resumed at a reduced dose; however only two dose reductions of BI 
836845 or enzalutamide will be permitted. If more than two dose reductions of the same drug
are required then the patient should be removed from the drug treatment. A patient will be 
kept on study until both BI 836845 and enzalutamide are stopped. Dose reduction below 500 
mg for BI 836845 or 80 mg for enzalutamide will not be permitted. See table 4.1.4.4:2 for 
details of dose reduction. 
Table 4.1.4.4: 2 Allowed dose reductions BI 836845 and enzalutamide
Dose Level
BI 836845 mg 
weekly total dose
BI 836845 mg 
weekly total dose
Enzalutamide mg 
daily total dose
Starting Dose 
(0)
1000
750
160
1st Reduced 
Dose (-1)
750
500
120
2nd Reduced 
Dose (-2)
500
OFF DRUG
80


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4.1.4.5
Additional cycles of treatment
Patients demonstrating clinical benefit from treatment with the combination of BI 836845 and 
enzalutamide in phase Ib, and who have recovered from any clinically relevant drug-related 
AE, are eligible for further treatment cycles as per the Flowchart, until they experience 
disease progression, or undue toxicities.  Safety will be continually assessed in repeated 
cycles of treatment and reported accordingly.
Patients demonstrating clinical benefit from treatment with the combination of BI 836845 and 
enzalutamide or enzalutamide alone in phase II, and who have recovered from any clinically 
relevant drug-related AE, are eligible for further treatment cycles as per the Flowchart, until 
they experience disease progression, or undue toxicities.  Safety will be continually assessed 
in repeated cycles of treatment and reported accordingly.
4.1.4.6
Preparation of BI 836845
Refer to the ISF for details of the preparation and handling regimen of BI 836845; including 
information on equipment, infusion procedure and process.
BI 836845 must be diluted in physiological sodium chloride solution (0.9%) in infusion bags.  
Infusion bags containing BI 836845 diluted solutions should be refrigerated at 2-8◦C; at this 
temperature they must be administered within 24 hours.  Infusion bags stored at room 
temperature must be administered within 6 hours.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label study. Blinding is not applicable. However, to reduce bias, the BI study 
team will be blinded for the aggregated phase II data at the treatment level until the trial 
database lock (see Section 3.2 and 3.1.1).
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The trial drugs, enzalutamide and BI 836845, where required, will be provided by Boehringer 
Ingelheim, or a CRO appointed by Boehringer Ingelheim. Medication will be labelled 
according to the legal requirements. Medication to be administered for premedication will not 
be provided and must be provided by the investigational site.
For details of packaging and the description of the label, refer to the ISF.


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Drug supply and resupply for phase Ib will be managed internally by BI and/or IRT. Drug 
supply and resupply in the phase II randomised study will be managed via the IRT system.
4.1.7
Storage conditions
The trial drug BI 836845, and enzalutamide, must be stored in their original packaging under 
the storage conditions stated on the label in the hospital pharmacy in a limited access area.
4.1.8
Drug accountability
Drug supplies provided by the sponsor and/or a CRO appointed by the sponsor, must be kept 
in a secure, limited access storage area under the storage conditions defined by the sponsor. 
Where necessary, a temperature log must be maintained to make certain that the drug 
supplies are stored at the correct temperature.
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:
∀
approval of the study protocol by the IRB / ethics committee,
∀
availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,
∀
approval/notification of the regulatory authority, e.g. competent authority,
∀
availability of the curriculum vitae of the principal investigator,
∀
availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol, in exceptional cases, medication could already be 
sent to the site, before its activation via IVRS
∀
if applicable availability of the proof of a medical licence for the principal 
investigator, 
∀
for USA availability of the Form 1572.
The investigator and/or pharmacist and/or investigational drug storage manager 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 / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational product(s) received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
All concomitant (non-oncological) therapies initiated during the trial to provide adequate care 
to the patient, where clinically required, are allowed but should be recorded in the eCRF. 
Patients should receive full supportive care, e.g. transfusions of blood and blood products, 
antibiotics, analgesia, according to local practice/guidelines where appropriate. Trade name 
and indication of concomitant therapies will be documented. If patients receive parenteral 
nutrition during the trial, the components need not be specified in detail. It should be 
indicated as “parenteral nutrition” and the eCRF completed accordingly. If a patient requires 
anaesthesia, it will be sufficient to indicate “anaesthesia” without specifying the details.
Rescue medication to reverse the effects of BI 836845 is not available. Potential side effects 
of BI 836845, as well as enzalutamide, should be treated symptomatically. Please refer to the 
current SPC for enzalutamide for details of side-effects and management.
Symptomatic treatment of tumour-associated symptoms is allowed (including the use of 
bisphosphonates for treatment of bone metastases).
Anti-emetic medication should be prescribed according to local practice and according to the 
label instructions from the manufacturer. All anti-emetic drugs administered shall be reported 
in the eCRF indicating whether the respective drug is given as prophylaxis and/or 
premedication or treatment of an adverse event.
Premedication to avoid allergic reactions shall be administered as recommended by the 
manufacturer and as requested by the local requirements at the site. Administration of the 
drugs shall be reported in the eCRF indicating whether the respective drug is given as 
prophylaxis and/or premedication or treatment of an adverse event.
Precaution should be taken to avoid extravasation. Patients should be asked to report any pain 
or burning at the site of injection immediately. If extravasation is suspected the infusions 
should be stopped immediately. Treatment should be initiated according to local practice and 
according to the manufacturer's instructions.
Patients should be instructed about signs and symptoms of hypoglycaemia and asked to take 
food once they suffer from sweating, hungriness and tremor.
If elective surgery is considered necessary for the patient, at least 7 days should elapse after 
the last dose of BI 836845 before surgery is performed wherever possible. Treatment can be 
resumed on the 3rd post-operative day.
Patients that are chemically castrated before entry to the trial must continue taking luteinizing 
hormone release hormone (LHRH) agonists throughout the duration of the trial treatment.
For patients entering the phase Ib expansion cohort: 
Enzalutamide taken by patients prior to entering the trial must be continued through the 
screening period up to the first day of the trial, in countries where the enzalutamide is 
supplied by Bohringer Ingelheim clinical trial supplies of enzalutamide will then be 


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dispensed.  The clinical supplies of enzalutamide must be taken by the patient continuously 
throughout the duration of the trial treatment.
4.2.1.1
Management of infusion reactions 
Infusion reactions may occur during infusion with BI 836845 and include pyrexia, chills, 
rigors, dyspnoea, urticaria, bronchospasm, hypotension and hypertension and should be 
treated symptomatically as judged clinically relevant by the investigator. 
A one hour observation period is recommended following each infusion for the first 3 cycles 
of treatment and at least a 15 minute observation period is recommended following 
subsequent infusions. Grade 1 to 2 infusion reactions may be managed with a slower infusion 
rate as per local guidelines. For symptomatic treatment of infusion reactions hydrocortisone, 
antihistamines such as chlorphenamine accompanied by an antipyretic/analgesic, and/or a 
bronchodilator may be administered according to the local recommendations. Severe 
reactions require immediate and permanent discontinuation of infusion. The grading of 
hypersensitivity reactions will be according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events CTCAE version 4.03, 14 June 2010 (R10-4848), 
see appendix 10.5.
Infusion reactions will not be reported on the standard AE page but will be reported on a 
separate page specifically for infusion reactions in the CRF.
Table 4.2.1.1: 1
Infusion reaction management
Infusion Reaction Grade
Management
CTCAE Grade 1 or 2
In the event of a mild to moderate CTCAE grade 1 or 2 non-
allergic infusion event, the infusion should be interrupted 
immediately with symptomatic treatment (e.g., antihistamines, 
NSAIDs, steroids, narcotics, IV fluids) if needed. Once the 
event has resolved, the infusion should be restarted at half of 
the previous rate. If the reduced infusion rate is tolerated for 
30 minutes, the infusion rate may then be increased to the next 
close rate on the patient’s infusion schedule. 
CTCAE Grade 3
For patients experiencing CTCAE grade 3 infusion related 
event, infusion should be interrupted immediately and patients 
should receive aggressive symptomatic treatment. Only after 
all the symptoms have disappeared the infusion should be 
started. The infusion rate at restart should be half of the 
infusion rate at the time of onset of the reaction.
CTCAE Grade 4
Patients experiencing CTCAE grade 4 such as anaphylaxis 
during an infusion should have infusion immediately stopped 
and receive appropriate treatment including use of 
resuscitation medications and equipment that must be 
available. Such patients should NOT receive any further BI 
836845 treatment.


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4.2.1.2
Management of potential hyperglycaemia 
Hyperglycaemia as a consequence of BI 836845 therapy can be treated with standard 
treatment regimens such as oral hyperglycaemic therapy, e.g. metformin, sulfonylurea and/or 
insulin as per standard and/or local guidance. When treatment with the study drug is 
discontinued the need for further antidiabetic treatment has to be evaluated depending on the 
blood glucose levels of the patient. The appropriate expert advice should be considered in the 
management of hyperglycaemia.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional chemo-, immuno-, hormone- or radiotherapies to treat the tumour disease are not 
allowed during the active treatment period of this trial. 
For symptom control palliative radiotherapy may be permitted for bone metastases after 
discussion with the sponsor provided that radiotherapy does not affect the target lesions, and 
the reason for the radiotherapy does not reflect progressive disease.
Strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8 are to be 
avoided. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of 
enzalutamide should be reduced to 80 mg once daily. 
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and 
CYP2C19. Patients taking medicinal products that are substrates of CYP3A4 (see appendix 
10.3 for example list), CYP2C9 (e.g. warfarin, phenytoin), or CYP2C19 (e.g. S-
mephenytoin), should be evaluated for possible loss of pharmacological effects (or increase 
in effects in cases where active metabolites are formed) during the first month of 
enzalutamide treatment, and dose adjustment should be considered as appropriate.
Enzymes that may also be induced include CYP2B6 and uridine 5'-diphospho-
glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). Patients taking 
medicinal products that are substrates of CYP2B6 (e.g. bupropion, efavirenz) or UGT1A1 
should be evaluated for possible loss of pharmacological effects (or increase in effects in 
cases where active metabolites are formed) during the first month of enzalutamide treatment, 
and dose adjustment should be considered as appropriate.
Enzalutamide may be an inhibitor of the efflux transporter P-gp. Medicinal products with a 
narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, 
digoxin) should be used with caution when administered concomitantly with enzalutamide 
and may require dose adjustment to maintain optimal plasma concentrations.
Please refer always to the current SPC/label for specific restrictions for enzalutamide.
Additional restrictions for patients in Phase Ib expansion:
In order to effectively assess the potential for pharmacokinetic drug interaction between 
enzalutamide and BI 836845 and to investigate potential alterations of pharmacokinetics 


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during co-administration, strong and moderate CYP2C8 inhibitors/inducers and CYP3A4 
inhibitors/inducers are prohibited during the periods specified below in the Ph Ib 
expansion cohort:
∀from Day -7 of the screening period till visit 1 of treatment course 1 (C1V1) and
∀from visit 4 of the first treatment course (C1V4) till visit 2 of treatment course 2 
(C2V2)
A list of examples is provided in appendix 10.3.2. Switching to a different class of drug that 
is not a strong or moderate CYP2C8 inhibitor/inducer or CYP3A4 inhibitor/inducer is 
recommended.
Outside the above time periods, follow the respective drug package insert/SPC when 
considering concomitant treatment with CYP2C8 inhibitors/inducers and CYP3A4 
inhibitors/inducers.
Anti-platelet medications (e.g. acetylsalicylic acid) should be discontinued 7 days prior to 
tumour biopsy. Anticoagulant medications should be discontinued prior to tumour biopsy. In 
all patients, the risk of discontinuing anti-platelet and/or anticoagulant medications must be 
weighed against the (potential) risk of bleeding during/after biopsy. Anti-platelet and 
anticoagulant may be restarted after tumour biopsy by the judgment of the investigators.
Any concomitant medication should be reduced to the clinically necessary minimum on the 
days of BI 836845 infusion.
Treatment with other investigational drugs or treatment within another clinical trial is not 
allowed at any time during this trial.
4.2.2.2
Restrictions on diet and life style
There are no major dietary or life style restrictions except that patients should attend visits in 
a fasting condition at the site for analysis of specific blood parameters (glucose and HbA1c 
on day 1 of every cycle).
Patients are requested to take enzalutamide at the same time every morning to facilitate 
accurate PK analysis. (This also applies to patients in the screening phase of the expansion 
cohort).
On day -1 of the screening period (expansion cohort only) and day 1 of cycle 2 (phase Ib
and phase II), patients should remain fasting for at least 1 hour after administration of 
enzalutamide, (i.e. food/water intake is not allowed before the 1:00 h PK sample). The 
timing of food intake prior to and after enzalutamide administration must be recorded 
in the eCRF.


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4.3
TREATMENT COMPLIANCE
BI 836845:
BI 836845 will be administered as a single infusion over one hour under supervision of the 
investigator or dedicated study personnel.
Enzalutamide:
On the days of PK sampling, patients must take enzalutamide in the clinic and should not 
take the dose at home prior to the visit. Sites should be encouraged to schedule PK visits 
early in the morning to accommodate consistent dosing schedules. 
For patients in the phase Ib expansion cohort:
Patients in the expansion cohort must be questioned by site staff  on day -1 (screening 
period) and at cycle 2 day 1, as to the date, time and dose of last enzalutamide intake 
prior to the visit, and this information must be recorded in the eCRF.   
Patients in the expansion cohort will be issued a diary card upon receipt of the patient 
information sheet. Date and time of enzalutamide administration must be completed in the
diary card from day -7 to -2 of the screening period. A second diary card will be issued in the 
expansion cohort at C1V4 for completion of the date and time of enzalutamide administration 
from day 23 to 28 of cycle 1. Enzalutamide compliance must be recorded in the eCRF.
For patients in the phase II arm B:
All patients in arm B of the Phase II part must be questioned by site staff at cycle 2 day 
1 as to the date, time and dose of last enzalutamide intake prior to the visit, and this 
information must be recorded in the eCRF.   
Site staff must check enzalutamide compliance and reconcile the returned medication every 
week during the first two cycles and, thereafter, at the end of every cycle /start of next cycle.  
Weekly checks can be completed, if required, throughout study participation.  Compliance 
must be reviewed prior to the dispensing of new enzalutamide kits to patients.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY 
5.1.1
Endpoint(s) of efficacy (anti-tumour activity)
5.1.1.1
Phase Ib Expansion Cohort 
Primary Endpoint:
∀
PSA response – defined as a decline in PSA value >50% (which is confirmed by a 
second value 3 to 4 weeks apart)R13_1642.
Secondary Endpoints: 
∀
Radiological progression free survival (PFS) - defined as time from start of treatment
until disease progression based on investigator assessment:
o
in bone based on the prostate cancer clinical trials working group (PCWG2)
criteria, (R13-1642) (see section 5.1.2.1)
o
or soft tissue, based on modified RECIST 1.1 (R09-0262) where applicable
(see Appendix 10.4)
o
or death. 
∀
Changes in circulating tumour cells (CTC) response – CTC reduction compared to 
baseline for at least one time point after treatment defined as CTC decline from ≥5 to 
<5 cells per 7.5ml blood (R14-0865) 
5.1.1.2
Phase II Randomised Trial
Primary Endpoint: 
∀
Radiological progression free survival (PFS) - defined as time from randomisation to 
disease progression based on investigator assessment:
o
in bone based on the prostate cancer clinical trials working group (PCWG2) 
criteria, (R13-1642) (see section 5.1.2.1)
o
or soft tissue based on modified RECIST 1.1 (R09-0262) where applicable
(see Appendix 10.4)
o
or death
Secondary Endpoints: 
∀
Radiological progression free survival (PFS) - defined as time from randomisation to 
disease progression based on central review:


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o
in bone based on the prostate cancer clinical trials working group (PCWG2) 
criteria, (R13-1642) (see section 5.1.2.1)
o
or soft tissue based on modified RECIST 1.1 (R09-0262) where applicable  
(see Appendix 10.4)
o
or death 
∀
Overall survival – defined as the time from randomisation to death from any cause 
∀
Time to PSA progression – defined as the date that a 25% or greater increase in PSA, 
and an absolute increase of 2 ng/mL or more from the nadir, is documented (which is 
confirmed by a second value 3 or more weeks later) (R13-1642)
∀
Maximum decline in PSA – compared to baseline that occurs at any point after 
treatment start
∀
Percentage change in PSA at week 12 – from baseline to week 12 of treatment
∀
PSA response – defined as a decline in PSA value >50% (which is confirmed by a 
second value 3 to 4 weeks apart)
∀
Changes in circulating tumour cells (CTC) response – CTC reduction compared to 
baseline for at least one time point after treatment start separately assessed by two 
criteria: 
o CTC decline from ≥5 to <5 cells per 7.5ml blood (R14-0865) 
o Maximum change in CTC counts compared to baseline that occurs at any point 
after treatment start
5.1.2
Assessment of efficacy (anti-tumour activity)
5.1.2.1
Assessment of tumours and bone
For soft tissue lesions:
Radiological disease progression will be evaluated at the investigative site and be based on 
tumour assessments in bone and/or soft tissue lesions. For patients with measurable disease at 
baseline, progression will be determined according to modified RECIST 1.1(R09-0262). See 
Appendix 10.4 for additional details of modified RECIST criteria.
The following modification applies only for lymph nodes as per the Prostate Cancer Clinical 
Trials Working Group (R13-1642): only lymph nodes > 20 mm in the short diameter at 
baseline should be used to assess a change in size during the trial and may be considered a 
target lesion. 
Re-appearing, or enlarging, lymph nodes < 20 mm in the short diameter shall not serve as the 
only trigger for PD. The radiologist will make every effort to assess the patient’s disease 


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elsewhere, and provide explanatory comments for the oncologist to take into consideration 
upon determining the final overall assessment, if applicable.
When a lymph node continues to increase over 20 mm in short diameter on subsequent 
images, or other accompanying findings on images change from equivocal to unequivocal, 
the time-point where the lymph node increase was first documented shall serve as the date of 
PD.
Tumour assessment must be by CT or MRI imaging of the chest, abdomen and pelvis at 
screening. If clinically indicated, imaging of any other known or suspected sites of disease 
using an appropriate method (CT scan or MRI) should be performed. After study entry, all 
lesions identified during the screening should be followed up at all specified imaging time 
points. 
The same radiological procedure should be used throughout the study at baseline and for all 
repeated measurements according to the Flow Chart. Clinical tumour assessment will 
contribute to the decision for continued patient participation in the trial. Every effort should 
be made to objectively evaluate tumour response for all patients who enter into the trial, 
including those who discontinue prematurely. 
If a patient presents with marginal or equivocal tumour progression at their first RECIST 
assessment, confirmation by a second scan 6 or more weeks later, after continued treatment, 
is recommended.
Bone lesions are to be reported on the assessment of bone metastases CRF page and not on 
the response to therapy RECIST assessment CRF page. 
For bone:
A bone scan should be performed at screening, at 8 week intervals until week 24 (i.e. weeks 
8, 16 and 24) and then at 12 week intervals thereafter (i.e. weeks 36, 48 etc) throughout the 
trial at until disease progression and/or new anticancer therapy is started. 
Radiographic progression on bone scans is defined by the following criteria (as per the 
Prostate Cancer Clinical Trials Working Group 2 (R13-1642)):
∀
≥ 2 new bone lesions on bone scan performed within the flare window plus ≥2 
additional at confirmation (“2 + 2”) on a second bone scan ≥ 6 weeks later. The date 
of progression is the date of the first scan that shows the change.
∀
≥ 2 new bone lesions on bone scans performed after the flare window, disease 
progression is determined at that assessment.
∀
If bone scan does not show new lesions OR new lesions are not consistent with 
progression, then patient should continue on study protocol and continue dosing until 
the next tumour assessment, as clinically indicated, until radiographic disease 
progression.
The flare window is considered as 12 weeks from randomization for patients in phase II and 
12 weeks from start of treatment for patients in phase Ib escalation and expansion.


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For examples of bone scan progression using the prostate cancer clinical trials working group 
guidelines (PCWG2), see appendix 10.7
Any changes in bone imaging should be evaluated radiographically by CT scan, MRI, or X-
ray to ascertain the presence of bone destruction versus a healing reaction. 
Only new bone lesions consistent with progression are to be counted towards defining 
radiographic progression in the bone scan eCRF page. New bone lesions should not be 
recorded in the RECIST evaluation eCRF page unless there is a soft tissue component that 
has met the modified RECIST 1.1 progression criteria.
In general:
Assessments will be performed at screening, or if valid results are available as part of routine 
clinical practice and are within 28 days prior to start of study treatment, repeat imaging will 
not be required. Imaging will be at baseline and then every 2 cycles (8 weeks) up to week 24 
and then every 3 cycles (12 weeks) thereafter i.e. prior to the start of cycles 3, 5, 7, 10 
onwards. Tumour assessments may be performed up to 7 days prior to the scheduled date for 
start of the relevant cycle/assessment date.
In the event of a delay, interruption or discontinuation of treatment, tumour assessment 
should continue to follow the original schedule. The schedule should be followed until 
progression is observed or until the patient commences further treatment for disease, 
whichever occurs first. For patients who prematurely discontinue study medication without 
disease progression, tumour assessments should continue to be performed until disease 
progression or start of further treatment.
5.1.2.2
Assessment of PSA
PSA assessments and determination of response, or progression, will be performed locally.
Early changes in PSA should not be considered in clinical decisions for continuation of 
participation in the trial. PSA will be assessed according to the schedule on the Flow chart. 
PSA will be measured during screening to confirm eligibility and at cycle 1 day 1 before 
study treatment for a baseline value.  PSA will be measured 8 weeks later at the start of cycle 
3 and every cycle thereafter to assess possible disease response or progression.
PSA progression is defined in this study as the date that a 25% or greater increase in PSA and 
an absolute increase of 2 ng/mL or more from the nadir is documented (which is confirmed 
by a second value 3 or more weeks later) (R13-1642).  Patients should be kept on trial until 
radiological or symptomatic progression is documented with or without confirmed PSA 
progression.
5.1.2.3 Circulating tumour cell (CTC) assessments
Circulating tumour cells will be analysed using the Veridex CellSearch technology. After cell 
counting, isolated CTCs might be used for morphological, protein or molecular
characterization by FISH. CTC counts will be exploratory evaluated as prognostic and 
surrogate efficacy markers.


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In phase Ib and phase II of the study at least 10 mL blood will be taken from a forearm vein 
at those time points specified in the Flow Chart and immediately shipped to a CRO with 
given authorization by BI.
Measurements and analysis will be made to determine the maximum decline in CTC counts 
compared to baseline that occurs at any point after treatment start. CTC response will be 
measured by a CTC reduction compared to baseline: CTC decline from ≥5 to <5 cells per 7.5
ml blood (R14-0865) for at least one time point after treatment start will be reported, as will
all declines in CTC counts of 30% or more. 
5.1.3
Central Imaging
Until the primary analysis, image data collection in phase II will be sent to a central imaging 
unit to obtain an independent blinded confirmation of tumour response assessment based on a 
uniform interpretation of radiographic image for all patients entered on to the trial. Upon 
receipt of image data, the central imaging unit will log all data onto a tracking system and 
perform quality control of digitised radiographic images.
An independent review of radiographic images including: (i) sequential lesion selection and 
measurement, (ii) incremental radiological response assessment followed by, (iii) global 
review of tumour response or progression, will be performed by blinded (with regard to 
patient, treatment, and visit) radiologist. 
The review of the image data will be performed by independent radiologists, who are not 
affiliated with the study. All procedures will be done according to the specifications provided 
in the investigator site file. The purpose of the blinded reading is to independently assess 
patient response to therapy and disease progression (for details, please refer to the ISF).
Further details of the independent review are described in the Imaging Charter. Modifications 
of the conventional RECIST 1.1 lesion measurement criteria will be introduced into the 
measurement process in an attempt to reduce variability in the measurements for the 
independent central imaging review. Eligibility and treatment decisions will be based on the 
assessment of disease by the investigator (as per Section 5.1.2.1 and appendix 10.4). Central 
imaging will not be used for this purpose and the results of the central imaging review will 
not be communicated to the investigator.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
Safety of BI 836845 when administered together with enzalutamide will be evaluated by 
intensity and incidence of AEs, and will be graded according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 dated 14 
June 2010 (R10-4848). Safety endpoints will include:


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Primary endpoints (Phase Ib Escalation):
∀
Number of patients with Dose Limiting Toxicities 
∀
Maximum Tolerated Dose (MTD) of BI 836845
All other safety endpoints will be defined in Section 5.3.1 and details are provided in Section 
5.2.2.
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 in a patient or clinical
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a
medicinal product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
∀
results in death,
∀
is life-threatening,
∀
requires inpatient hospitalisation or prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity,
∀
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 jeopardize 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.
An AE does not meet the SAE criteria for hospitalisation if:
∀
The subject was treated in the emergency room but was not admitted for an overnight 
stay
∀
Hospitalisation due to pre-planned treatments or procedures


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∀
Hospitalisation due to social circumstances or administrative reasons
∀
Hospitalisation for diagnostic reasons without AE
AEs  considered “Always  Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events,
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be
considered to be “serious” even though they may not have met the criteria of an SAE as
given above.
The latest list of “Always Serious AEs” can be found in the RDC system. A copy of the 
latest list of “Always Serious AEs” will be provided to you upon request. These events 
should always be reported as SAEs as described in Section 5.2.2.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as 
being of particular concern for prospective safety monitoring and safety assessment within 
this trial, e.g. the potential for AEs based on knowledge from other compounds in the same 
class. AESI need to be reported to the Sponsor’s Pharmacovigilance Department within the 
same timeframe that applies to SAE, see Section 5.2.2.
The following are considered as AESIs: 
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 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 transaminase ≥ (baseline + 4 x ULN) combined with an elevation 
of total bilirubin ≥ 2 fold ULN measured in the same blood draw sample.
∀
patients with abnormal liver function tests must have their abnormalities and the 
etiology documented in detail as baseline conditions. Every effort should be 
made to explain possible deteriorations of baseline conditions
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.


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Dose Limiting Toxicities (DLTs):
∀
DLTs occurring during the phase Ib escalation cohort will be considered protocol-
specified AESI. See section 5.2.3 for DLT definitions. AESI will be reported on the 
eCRFs/SAE reporting forms, as per the SAE reporting instructions detailed in the 
‘Adverse Event Reporting’ section of the Investigator Site File.
AESI 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.
Intensity of AEs
The intensity of adverse events should be classified and recorded in the (e) CRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 dated 14 June 
2010 (R10-4848) in the (e)CRF.
Causal relationship of AEs
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.
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).
5.2.2.2
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the
Investigator:
-
From signing the informed consent onwards through the Residual Effect 
period (REP), until the end of the REP all AEs (non-serious and serious), and 
AESIs.
-
After the end of the REP until trial completion, all related SAEs and related AESIs.
-
If in an individual patient only vital status information (Phase II patients only)
is collected from a certain timepoint on, no further AEs or AESIs will be
reported for this patient.


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Figure 5.2.2.2: 1 Adverse Event Collection and Reporting
The REP is defined as 42 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see section 7.3.3. Events which occurred after the REP will be considered
as post treatment events.
After the last per protocol contact 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.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific reporting process will be provided in the
ISF). In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to 
be provided. For follow-up information the same rules and timeline apply as for
initial information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication, the trial procedures 
outlined under section 6.2, and any possible interactions between the investigational
drug(s) and a non-investigational product (NIMP)
The following should also be recorded as an (S)AE in the (e)CRF and SAE form 
(if applicable):
∀  Worsening of the underlying disease or of other pre-existing conditions


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∀  Changes in vital signs, ECG, physical examination and laboratory test results, 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.
All (S)AEs, including those persisting after trial completion must be followed up until 
they have resolved, have been sufficiently characterized, or no further information can be 
obtained.
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. SAE which occurred 
during the screening period are to be reported according to standard practices.
Pregnancy
In the rare case that a female partner of a subject participating in this clinical trial becomes 
pregnant, the Investigator must report immediately (within 24 hours) the drug exposure to 
female partners of male participants during pregnancy (DEDP) to the Sponsor’s unique entry
point (country- specific contact details will be provided in the ISF). The Pregnancy
Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must
be followed up and reported to the Sponsor’s unique entry point on the Pregnancy
Monitoring Form for Clinical Trials (Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying
SAE, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to 
be completed. If there is an SAE associated with the pregnancy then the SAE has to be
reported on the SAE form in addition.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemption to (S)AE Reporting:
Disease Progression is a trial endpoint for analysis of efficacy and as such is exempted from 
reporting as an (S)AE.  Progression of the patients underlying malignancy will be recorded 
on the appropriate pages of the (e)CRF as part of efficacy data collection only and will not 
be reported on the SAE Form. It will therefore not be entered in the safety database (ARISg) 
and hence not get expeditiously reported. Death due to disease progression is also to be 
recorded on the appropriate (e)CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy, the event must be reported as an SAE on 
the SAE Form and on the (e)CRF.
Examples of exempted events of PD may be:


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•
Progression of underlying malignancy (Progressive disease [PD]):  if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 
•
Hospitalization/Procedures due solely to the progression of underlying malignancy 
(PD)
•
Clinical symptoms and/or signs of progression (without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be determined 
to be due to the progression of the underlying malignancy and does meet the expected 
pattern of progression for the disease under study. 
Exempted events are collected and tracked following a protocol-specified monitoring plan.
Exempted events are monitored at appropriate intervals by the Data Monitoring Committee.
5.2.3
Dose Limiting Toxicity (DLT) definitions
DLTs will be assessed during the phase Ib escalation part of the study. The determination of 
the number of DLTs experienced during the first cycle of treatment will be used to identify 
the MTD of BI 836845 in combination with enzalutamide.
A study drug-related adverse event constitutes a DLT, if one of the following applies during 
treatment in the phase Ib escalation cohort:
∀
AST or ALT > 5x ULN (for baseline AST/ALT ≤ ULN) or > (baseline value + 4x ULN) 
(for baseline AST/ALT > ULN)
∀
CTCAE Grade 3 or 4 toxicity (except for incompletely treated nausea, untreated 
vomiting, untreated diarrhoea, fatigue, infusion reaction, electrolyte, or AST/ALT).
∀
CTCAE Grade ≥2 infusion reaction despite adequate pre-medication.
∀
CTCAE Grade ≥2 nausea and/or vomiting persisting for 7 or more days despite 
antiemetic treatment.
∀
Any grade 4 hyperglycaemia (symptomatic or asymptomatic).
∀
Any Grade 3 hyperglycaemia lasting >48 hours.
∀
Any electrolyte grade 3 AE which is refractory to optimal correction therapy
∀
Seizure event of any CTCAE grade
∀
No recovery from a non-DLT CTCAE grade >2 toxicity to grade 1 within 14 days of 
administered dose
∀
Sustained fatigue/asthenia grade 3 for longer than 96 hours associated with deterioration 
of ECOG Performance Score
∀
Any other study drug related toxicity at any time point during the study considered 
significant enough to be qualified as DLT in the opinion of the investigators and 
confirmed by the safety review with the BI clinical monitor, will be reported as a DLT.
It is essential that patients are treated sufficiently according to supportive care standards.
As patients with a documented clinical benefit, e.g. objective tumour response or absence of 
tumour progression, will receive further treatment with the trial drug all DLT events in 
individual patients occurring at any time during treatment cycles, or the follow-up period, 
must be reported as an AESI.


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The decisions regarding dose escalation steps in the tolerability and safety phase will be made 
only upon review of the DLTs during the first cycle of treatment and after discussion between 
the sponsor and the clinical investigators at all sites, and in consideration of all the available 
toxicity, pharmacokinetic and pharmacodynamic data.
5.2.4
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)
The maximum tolerated dose in this study is defined as the highest protocol dose level of BI 
836845 in combination with enzalutamide, at which no more than 1 out of 6 patients in a 
cohort experiences a drug related DLT during the first 28 day treatment cycle – i.e. the 
incidence of a dose limiting toxicity is no more than 17%. DLT events experienced after the 
start of the second treatment course will be examined separately.
The MTD or a lower dose level will be chosen as the recommended phase II dose (RP2D) 
based on the totality of the safety data available at the time that 6 evaluable patients have 
finished course 1 of treatment at the MTD (or RP2D if MTD not reached); at the earliest. 
The discussion and agreement on dose selection between the phase Ib escalation investigators 
and the sponsor will be documented and communicated to all participating sites. The 
recommended phase II dose (RP2D) will also be used for the phase Ib expansion cohort.
5.2.5
Assessment of safety laboratory parameters
Safety assessments, including clinical and laboratory evaluations will be assessed during 
treatment cycles according to Flow Chart. Adverse events are to be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, CTCAE 
version 4.03, 14 June 2010 (R10-4848). Changes in laboratory tests from baseline will be 
assessed.
Assessment of safety laboratory parameters prior to approval of protocol version 10
Blood samples, including fasting serum samples (fasting state from midnight the night 
before), will be collected up to one day prior to the scheduled time points as specified in the 
Flow Chart and analysed in a laboratory facility at (or close to) the investigational site. Safety 
laboratory examinations include hematology, biochemistry, coagulation and urine 
examination. See Table 5.2.5: 1 for details. Futher samples may be taken throughout the 
course of the study when deemed appropriate by the investigator. All analyses are to be 
performed by the local clinical laboratory.
Table 5.2.5: 1
Safety Laboratory Parameters to be performed prior to approval of 
protocol version 10
Category
Test Name
Haematology:
Red blood cell count (RBC), haemoglobin, white blood cell count 
(WBC), reticulocytes and differential, platelets
Biochemistry:
Sodium, potassium, calcium, magnesium, creatinine, aspartate 
amino transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, urea, uric acid, 
creatine phosphokinase (CPK). In case of pathological CPK further 
evaluation (e.g., by Troponin assays, CK-MM, CKMB, ECG exam) 


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Table 5.2.5: 1
Safety Laboratory Parameters to be performed prior to approval of 
protocol version 10 (continued)
Category
Test Name
should be performed and the findings documented. GFR will be 
estimated by the Cockgroft-Gault formula utilizing serum creatinine 
values and recorded in the eCRF.
Coagulation 
parameters
Prothrombin time (PT), international normalised ratio (INR) where 
therapeutically indicated and activated partial thromboplastin time 
(aPTT).
Urine examination:
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analyzed by dipstick (semi-quantitative measurements: -, +, ++, 
+++, ++++). In case of abnormal findings, further evaluation should 
be performed and the findings documented.
Other – fasting 
(only at screening and 
Day 1 of every cycle)
Blood glucose and HbA1C
Assessment of safety laboratory parameters after approval of Protocol version 10
Blood samples will be collected up to one day prior to the scheduled time points as specified 
in the Flow Chart and analysed in a laboratory facility at (or close to) the investigational site. 
Safety laboratory examinations include hematology, biochemistry and electrolytes. See Table 
5.2.5: 2 for details. Futher samples may be taken throughout the course of the study when 
deemed appropriate by the investigator. All analyses are to be performed by the local clinical 
laboratory.
Table 5.2.5: 2
Safety Laboratory Parameters to be performed after approval of 
protocol version 10
Category
Test Name
Haematology:
haemoglobin, white blood cell count (WBC), platelets
Biochemistry:
Sodium, potassium, creatinine, aspartate amino transferase (AST), 
alanine amino transferase (ALT), lactate dehydrogenase, total 
bilirubin
Other 
Blood glucose*
* Glucose may be obtained non-fasting, but in case elevated should be repeated fasting. If Glucose is repeated fasting, only the fasting value 
should be captured in the eCRF.


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If blood sampling at the trial site is not possible, safety lab analyses can be performed at a 
local lab. The results of the lab tests must be transferred to the investigator who ensures 
medical review and proper documentation in the eCRF.
5.2.6
Electrocardiogram
5.2.6.1
ECG Recording – Phase Ib and Phase II 
Triplicate 12-lead ECGs (each ECG to be taken approximately 2-3 minutes apart) will be 
performed in all patients at the time-points as specified in the Flow Chart and Appendix 10.6
and will be coincident to PK sampling. The investigator will review the ECG recording, 
comment on any clinical significance and if applicable record any ECG abnormality that 
meets AE criteria. 
Triplicate ECGs will be recorded at the following time-points:
∀
Screening
∀
Pre-dose (-20 min. to -5 min. before administration of BI 836845 and/or 
enzalutamide) and immediately after the end of infusion of BI 836845 (within 15
minutes after the end infusion to ensure PK sampling is also completed within 15 
minutes), or one hour after the administration of enzalutamide on the following days*:
o
Cycle 1: Day 1, Day 8, Day 15 
o
Cycle 2: Day 8, Day 15 
o
Cycle 3: Day 1, Day 8, Day 15
o
Cycles 6, 9, 12 and in 12 weeks intervals thereafter on Day 1
∀
EOT
∀
First follow-up visit only
* ECGs to be taken prior to PK sample time-points where applicable. See appendix 10.6 for 
ECG flowchart.
ECGs will only be correlated to PK for the drug combination (BI 836845 and enzalutamide) 
during phase Ib and phase II arm A.
All ECGs will be recorded digitally with ECG equipment provided by a CRO ECG core lab.
Before study start the study sites will be trained for the proper use of the equipment and 
transfer of the electronic data to the CRO core lab. To be able to assess the 
electrocardiographic variables in resting phases the ECGs have to be recorded in supine 
position after the subjects were at rest for at least ten minutes. At specific time-points 
triplicate ECGs will be recorded to minimize the physiologically induced QT and heart rate 
variability. The recordings will be evaluated at the site by the investigator (or 
 delegate) to 
assess any ECG abnormalities and changes in interval duration. ECG abnormalities will be 


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carefully monitored and, if necessary, the subject will be removed from the trial and 
medically treated.
All ECGs will be sent to the CRO core lab to centrally and independently evaluate the
electrocardiograms.
After the primary analysis of the study, a decision can be made by the sponsor and
communicated by the trial clinical monitor to stop the centralized ECG review if necessary. 
Thereafter the ECG will be evaluated locally by the investigator if clinically indicated
5.2.6.2 ECG evaluation
The digitally recorded ECGs sent to the CRO core lab will be evaluated for cardiac intervals 
(RR, PR/PQ, QRS, QT and heart rate-corrected QT (QTc)). Measurements of the cardiac 
intervals will be done from three (possibly consecutive) normal heart complexes in lead II 
using the core lab’s procedures. Heart rate correction of QT intervals will be done using 
Fridericia’s and Bazett’s formula. In addition, the ECGs will be reviewed by a board-certified 
cardiologist using a standardized worksheet to obtain clinically significant findings such as 
rhythm, morphology, and conduction abnormalities as well as those of ST Segments, T and U 
waves. The central measurement of the ECG intervals will be done in all ECGs. In triplicate 
ECG recordings one randomly selected ECG from this time-point will be evaluated. In case 
of clinically significant abnormalities (e.g. heart blocks or large changes in interval duration) 
the CRO core lab may contact the investigator and vice versa. Changes in QT interval 
compared to baseline will be evaluated internally at BI.
5.2.7
Left ventricular ejection fraction
Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography or MUGA scan 
will be assessed at screening and post treatment if clinically indicated. The same method of 
measurement should be used throughout the study.
5.2.8
Assessment of vital signs and physical examination
Vital signs (blood pressure, pulse and respiration rate after two minutes supine rest) and 
temperature will be recorded at the screening visit and at the time points specified in the Flow 
Chart.
A physical examination, including weight, will be performed at screening and at the time 
points specified in the Flow Chart. The physical examination should include a thorough 
cardiopulmonary examination, an examination of the regional lymph nodes, an examination 
of the abdomen and an assessment of the mental and neurological status. Additional 
symptoms which have not been reported during a previous examination should be clarified. A 
physician should perform this examination. Measurement of height (in cm) and body weight 
(in kg) and the evaluation of the ECOG performance score and 
 
will be performed at the time points specified in the Flow Chart.
5.2.9
Demographics and medical history
Demographics (sex, birth date and race) and baseline conditions will be collected during the 
screening visit. 


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Cancer history will also be obtained.
∀
The month/year of first biochemical/histological/cytological diagnosis of prostate cancer.
∀
Age at diagnosis
∀
Gleason score at the time of diagnosis (if known).
∀
Site of metastasis, e.g. visceral (specify such as liver or lung), bone, lymph nodes
∀
Type of progression at study entry, i.e. PSA, radiological and/or symptomatic
∀
Confirmation on whether documented information on relapse or progressive disease is 
present at screening.
∀
Previous surgeries and dates of surgeries will be reported (if known). 
∀
Number and type of previously administered chemo-, immuno-, hormone-, molecular 
targeted and biological therapies, including radiotherapy, will be reported, only if known, 
including specification of the treatment protocol/name of treatment for prostate cancer.
All treatment start and stop dates will be recorded.
∀
The best response obtained to these treatments should also be recorded if information is 
available (Complete Response, Partial Response, Stable Disease, Progressive Disease, or 
unknown).


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5.4
APPROPRIATENESS OF MEASUREMENTS
The RECIST criteria version 1.1 (R09-0262 and appendix 10.4) to be used for evaluation of 
tumour response are well established and scientifically accepted. The Common Terminology 
Criteria, CTCAE version 4.03, 14 June 2010 (R10-4848 and 5.1.2.1) are used in the 
assessment of adverse events in cancer patients.
All measurements performed during this trial will be to monitor safety and tolerability of BI 
836845 in combination with enzalutamide, to determine the MTD and /or recommended 
phase II dose during the phase Ib tolerability and safety phase, and to collect further safety 
data during the randomised phase II phase of the trial.
The scheduled assessments are to monitor drug induced changes in respect to vital signs, 
standard laboratory values and ECG. Tumour evaluations are necessary for determination of 
tumour response to treatment 
 
PSA 
measurements will be used to confirm changes from baseline during treatment and to confirm 
PSA response and progression. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
6.1.1
Screening Visit: -28 to day -1 
All screening assessments will be performed within 28 days of first administration of study 
drug/s on day 1 (visit 1) of cycle 1. Patients who have signed the informed consent and meet 
all eligibility criteria will be scheduled to begin treatment with either: BI 836845 and 
enzalutamide (phase Ib and phase II arm A), or enzalutamide alone (phase II arm B).
6.1.2
Treatment Visits 
The treatment phase of the study will start on the first day of infusion of BI 836845 in cycle 
1. Administration of BI 836845 will be weekly and enzalutamide will be daily over a 28 day
cycle of treatment in phase Ib and phase II of the study.
All treatment cycles will comprise of four visit days as per the Flow Chart Phase Ib and 
Phase II. 
During the phase II randomised trial of the study from cycle 4 onwards patients on arm B 
(enzalutamide only) will only be required to attend for one visit per cycle on day 1 and when 
imaging assessments are scheduled; optional telephone contact calls may be included at day 
8, day 15 and day 22 per cycle where required, and at the discretion of the investigator, for 
the collection of AE and concomitant medication information. For those patients receiving 
the combination treatment in any part of the trial, and who later discontinue BI 836845 
permanently, they may attend only on day 1 of every cycle, from cycle 4 onwards, and when 
imaging assessments are scheduled.
For those patients that complete cycle 3 in phase Ib and phase II, these cycles will be repeated 
where clinical benefit is indicated. All assessments stated for cycle 3 in phase Ib and phase II 
will be repeated for all subsequent cycles, unless otherwise indicated in the Flow Chart. 
Tumour assessments, including bone scans, will be performed as per the Flow Chart at week 
8, week 16, week 24, week 36 and every 12 weeks thereafter. All tumour assessment visits 
may be within 7 days prior to the start of the respective cycle of treatment.
PK, biomarker assessments, PSA, CTC and immunogenicity sampling will be conducted for 
all days stated in the Flow Chart and Appendix 10.6.
No visit windows will be permitted on day 1 (visit 1) at the start of a cycle. On days 8, day 15 
and 22 of every cycle a ±1 day window will be permitted.
All planned visit dates are programmed from the start of day 1 (visit 1) of cycle 1. If a visit is 
missed there will be no re-scheduling; if a patient should attend the study site between the 
“missed” and scheduled visit, then the missed visit assessments should be performed. The 
current date and the reason for the delay must be noted in the medical records. All subsequent 
visits must adhere to the scheduled programme of visits for all cycles of treatment.
In situations where a patient is unable or unwilling to attend a clinic visit, the investigator 
must assess the risk-benefit balance for the individual patient and may decide to perform a 


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visit remotely if this is in the best interests of the patient and if agreed with the sponsor, 
provided that it is allowed by local country regulations and the investigator ensures that the local 
facilities are adequately qualified to perform the tests required per protocol for the given visit.
The following assessment can be done remotely: assessment of ongoing and/ or new adverse 
events and concomitant medications and compliance check for enzalutamide.
All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data.
The treatment phase of the study will continue for an indeterminate number of cycles until 
one of the criteria for patient removal applies and the end of treatment (EOT), plus the first 
follow-up visit has been performed. 
6.1.3
Follow Up Period and Trial Completion 
The different visits and trial periods are as displayed below in Figure 6.1.3: 1.
FU
Screening
R
Treatment
REP
Observation
Non-intervention 
period
Intervention period
EOT
EoR
EoFU
R, Randomization visit; EOT, End Of Treatment visit; REP, Residual Effect period; EoR, End Of Residual Effect Period visit; FU, 
Follow-Up period; EoFU, End of Follow-Up visit
Figure 6.1.3: 1: Visits and trial periods
6.1.3.1
End of treatment visit (EOT)
The EOT visit will be performed after permanent discontinuation of trial medication (either 
BI 836845, or enzalutamide, whichever is the last drug to be taken) for any reason. The EOT 
assessment will then be performed as soon as possible (within 7 days), instead of the next 
planned visit. 


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6.1.3.2 Residual effect period (REP)
The REP starts immediately after permanent discontinuation of trial medication and ends 
after 42 days. In this study, the End of Residual Effect Period visit (EoR) is combined with 
the scheduled FU visit. All AEs collected during this period will also be considered as ‘on 
treatment’.
6.1.3.3
Follow-up period
The follow-up period starts immediately after permanent discontinuation of trial medication. 
All patients should have at least one follow-up visit 42 days (+7) after permanent 
discontinuation of trial medication which coincides with the EoR visit. 
Additional follow-up visits should be performed in phases Ib and II (until approval of 
protocol version 10) for patients who withdrew for reasons other than progressive disease or 
start of further anti-cancer treatment; the additional visits will follow the usual tumour scan 
assessment schedule as per the Flow Chart, i.e. every 12 weeks from the start of trial. 
Prior to approval of protocol version 10, follow-up period for every patient will end at the 
earliest of the following events
∀
Lost to follow-up
∀
Disease progression 
∀
Start of a new anti–cancer therapy
∀
Death
After approval of protocol version 10, the follow up period for every patient will end after the 
first follow up visit.
6.1.3.4
Observation period 
Until approval of protocol version 10, all patients in the phase II randomised trial will be 
followed-up for overall survival every 90 days after the last follow-up visit (as specified in 
Section 6.1.3.3) until death, lost to follow-up or completion of the whole trial (as specified in 
Section 6.1.3.6) whatever occurs earlier. For patients who progressed on treatment, this 
period starts after the first follow up visit. For patients who have not progressed on treatment, 
this period starts after the last FU visit. 
These visits may also be performed by telephone interview in case the patient is unable to 
visit the investigator. 
The following information will be collected during the observation period:
∀
Date and method of contact
∀
Further treatment : regimen and drugs name, start and stop dates, reason for stopping 
this treatment
∀
Outcome death (date of and reason for death [if applicable])
∀
Follow-up of adverse events in case they were not yet recovered at the last FU visit.


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6.1.3.5
Patient completion
A patient has to be considered to have completed the trial if no further information is 
collected, i.e. in case any of the following applies:
∀
Completion of planned follow-up period (or planned observation period if applicable)
∀
Lost to follow-up
∀
Withdrawal to be followed-up
∀
Death
At the earliest of the above criteria, the Patient Completion (PC) information should be 
entered in the CRF. 
6.1.3.6
End of whole trial
The trial will end when the last patient in both the phase Ib expansion and phase II has 
completed at least the last follow-up visit (as specified in Section 6.1.3.3) and an adequate 
number of overall survival events have been observed in phase II.  
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations and assessments will be performed as outlined in the Flow Chart and as 
per the descriptions listed below.
6.2.1
Screening period
Patients who failed screening may repeat the screening after discussion between investigator
and sponsor providing that reasons for screening failure were reversible and have resolved.
Informed consent
Written informed consent must be obtained before 
any screening assessments are performed (with the 
exception of tumour scans as described in footnote 19
and 20 of the respective Flow Charts).
Separate consent will be obtained, within the main 
consent form, for retaining blood and tissue samples 
for up to 15 years for future tests.
Separate consent will be obtained, within the main 
consent form, for optional fresh biopsy for biomarker 
tumour analysis only in the phase II trial.
See section 8.1.
Demographics and Medical History
Section 5.2.9.
Inclusion and exclusion criteria
See section 3.3.2 and 3.3.3.


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Physical examination, vital signs, height and body 
weight
Height recorded only at baseline visit and at no 
further visits. See section 5.2.8.
Baseline conditions should be recorded at screening 
and up to start of treatment.
 
ECG 12-lead (triplicate) 
See section 5.2.6.
ECHO/MUGA 
See section 5.2.7.
ECOG performance score
As per Appendix 10.2.
Safety laboratory
Including haematology, biochemistry, coagulation 
parameters, urinalysis by dipstick.
Fasting glucose and HbA1c only at screening and on 
Day 1 of every cycle. See section 5.2.5.
Prostate Serum Antigen (PSA)
Single blood sample collected for baseline PSA
Tumour assessment and bone scans/
To be performed within 28 days of day 1 of first 
treatment according to modified RECIST criteria 
version 1.1 (R09-0262) and prostate cancer clinical 
trials working group (PCWG2) criteria (R13-1642)
as per section 5.1.2.1.
 
Concomitant therapy
Collected from baseline and throughout study.
 
 
 
 
 
 
Compliance check of enzalutamide - Phase Ib 
expansion cohort only (for patients already taking 
enzalutamide throughout the screening period)
Review of diary card and compliance check of 
enzalutamide taken during screening period 7 days 
prior to C1 Day -1.
6.2.2
Treatment period
The first dose will be on day 1 of cycle 1 and will be considered the start of the treatment 
period. The starting dose in phase Ib (escalation) of the study will be determined from the 
dose escalation regimen; for patients entering phase Ib (expansion cohort) and phase II of the 
study the MTD, or recommended phase II dose, will be the starting dose. Patients in phase Ib
will be assigned to cohorts as per instruction from the BI clinical monitor and in consultation 
with the investigator and site. 


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Safety assessments (safety laboratory tests and vital signs) must be performed prior to dosing 
on the infusion days in both phase Ib and phase II.
Inclusion and exclusion
Re-check criteria before dosing at C1D1, as per 
section 3.3.2 and 3.3.3.
Randomisation – Phase II only
Randomisation in IXRS. : Randomization may take 
place up to 3 days prior to the C1D1 if site 
procedures require advance randomization to 
accommodate the logistics of dispensing study 
medication to patients. Sites that use this option must 
include a copy of site policy/written justification in 
the ISF and submit a copy to the sponsor. If 
randomization is performed prior to C1D1, the 
subsequent visits must be scheduled with reference to 
C1D1.
Physical examination and body weight
Performed according to Flow Chart - see section 
5.2.8.
Vital signs 
Performed according to Flow Chart. See section 
5.2.8.
For Phase II Arm B enzalutamide only – vitals 
performed weekly as per the Flow Chart; however 
from C4 onwards only at the start of every cycle of 
treatment on Day 1 until approval of protocol version
10. After approval of protocol version 10 should be 
done according to standard of care.
ECG – 12 lead (triplicate)
For C1, ECGs to be taken pre-infusion/enzalutamide, 
and immediately after the end of infusion or one hour 
after enzalutamide intake at D1, D8 and D15 of the 
cycle.
For C2 only ECGs at D8 and D15 of the cycle – pre-
and post-dosing (as described above).
For C3 ECGs will be performed as described in C1 
for on D1, D8 and D15.
Further ECGs to be taken at C6, C9, C12 and in 12 
week intervals only on Day 1, as per the Flow Chart 
and footnotes – all ECGs taken pre-
infusion/enzalutamide, and immediately after the end 
of infusion, or one hour after enzalutamide intake. 
See section 5.2.6.
ECOG
On Day 1 of cycles as per Appendix 10.1 and the 
Flow Chart.
 


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Safety lab parameters 
Including haematology, biochemistry, coagulation 
parameters, urinalysis by dipstick. To be conducted 
at visit prior to administration of study drug/s
according to Flow Chart.
Fasting glucose and HbA1c only at screening and on 
Day 1 of cycles according to Flow Chart. See section 
5.2.5. 
Dispensing of enzalutamide 
Enzalutamide to be dispensed at every weekly visit 
and/or the start of every cycle dependent to which 
part of the trial the patient has entered.  Supply will 
cover exactly 7 days of treatment, or 28 days of 
treatment.  Spare drug kits will be provided
Administration of enzalutamide 
Enzalutamide to be taken daily in the morning 
preferably at the same time of day. 
On PK sampling days, enzalutamide must be taken in 
the clinic and should not be taken prior to the visit.  
See section 4.3 and appendix 10.6.
For patients also receiving BI 836845; on infusion
days (D1, D8, D15 and D22 of every cycle), the 
enzalutamide dose must be taken in clinic 
immediately following the start of infusion. For all 
other non-infusion days the enzalutamide may be 
taken at home at the same time of the morning.
Administration BI 836845 – Phase Ib and Phase II 
Arm A only
One hour infusion of BI 836845; duration may be 
adjusted in cases of infusion reaction or AE. 
PK/biomarker sampling time-points will be adjusted 
accordingly to correspond with the end of the 
infusion time. See appendix 10.6 “Pharmacokinetic 
sampling time points”.
Diary card issue – Phase Ib expansion cohort only
Diary card issued only in expansion cohort at the 
time of informed consent and at C1 Day 22. Diary 
card to be completed for 7 days in screening period 
prior to C1 Day-1 (Day-7 to Day-2), and for 7 days 
prior to C2 Day 1 (C1 Day 23 to Day 28).
Compliance check of enzalutamide
A compliance check of enzalutamide is to be made 
weekly at C1D8, C1D15 and C1D22, and weekly 
throughout C2 and at the start of every cycle 
thereafter.
At C2D1, site staff must question the patient as to the 
date, time and dose of last enzalutamide intake prior 
to the visit; this information must be recorded in the 
eCRF.   


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In Phase Ib expansion cohort only - Review of diary 
card and compliance check of enzalutamide taken 7 
days prior to C2 D1.
 
 
 
Circulating tumour cells (CTCs) 
As per the time-points on the Flow Chart and 
Appendix 10.6: Prior to study drug administration at 
C1D1, C2D1, C3D1, C5D1, C7D1 and every 12 
weeks thereafter at C10D1, C13D1 onwards (until 
approval of protocol version 10).
Prostate Serum Antigen (PSA)
Single blood sample collected prior to dosing at 
C1D1, C3D1 and at the start of the cycle thereafter as 
per the Flow Chart.
 
 
 
 
 
 
 
Tumour assessments and bone scans
Every 8 weeks (every 2 cycles) up to week 24 and 
then every 12 weeks (every three cycles) thereafter 
from start of study treatment in phase Ib escalation 
and expansion cohort and from randomisation in 
phase II, i.e. within 7 days prior to theoretical C3, 
C5, C7, C10 and onwards. Following implementation 
of Protocol Version 12 as per standard of care.
Assessment by modified RECIST criteria version 1.1 
(R09-0262) and prostate cancer clinical trials 
working group (PCWG2) criteria , (R13-1642) see 
appendix 10.4 and section 5.1.2.1
 
 
 
Adverse event and concomitant therapy
Collection of data throughout study treatment period
until after approval of protocol version 10 when only 
adverse event data will be collected.


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From cycle 3 onwards for phase Ib and phase II – the assessments and dosing schedule will 
be repeated for all subsequent cycles unless otherwise stated in the Flow Chart, e.g. tumour 
assessment schedule.
6.2.3
End of trial and follow-up period
During the end of treatment and follow up visits all procedures stated in the Flow Chart 
should be performed.
End of treatment:
All patients
Safety labs
See section 5.2.5. 
Tumour assessments and bone scans
Assessment, if applicable, by modified RECIST 
criteria version 1.1 (R09-0262) and prostate cancer 
clinical trials working group (PCWG2) criteria 
(R13-1642), see appendix 10.4.and section 5.1.2.1.
All patients should have a tumour assessment/bone 
scan at EOT visit regardless of the reason for 
discontinuation, unless the last evaluation was 
performed within 4 weeks of EOT
Adverse event 
Collection of data.
Compliance check of enzalutamide
Final compliance check for enzalutamide intake.
Termination of trial medication
At end of treatment visit.
Any assessments, for example vital signs, to ensure patient safety should be done as per 
standard of care.
Additional procedures for patients with end of treatment visit prior to approval of 
protocol version 10:
Physical examination and weight
Performed as per section 5.2.8.
Vital signs
Performed as per section 5.2.8
ECG – 12 lead (triplicate)
See section 5.2.6.
ECOG performance score
As per Appendix 10.1 and the Flow Chart.


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Circulating tumour cells (CTCs) 
See Flow Chart and appendix 10.6 for details.
Prostate Serum Antigen (PSA)
Single blood sample collected as per Flow Chart.
 
 
 
 
Concomitant medications
Collection of data
Follow-Up Visits:
All patients
Adverse event 
Data will be collected through to the last follow up 
visit.
Safety lab parameters 
See section 5.2.5. 
Additional procedures for patients with follow up visits prior to approval of protocol 
version 10:
Physical exam and weight (optional)
Performed as per section 5.2.8
Vitals 
Performed as per section 5.2.8
ECG – 12 lead (triplicate)
See section 5.2.6.
ECOG performance score
As per Appendix 10.1 and the Flow Chart.
Concomitant medications
Collection of data
Tumour assessments and bone scans
Assessment, if applicable, by modified RECIST 
criteria version 1.1 (R09-0262) and prostate cancer 
clinical trials working group (PCWG2) criteria 
(R13-1642), see appendix 10.4.and section 5.1.2.1
 


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Patient status
To be collected at every follow-up visit. Information 
collected on last contact date, start of new anti-
cancer therapy, or death.
Patient completion
Performed as per section 6.1.3.5
Additional follow-up visits:  
Until approval of protocol version 10, subsequent follow-up visits will be required where a 
patient has withdrawn from the study treatment for reasons other than disease progression, or 
start of further anti-cancer therapy, or death, will continue with follow-up visits at scheduled 
tumour assessments until one of the above mentioned criteria have been met.  Only AE and 
concomitant medication information will be collected at these visits.
Observation Visits:
Until approval of protocol version 10, patients that have withdrawn from the study 
participation due to disease progression, or start of other anti-cancer therapy, they will enter 
an observation period and be contacted every 90 days (3 months).
Patient status
Information collected on last contact date, start of 
new anti-cancer therapy, or death.
Patient completion
Performed as per section 6.1.3.5


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This is a Phase Ib/II open label trial split into three parts. Phase Ib escalation follows a 3+3 
design, and the objective of this phase is to determine the maximum tolerated dose of BI 
836845 in combination with enzalutamide. There is also an exploratory expansion cohort in 
phase Ib; the objective is to evaluate restoration of anti-tumour activity of BI 836845 in 
combination with enzalutamide. In phase II, patients will be randomised in a 1:1 ratio to two 
treatment arms: BI 836845 + enzalutamide (Arm A), and enzalutamide alone (Arm B). The 
objective of phase II is to further explore the anti-tumour activity and safety of BI 836845 in 
combination with enzalutamide, versus enzalutamide alone, in patients with diagnosed and 
histologically, or cytologically, confirmed metastatic CRPC that have received and 
progressed after docetaxel and abiraterone treatment.
7.2
NULL AND ALTERNATIVE HYPOTHESES
As an exploratory Phase Ib/II trial, inferences about the efficacy of BI 836845 in combination 
with enzalutamide will be based on the magnitude of the observed difference in PFS and 
other efficacy endpoints (including overall survival), rather than formal hypothesis testing. 
7.3
PLANNED ANALYSES
During phase Ib (escalation), cohorts of patients treated with BI 836845 in combination with 
enzalutamide will be evaluated continuously based on the safety profile in order to determine 
the MTD and /or recommended phase II dose. This MTD, and /or recommended phase II
dose will be used in the phase Ib expansion cohort and in phase II. 
Efficacy analyses will include all randomised patients in phase II. For phase Ib expansion 
cohort PFS will be summarised on cohort level. No comparisons between dose cohorts will 
be performed for phase Ib escalation.
Safety analyses will be summarized separately for patients treated in phase Ib and phase II. 
The safety profile for the phase II patients will be compared in a descriptive manner between 
the BI 836845 in combination with enzalutamide arm, and the enzalutamide only arm.
7.3.1
Primary analyses
The primary analysis of PFS for the phase II will be conducted and reported when 
approximately 60 patients (out of 80 randomised patients) have progressed or died. However, 
it may be performed with fewer events after approximately 23 months of the first patient 
being randomized in the Phase II part. Any additional information collected after the data cut-
off for the primary analysis will be part of a revised report.
A Cox proportional hazards model (using Breslow’s method for dealing with ties) will be 
used to analyse PFS for the phase II patients. The model will be used to estimate the hazard 
ratio of BI 836845 in combination with enzalutamide vs. enzalutamide alone, where a value 


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of less than one favours BI 836845 in combination with enzalutamide. The estimate of the 
hazard ratio, its asymptotic two-sided 95% confidence interval and asymptotic two-sided p-
value when testing against a value of one will be displayed. The proportional hazards 
assumption will also be checked.
The Kaplan-Meier survival rate quartiles (with two-sided 95% confidence intervals found 
using Greenwood’s variance estimate) will be presented for each treatment group. The 
equality of the survival curves will be tested by the log-rank test at the 5% significance level.
PFS for phase Ib expansion, patients will be summarized separately to phase II patients using 
descriptive statistics only.
PFS is defined as the time from randomisation for phase II (from the start of treatment for 
phase Ib) to disease progression in bone based on prostate cancer clinical trials working 
group (PCWG2) criteria, or soft tissue based on modified RECIST 1.1 (as detailed in Section 
5.1.2.1), or death. Patients without image-based progression or death at any time during the 
study will be censored at the date of their last imaging. Detailed censoring rules will be 
specified in the TSAP.
For the exploratory expansion cohort, PSA response, defined as a decline in PSA >50% 
(which is confirmed by a second value 3 to 4 weeks apart), will be used as primary endpoint. 
Descriptive statistics for PSA response will be provided for all treated patients. 
7.3.2
Secondary analyses
The analysis of PFS based on independent review data will be performed in the same way as 
the primary evaluation on investigator assessments.
Overall survival will be analysed using a Cox proportional hazards model in the same way as 
the primary endpoint for phase II (see Section 7.3.1). A hazard ratio and 95% confidence 
interval for BI 836845 in combination with enzalutamide vs. enzalutamide alone will be 
presented. Kaplan-Meier estimates of overall survival will be plotted by treatment group. A 
log-rank test will also be performed to compare the survival curves. 
The first analysis of overall survival will be performed at the time of primary PFS analysis. 
The analysis will be updated once all patients have completed the last follow-up visit and/or 
when an adequate number of patients have died. The time to PSA progression will be 
analysed using a Cox proportional hazards model in the same way as the primary endpoint 
for phase II (see Section 7.3.1). In addition, the percentage change from baseline in PSA will 
be summarized descriptively. The maximum decline in PSA compared to baseline will be 
explored graphically. Further details will be provided in the TSAP. 
7.3.3
Safety analyses
DLTs will be tabulated for each dose cohort in phase Ib (escalation). The tabulation will be 
done in two ways:


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• DLTs with onset in the first treatment course, and
• All DLTs regardless of treatment course at onset
The MTD analysis is defined in Section 5.2.4.
Adverse events will be graded according to CTCAE, Version 4.03 (R10-4848). Key safety 
measures will include:
∀
Events leading to dose reduction or permanent treatment discontinuation
∀
The overall incidence and intensity of AEs, as well as seriousness and relatedness of 
adverse events to treatment
Other safety-relevant assessments including those involving ECG, and ECOG score, will be 
described with respect to possible changes compared to baseline values. Further details on the 
analysis of ECG data will be specified in the TSAP.
7.3.4
Interim analyses
No formal interim analysis is planned for efficacy. In the phase Ib escalation, the study team 
will continuously monitor and assess safety data to ensure patients’ safety, as well as to 
determine the dose for the exploratory expansion cohort and phase II. If considered 
necessary, as soon as the MTD and/or the recommended phase II dose is determined, an 
evaluation of the safety and efficacy aspects will be performed via a snapshot of the database. 
Results of this evaluation will be documented and stored.
Continuous monitoring of safety data for phase Ib expansion cohort will be done by the BI 
study team and trial investigators and phase II will be done by an internal DMC to ensure a 
benefit risk assessment during the DMC meetings. During regular meetings, the committee 
may examine the efficacy data in order to completely assess the benefit risk advantage of BI 
836845 in combination with enzalutamide.
The results of the phase Ib expansion cohort and the phase II will be analysed separately. 


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7.4
HANDLING OF MISSING DATA
In general, missing data will not be imputed. Further details for handling of missing PSA 
values will be specified in the TSAP. 
See section 3.3.5 for replacement of patients.
For PFS, every effort will be made to obtain date of progression for patients known to have 
progressed. Detailed censoring rules will be specified in the TSAP.


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For partial or missing AE onset and/or end dates, BI internal rules will be followed for 
imputation (see Reference Document 001-MCG-156_RD01 “Handling of missing and 
incomplete AE dates”).
7.5
RANDOMISATION
No randomisation is needed for phase Ib. Patients will be assigned sequentially to the dose 
cohort at the time for the escalation part, and to the MTD and/or recommended phase II dose.
In phase II, patients will be randomised in a 1:1 ratio to each of the two treatment groups. 
Treatment assignment will be centrally managed by means of a third-party phone/web-based 
randomisation during the screening phase. This will involve the use of an interactive response 
technology (IRT i.e. Interactive Voice Response System [IVRS]/Interactive Web Response 
System [IWRS]). Boehringer Ingelheim will arrange the randomisation. A randomisation list 
will be generated using a validated pseudo-random number generator, yielding reproducible 
and non-predictable results.
7.6
DETERMINATION OF SAMPLE SIZE
Phase Ib escalation follows a 3+3 design to determine the MTD and/or recommended phase 
II dose of BI 836845 in combination with enzalutamide. Approximately 9-12 patients may be 
assessed. Assuming two cohorts are needed to determine the MTD, 3-6 patients may be 
treated in the first cohort, followed by 3-6 patients in the second cohort. 
The phase Ib exploratory expansion cohort consists of one cohort treated at the MTD and/or 
recommended phase II dose. In this cohort, approximately 25 additional patients will be 


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treated to ensure 21 evaluable patients. Assuming a PSA response rate of 30% (P14-02928, 
see Arm B2), a sample size of evaluable 21 patients leads to a probability of about 80% of 
observing at least 5 patients with a PSA response (as shown in Table 7.6: 1 below).
If the true PSA response rate is less i.e. 25%, then the probability of observing at least 5 PSA 
responses is 63%. If the true PSA response rate is higher i.e. 35%, then the probability of 
observing at least 5 PSA responses is 91%. A probability of 80% was seen as sufficient, 
leading to the chosen sample size of 21 evaluable patients. In the phase Ib expansion part of 
the study an evaluable patient is defined as a patient where data for the assessments of the 
primary endpoint is available.
The probability of a false positive signal is also sufficiently small given a sample size of 21 
evaluable patients. For example, the probability of observing 5 PSA responses if the true PSA 
response rate is 5% is less than 0.5%.
Table 7.6: 1
Probability of observing at least x events, given a true PSA response 
rate and sample size
True 
PSA response 
Rate
Number of 
patients in 
cohort
Probability of observing at least
3 events* 4 events* 5 events* 6 events* 7 events*
0.25
18
0.8647
0.6943
0.4813
0.2825
0.1390
21
0.9255
0.8083
0.6326
0.4334
0.2564
24
0.9602
0.8850
0.7534
0.5778
0.3926
0.30
18
0.9400
0.8354
0.6673
0.4656
0.2783
21
0.9729
0.9144
0.8016
0.6373
0.4495
24
0.9881
0.9576
0.8889
0.7712
0.6114
0.35
18
0.9764
0.9217
0.8114
0.6450
0.4509
21
0.9914
0.9669
0.9076
0.7991
0.6433
24
0.9970
0.9867
0.9578
0.8956
0.7894
0.05
18
0.0581
0.0109
0.0015
0.0002
0.0000
21
0.0849
0.0189
0.0032
0.0004
0.0000
24
0.1159
0.0298
0.0060
0.0010
0.0001
* event = decline in PSA > 50% from baseline.
The phase II of the trial is intended to provide evidence that will allow informed decision 
making during the next stages of development. The phase II is therefore sized such that, if the 
true hazard ratio of BI 836845 in combination with enzalutamide versus enzalutamide alone 
was 0.65, the probability of observing a small hazard ratio is sufficiently large. Similarly, if 
the true hazard ratio was 1, the probability of observing a small hazard ratio should be 
sufficiently small. Table 7.6: 2 displays the probability of observing a hazard ratio less than a 
threshold X, given a true hazard ratio and a pre-specified number of events.


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Table 7.6: 2
Probability of observing a hazard ratio ≤ X, given a true hazard ratio 
and a pre-specified number of events
True hazard ratio
(Arm A / Arm B)1
Number of PFS 
events3
Probability2 of observing a hazard ratio ≤ X
X = 0.7
X = 0.8
X = 0.9
X = 1.0
0.65
40
0.59
0.74
0.85
0.91
50
0.60
0.77
0.88
0.94
60
0.61
0.79
0.90
0.95
70
0.62
0.81
0.91
0.96
0.67
40
0.56
0.71
0.82
0.90
50
0.56
0.73
0.85
0.92
60
0.57
0.75
0.87
0.94
70
0.57
0.77
0.89
0.95
0.70
40
0.5
0.66
0.79
0.87
50
0.50
0.68
0.81
0.90
60
0.50
0.70
0.83
0.92
70
0.50
0.71
0.85
0.93
1.0
40
0.13
0.24
0.37
0.5
50
0.10
0.22
0.35
0.50
60
0.08
0.19
0.34
0.50
70
0.07
0.18
0.33
0.50
1 Arm A = BI 836845 in combination with enzalutamide, Arm B = enzalutamide alone.
2 Calculated based on the approximate normal distribution of the estimated log hazard ratio, i.e. assuming the log hazard ratio
is normally distributed with mean log(true hazard ratio), and variance (4 / number of PFS events) (R10-4988).
3 Note that 70 events out of 80 patients can only be seen if the number of permanently censored patients is very low.
Assuming the true hazard ratio is between 0.65 and 0.70, and given 60 events, the probability
of observing a hazard ratio of less than 0.8 is sufficiently high, between 0.70 and 0.79. In 
comparison, if the true hazard ratio is 1.0 (i.e. no treatment effect) and given 60 events, the 
probability of observing a hazard ratio of less than 0.8 is sufficiently low at 0.19. 
Due to the inherent difficulties determining radiographic progression in this indication, a 
central imaging unit is employed to interpret the radiographic images and obtain an 
independent tumour assessment in addition to the investigator’s assessment. However, due to 
these difficulties, there is potentially a high discordance rate between the independent review 
and the investigators (fewer independent review events compared to investigator assessed 
events). From Table 7.6: 2 it can be seen that having a discordance rate of going up to 33% –
leaving potentially only 40 independent review events – still gives a probability of between 
0.66 and 0.74 (corresponding true underling HR of between 0.65 and 0.70) of observing a HR 
of less than 0.8 in the evaluation of the independent review as well. If the true underlying HR 
should be 1.0, then the probability of observing a HR of 0.8 is still sufficiently low with 0.24.
Due to the patients’ advanced condition and previous treatment regiments obtained before 
joining this study, the estimated median PFS time in the enzalutamide arm is around 3 
months, and between 4.3-4.6 months in the combination arm of BI 836845 + enzalutamide. 


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Assuming recruitment rates of 10-13 patients per month for a period of A months, the 
percentage of observed PFS events relative to sample size is a function of study duration T:
&
∋
&
∋
(
)
∗
+
,
−
..
/
0
11
2
3
#
#
4
..
/
0
11
2
3
#
#
#
#
#
#
#
#
2
1
2
2
1
1
1
1
2
1
5
5
5
5
5
5
A
e
e
A
e
e
T
A
T
T
A
T
,
where λ1=0.151 and λ2=0.231 are the parameters of exponential distribution assuming median 
PFS of 4.6 months for BI 836845 in combination with enzalutamide and 3 months for 
emzalutamide alone. Based on the formula above, and taking multiple parameter 
combinations into consideration, the study duration until the required numbers of events are 
obtained is estimated to be between 17-23 months. Therefore, the primary analysis is targeted 
when 60 PFS events by investigator’s assessment are observed or 23 months after the first 
patient was randomized in the phase II part.
Table 7.6: 3
Study duration until targeted number of 60 PFS events from 80 
randomised patients are observed for different possible underlying 
scenarios
Median PFS
Enzalutamide
alone
[months]
Median PFS
BI 836845 +
Enzalutamide
[months]
Rate of 
permanently 
censored 
patients*
Accrual 
period
[months]
Expected trial duration to 
reach the expected 
number of PFS events 
[months]
3
4.3
20%
9
19.9
3
4.6
20%
9
20.6
3
4.3
15%
9
16.4
3
4.6
15%
9
16.9
3
4.3
20%
12
21.9
3
4.6
20%
12
22.5
3
4.3
15%
12
18.4
3
4.6
15%
12
18.8
* Percentage of patients that leave the study without a PFS event


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
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 


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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. 
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. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For BI 836845 this is the current version of the Investigator’s Brochure (U10-2830). For the 
enzalutamide this is the SPC. The current versions of these reference documents are to be 
provided in the ISF. No AEs are classified as listed for matching placebo, study design, or 
invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 


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regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities <for EU>, 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 (last patient/patient out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and 
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Nickerson T, Chang F, Lorimer D, Smeekens SP, Sawyers CL, Pollak M. In 
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Plymate SR, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P, 
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androgen-dependent prostate cancer. Clin Cancer Res 2007;13(21):6429-6439
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Wu JD, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P, Montgomery 
RB, Ludwig DL, Plymate SR. Combined in vivo effect of A12, a type 1 
insulin-like growth factor receptor antibody, and docetaxel against prostate 
cancer tumors. Clin Cancer Res 2006;12(20):6153-6160
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Wu JD, Odman A, Higgins LM, Haugk K, Vessella R, Ludwig DL, Plymate 
SR. In vivo effects of the human type I insulin-like growth factor receptor 
antibody A12 on androgen-dependent and androgen-independent xenograft 
human prostate tumors. Clin Cancer Res 2005;11(8):3065-3074
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Chi KN, Gleave ME, Fazli L, Goldenberg SL, So A, Kollmannsberger C, 
Murray N, Tinker A, Pollak M. A phase II pharmacodynamic study of 
preoperative figitumumab in patients with localized prostate cancer. Clin 
Cancer Res 2012;18(12):3407-3413
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O'Brian MF, Watson RWG, Fitzpatrick JM. Insulin-like growth factor I and 
prostate cancer. Urology 2001;58(1):1-7.
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Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: 
systematic review and meta-regression analysis. Lancet 2004;363:1346-1353.


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Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano M, Pollak M, Giovannucci E. 
Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of 
advanced-stage prostate cancer. J Natl Cancer Inst 2002;94(14):1099-1106.
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Shariat SF, Lamb DJ, Kattan MW, Nguyen C, Kim J, Beck J, Wheeler TM, 
Slawin KM. Association of preoperative plasma levels of insulin-like growth 
factor I and insulin-like growth factor binding proteins-2 and -3 with prostate 
cancer invasion, progression, and metastasis. J Clin Oncol 2002;20(3):833-
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like growth factor (IGF)-I, IGF-II and IGF type I receptor (IGFR-I) expression 
in prostatic cancer. Anticancer Res 2003;23:3825-3835
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Ouban A, Muraca P, Yeatman T, Coppola D. Expression and distribution of 
insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol 
2003;34:803–8.
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Liao Y, Abel U, Grobholz R, Hermani A, Trojan L, Angel P, et al. 
Upregulation of insulin-like growth factor axis components in human primary 
prostate cancer correlates with tumor grade. Hum Pathol 2005;36:1186–96.
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Krueckl SL, Sikes RA, Edlund NM, Bell RH, Hurtado-Coll A, Fazli L, Gleave 
ME, Cox ME. Increased insulin-like growth factor I receptor expression and 
signaling are components of androgen-independent progression in a lineage-
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Acad Sci USA 2000;97(7):3455-3460
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Rubin J, Chung LWK, Fan X, Zhu L, Murphy TC, Nanes MS, Rosen CJ. 
Prostate carcinoma cells that have resided in bone have an upregulated IGF-I 
axis. Prostate 2004;58:41-49.
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Kawada M, Inoue H, Masuda T, Ikeda D. Insulin-like growth factor I secreted 
from prostate stromal cells mediates tumor-stromal cell interactions of prostate 
cancer. Cancer Res 2006;66(8):4419-4425
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growth factor-I promotes migration in human androgen-independent prostate 
cancer cells via the alphavbeta3 integrin and PI3-K/Akt signaling. Int J Oncol 
2006;28:723–30.
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Verras M, Sun Z. Beta-catenin is involved in insulin-like growth factor 1-
mediated transactivation of the androgen receptor. Mol Endocrinol 
2005;19(2):391-398
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protein 2 promotes proliferation of androgen-independent human prostate 
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of phosphatidylinositol 3'-kinase pathway. Endocrinology 2000;141(6):2257-
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Tengowski MW, Wang F, Gualberto A, Beebe JS, Moyer JD. Combination 
therapy enhances the inhibition of tumor growth with the fully human anti-
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Wit, M.D., Peter Mulders, M.D., Ph.D., Kim N. Chi, M.D., Neal D. Shore, 
M.D., Andrew J. Armstrong, M.D., Thomas W. Flaig, M.D., Aude Fléchon, 
M.D., Ph.D., Paul Mainwaring, M.D., Mark Fleming, M.D., John D. 
Hainsworth, M.D., Mohammad Hirmand, M.D., Bryan Selby, M.S., Lynn 
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Investigators. Increased Survival with Enzalutamide in Prostate Cancer after 
Chemotherapy N Engl J Med 2012; 367:1187-1197, September 27, 2012
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Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, 
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R15-1307
T.M. Beer, A.J. Armstrong, D.E. Rathkopf, Y. Loriot, C.N. Sternberg, C.S. 
Higano, P. Iversen, S. Bhattacharya, J. Carles, S. Chowdhury, I.D. Davis, J.S. 
de Bono, C.P. Evans, K. Fizazi, A.M. Joshua, C.-S. Kim, G. Kimura, P. 
Mainwaring, H. Mansbach, K. Miller, S.B. Noonberg, F. Perabo, D. Phung, F. 
Saad, H.I. Scher, M.-E. Taplin, P.M. Venner, and B. Tombal, for the 
PREVAIL Investigators. Enzalutamide in Metastatic Prostate Cancer before 
Chemotherapy, NEJM 2014
9.2
UNPUBLISHED REFERENCES
c01690707
Investigator’s Brochure: Xentuzumab (BI 836845); current version
U11-3025-02
; Phase I dose escalation trial of 
weekly intravenous administrations of BI 836845 in patients with advanced 
solid cancers with repeated administrations in patients showing clinical 
benefit. 1280.1 Revised, Version 2, 23 July 2013
U10-2994-03
; A Phase I dose escalation trial of BI 836845 administered 
intravenously once every three weeks in patients with advanced solid tumours 
with repeated administrations in patients showing clinical benefit. 1280.2 
Revised, Version 3, 18 July 2013


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10.
APPENDICES
10.1
COCKCROFT-GAULT FORMULA 
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula.  The use of on-line calculators or formulas which are institution 
standards for eCCR and differ slightly may also be used.  The calculations and results must be 
filed in the patient’s chart.
When serum creatinine is measured in mg/dL;
&
∋
&
∋6
7
&
∋
mg/dL
in 
Creatinine
Serum
72
85
.0
kilograms
in 
Mass
Age
140
eCCR
8
8
8
#
9
Female
if
When serum creatinine is measured in μmol/L;
&
∋
&
∋
&
∋
μmol/L
in 
Creatinine
Serum
Constant
kilograms
in 
Mass
Age
140
eC CR
8
8
#
9
Where Constant is 1.23 for men and 1.04 for women.


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10.2
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
* As published in Am. J. Clin. R01-0787


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10.3
EXAMPLES OF CYP 3A4 AND CYP2C8 INHIBITORS, INDUCERS AND
CYP3A4 SUBSTRATES
Please be aware that the below provided lists include only examples. Listings of potentially 
interacting substances don´t claim to be complete and cannot be up to date as new scientific 
information are gathered day-to-day. Investigators are adviced to check in the labels of 
concomitantly administered drugs or treatments for potential drug interactions. In any case of 
uncertainty with respect to the drug interaction potential of comedications, the sponsor of the 
study should be consulated for specific advice.
10.3.1 Examples of CYP3A4 substrates
Abiraterone,  Alfentanil,  Alfuzosin,  Aliskiren, Almotriptan,  Alprazolam,  Amitriptyline, Amiodarone,  
Amlodipine, Amprenavir, Aprepitant,  Aripiprazole, Astemizole, Atazanavir, Atorvastatin, Bepridil, 
Bexarotene, Boceprevir, Bromocriptine, Budesonide, Buprenorphine, Buspirone, Cafergot, Caffeine, 
Cannabinoids, Carbamazepine, Cerivastatin, Cevimeline, Chlordiazepoxide Cilostazol, Cinacalcet, 
Citalopram, Clarithromycin, Clindamycin, Clomipramine, Clonazepam, Clopidogrel, Clorazepate, 
Clozapine, Cocaine, Codeine, Colchicine, Cyclophosphamide, Cyclosporine, Dapsone, Darifenacin, 
Darunavir, Delavirdine, Desogestrel, Dextromethorphan, Diazepam, Dihdroergotamine, Disopyramide, 
Diltiazem, Docetaxel, Dofetilide, Dolasetron, Domperidone, Donepezil, Doxorubicin, Dronabinol, 
Dutasteride, Efavirenz, Eplerenone, Ergotamine, Erlotinib, Erythromycin, Esomeprazole, Eszoplicone, 
Ethinylestradiol, Ethosuximide, Etonogestrel, Etoposide, Everolimus, Exemestane, Felodipine, Fentanyl, 
Finasteride, Fexofenadine, Flurazepam, Flutamide, Fluticasone, Galantamine, Haloperidol, Hydrocodone, 
Iloperidone, Imatinib, Imipramine, Indinavir, Irinotecan, Isradipine, Itraconazole, Ketamine, Ketoconazole, 
Lansoprazole, Letrozole, Lercanidipine, Lidocaine, Loratadine, Lopinavir, Lovastatin, Methadone, 
Midazolam, Mifepristone, Mirtazapine, Modafinil, Mometasone, Montelukast, Nateglinide, Nelfinavir, 
Nevirapine, Nicardipine, Nifedipine, Nisoldipine, Nitrendipine, Norethindrone, Ondansetron, Omeprazole, 
Oxybutynin, Oxycodone, Paclitaxel, Pantoprazole, Pioglitazone, Propafenone, Propranolol, Quetiapine, 
Quinidine, Quinine, Rabeprazole, Ramelteon, Ranitidine, Ranolazine, Repaglinide, Rifampin, Ritonavir, 
Rivaroxaban, Roflumilast, Salmeterol, Saquinavir, Saxagliptin, Sertraline, Sibutramine, Sildenafil, 
Simvastatin, Sirolimus, Solifenacin, Sorafenib, Sufentanil, Sunitinib, Steroids, Tacrolimus, Tadalafil, 
Tamoxifen, Telaprevir, Telithromycin, Temazepam, Temsirolimus, THC, Theophylline, Tiagabine, 
Tinidazole, Tipranavir, Tolterodine, Toremifene, Tramadol, Trazadone, Triazolam, Trimetrexate, 
Valdecoxib, Valproic acid, Vardenafil, Verapamil, Vinblastine, Vincristine, Voriconazole, Warfarin (r), 
Zaleplon, Zileuton, Ziprasidone, Zolpidem, Zonisamide
10.3.2 Strong and moderate CYP3A4 and CYP2C8 inhibitors and inducers
Strong CYP3A4 inhibitors
Moderate CYP3A4 inhibitors
boceprevir
clarithromycin
cobicistat 
conivaptan
danoprevir  + ritonavir
elvitegravir  + ritonavir
grapefruit juice
idelalisib
indinavir + ritonavir
itraconazole
ketoconazole
LCL161
lopinavir + ritonavir
mibefradil
nefazodone
nelfinavir
ACT-178882
amprenavir
aprepitant
atazanavir + ritonavir
casopitant
cimetidine
ciprofloxacin
crizotinib
cyclosporine
darunavir + ritonavir
diltiazem
dronedarone
erythromycin
faldaprevir
FK1706 
fluconazole


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Strong CYP3A4 inhibitors
Moderate CYP3A4 inhibitors
posaconazole
ritonavir
saquinavir + ritonavir
telaprevir
telithromycin
tipranavir + ritonavir
troleandomycin
voriconazole
grapefruit juice
imatinib
netupitant
nilotinib
schisandra sphenanthera 
tofisopam
verapamil
Strong CYP3A4 inducers
Moderate CYP3A4 inducers
avasimibe
carbamazepine
enzalutamide
mitotane
phenobarbital
phenytoin
rifabutin
rifampin
St John's Wort
bosentan
efavirenz
genistein
nafcillin
ritonavir + St. John's Wort
semagacestat
thioridazine
tipranavir + ritonavir
Strong CYP2C8 inhibitors
Moderate CYP2C8 inhibitors
clopidogrel
gemfibrozil
deferasirox
teriflunomide
Strong and moderate CYP2C8 inducers
flucloxacillin
rifampin


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10.4
TUMOUR RESPONSE ASSESSMENT ACCORDING TO MODIFIED
RECIST 1.1
The RECIST response evaluation criteria version 1.1 will be adhered to as described in the 
guidelines published in the European Journal of Cancer (R09-0262) and the accompanying 
articles.  Study personnel involved in tumour assessment for this trial must be trained and 
knowledgeable of RECIST criteria version 1.1.
Modification re Lymph Nodes:
The following modification applies only for lymph nodes as per the Prostate Cancer Clinical 
Trials Working Group (R13-1642): only lymph nodes > 20 mm in the short diameter at 
baseline should be used to assess a change in size during the trial and may be considered a 
target lesion. 
Re-appearing, or enlarging, lymph nodes < 20 mm in the short diameter shall not serve as the 
only trigger for PD. The radiologist will make every effort to assess the patient’s disease 
elsewhere, and provide explanatory comments for the oncologist to take into consideration 
upon determining the final overall assessment, if applicable.
When a lymph node continues to increase over 20 mm in short diameter on subsequent 
images, or other accompanying findings on images change from equivocal to unequivocal, 
the time-point where the lymph node increase was first documented shall serve as the date of 
PD.
Bone lesions are to be reported on the assessment of bone metastases CRF page and not on 
the response to therapy RECIST assessment CRF page. 
Response criteria for target lesions:
1.   Complete Response 
(CR):
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have a reduction 
in short axis to <10mm)
2.   Partial Response (PR):
At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum diameters
3.   Progression (PD):
At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of a least 5mm (note: the 
appearance of one or more new lesions is also considered 
progression).
4.   Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as references the smallest 
sum diameters while on study


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Response criteria for non-target lesions:
1.   Complete Response 
(CR):
Disappearance of all non-target lesions and normalization of 
tumour marker level. All lymph nodes must be non-
pathological in size (<10mm short axis)
2.   Non-CR/ Non-PD:
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumour marker level above the normal limits
3.   Progression (PD):
Unequivocal progression of existing non-target lesions 
(Note: the appearance of one or more new lesions is also 
considered progression)
Timepoint response for patients with measurable disease at baseline:
Target lesions
Non-Target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Timepoint response for patients with non-measurable disease at baseline:
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/ Non-PD
No
Non-CR/ Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
.


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10.5
COMMON TERMINOLGY CRITERIA FOR ADVERSE EVENTS (CTCAE)
The CTCAE version 4.03, 14 June 2010(R10-4848) will be use to classify and record the 
intensity of adverse events in the (e)CRF.
Grading of Hypersensitivity Reactions According to the National Cancer Institute CTCAE 
version 4.03, 14 June 2010, described above, will be used for the grading of infusion 
reactions and subsequent management will be according to the protocol and/or local hospital 
guidelines. 


Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                               
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Boehringer Ingelheim                                                                                     06 Jun 2022                                               
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10.7
EXAMPLES OF BONE SCAN PROGRESSIONS USING PROSTATE 
CANCER CLINICAL TRIALS WORKING GROUP GUIDELINES 
(PCWG2)
BL = Baseline


Boehringer Ingelheim                                                                                                    06 Jun 2022
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
11 September 2014
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
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
TITLE PAGE
Description of change
Change of Trial Clinical Monitor
Rationale for change
Change of Trial Clinical Monitor
Section to be changed
FLOW CHART - PHASE IB TOLERABILITY 
& SAFETY / EXPANSION COHORT
Description of change
Additional text to clarify laboratory tests should 
be done prior to dosing.
Rationale for change
Clarification that laboratory tests should be 
completed before dosing.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
FLOW CHART - PHASE II RANDOMISED 
TRIAL 
Description of change
Additional text to clarify laboratory tests should 
be done prior to dosing.
Rationale for change
Clarification that laboratory tests should be 
completed before dosing.
Section to be changed
Overall Trial Design and Plan, Section 3.1
Description of change
Removal of de-escalation step 
Rationale for change
Removal of de-escalation step at request of 
MHRA
Section to be changed
Overall Trial Design and Plan, Section 3.1
Description of change
Change of hyperlink as incorrect one inserted
Rationale for change
Update
Section to be changed
Overall Trial Design and Plan, Section 3.1
Description of change
Clarification on when patients can continue on
treatment in the study that this may include 
symptomatic progression and/or PSA progression
Rationale for change
Clarification
Section to be changed
Selection of Trial Population, Section 3.3
Description of change
Only maximum dose of enzalutamide (160mg) 
will be used as starting dose in exploratory 
expansion cohort
Rationale for change
Clarification
Section to be changed
Exclusion criteria, Section 3.3.3
Description of change
Change of contraceptive use for patients entering 
the study. Males patients must use condom plus 
spermicide.  Female partner must also use another 
form of birth control such as implants, injectables, 
combined oral contraceptives
Rationale for change
Change at request of MHRA to allow stricter birth 
control


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Treatments to be administered, Section 4.1.1  
Description of change
Removal of option of de-escalation of 
enzalutamide
Rationale for change
Change at request of MHRA
Section to be changed
Method of assigning patients to treatment groups,   
Section 4.1.2
Description of change
Removal of option of de-escalation of 
enzalutamide
Rationale for change
Change at request of MHRA
Section to be changed
Selection of doses in the trial, section 4.1.3 
Description of change
Removal of option of de-escalation of 
enzalutamide and clarification on rules for dose 
escalation
Rationale for change
Change at request of MHRA and simplification 
now only 2 possible dose regimens
Section to be changed
Drug assignment and administration of doses for 
each patient, section 4.1.4 
Description of change
Multiple changes to remove the option of de-
escalation of enzalutamide
Rationale for change
Change at request of MHRA
Section to be changed
Management of potential hyperglycaemia, section 
4.2.2.2 
Description of change
Correction of spelling mistake
Rationale for change
As above
Section to be changed
Assessment of tumours and bone, section 5.1.2.1 
Description of change
Removal of ≤
Rationale for change
Correction of error in protocol
Section to be changed
Central Imaging, section 5.1.3 
Description of change
Change to only require a primary review of 
images by central imaging vendor
Rationale for change
Advice that for phase II a dual read by two 
independent reviewers is not required
Section to be changed
Adverse event and serious adverse event 
reporting, section 5.2.2.2 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
Removal of table 5.2.2.2.1 due to changes in BI 
standard for AE section of protocol
Rationale for change
Due to changes in BI standard for AE section of 
protocol
Section to be changed
Adverse event and serious adverse event 
reporting, section 5.2.2.2.
Description of change
Addition of text regarding reporting pregnancies 
of female partners of male participants
Rationale for change
Updated following request from MHRA to clarify 
pregnancy reporting
Section to be changed
ECG evaluation, section 5.2.6.2
Description of change
Correction from four to three measurements of the 
cardiac intervals and clarification that ECGs will 
be evaluated by BI
Rationale for change
Error in original protocol regarding number of 
measurements and clarification on who will 
review ECGs.
Section to be changed
Appendix 10.4
Description of change
Removal of ≤and clarification on PSA 
progression
Rationale for change
Correction of error in original protocol


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Number of global amendment
2
Date of CTP revision
20 March 2015
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate 
Cancer (CRPC) Following Disease Progression 
on Docetaxel-Based Chemotherapy and 
Abiraterone
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 – Trial Site(s)
Description of change
The number of Trial Sites is updated from 15 or 
more to 30 or more
Rationale for change
Based on the feasibility and required recruitment 
timelines the number of sites within countries has 
been increased to 30 or more
Section to be changed
Clinical Trial Protocol Synopsis – Objective(s)
Description of change
Primary and Secondary Objectives: The primary 
objectives have been updated to clarify the
treatment regimens that patients must/must not 
have received prior to entering the trial. Patients 
in the phase Ib escalation and phase II cohorts 
must have been treated with a docetaxel-based 
chemotherapy and abiraterone prior to inclusion 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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into the trial. Patients in the phase Ib expansion 
cohort must not have received any taxane or 
abiraterone prior to inclusion into the trial.
The secondary objectives have been updated to 
include overall survival for the phase II part of 
the trial and to remove pharmacokinetics, 
pharmacodynamics and pharmacogenomics.
The word treatment also had a spelling mistake 
corrected.
Rationale for change
The USA is being added as an additional country 
for the Phase Ib expansion cohort. This addition
required the expansion group of patients to be pre
taxane-based therapy only. The other two cohorts 
(phase Ib escalation and phase II) have been 
updated to clarify difference in the 3 cohorts. 
Overall survival was missing as a secondary 
endpoint in the synopsis so this section has been 
updated.
 
 
Section to be changed
Clinical Trial Protocol Synopsis – Methodology
Description of change
The number of parts of the trial updated from two 
to three
Rationale for change
Administrative change due to error in protocol 
version 1 and 2.
Section to be changed
Clinical Trial Protocol Synopsis – Number of 
patients
Description of change
The wording concerning the total number of 
patients entered into the trial has been changed 
from Part I and Part II to all parts of the study.
Rationale for change
Administrative change to clarify that the total 
number of patients is for all parts of the trial. 
Section to be changed
Clinical Trial Protocol Synopsis – Main criteria 
for Inclusion
Description of change
This section has been updated to clarify the
treatment regimens patients must/must not have 
received prior to entering the trial. 
Rationale for change
The USA is being added an additional country for 
the Phase Ib expansion cohort and this added the


Boehringer Ingelheim                                                                                                    06 Jun 2022
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requirement to make the expansion group of 
patients pre taxane-based therapy only and having 
a rise in PSA. 
Section to be changed
Clinical Trial Protocol Synopsis – Criteria for 
efficacy
 
Description of change
The phase II Randomised Trial Secondary 
endpoints have been updated to clarify that the 
percentage change in PSA is measured at week 
12
Rationale for change
Clarification in the label of the endpoint, already 
defined in section 5.1.
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort
Description of change
Change of title from safety and tolerability to 
escalation.
Rationale for change
Administrative change
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 5
Description of change
 
Links to exclusion 20 and section 2.3 have also 
been added to the footnote. 
 
 
 
 
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 6
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 11
Description of change
Footnote 11 updated to correct section reference 
from 5.2.3 to 5.2.5
Rationale for change
Administrative change
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 13
Description of change
Additional time point added to footnote to collect 
circulating DNA at cycle 4 day 1. 
Rationale for change
It has been decided to perform an additional 
blood sample to look at the circulating DNA in 
the blood. This is a less invasive procedure for 
patient than fresh tissue biopsy and will provide 
useful information about the status of patients 
tumour at week 12.
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 17
Description of change
Footnote updated to remove wording about “on 
days of BI 836845 administration”
 
 
 
 
 
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 18
 
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 19
Description of change
Footnote updated to state that all lesions 
identified at screening should be followed by 
imaging throughout the trial.
Footnote updated to state that bone scans must be 
performed at screening and then if clinically 
indicated every 12 weeks until start of new anti-
cancer therapy if clinically indicated.
Footnote was also updated to clarify the imaging 
timelines from baseline. Imaging time points will 
be calculated from start of treatment.
Rationale for change
Clarification on imaging requirements and 
timelines. Imaging should be calculated from start 
of treatment.
Section to be changed
FLOW CHART – Phase Ib Escalation/Expansion 
Cohort: Footnote 27
 
 
 
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Footnote 6
 
 
Links to exclusion 20 and section 2.3 have also 
been added to the footnote. 
 
 
 
 
 
 
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Footnote 7
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Footnote  12
Description of change
Footnote 12 updated to correct section reference 
from 5.2.3 to 5.2.5
Rationale for change
Administrative change
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Footnote 14
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Footnote 18
Description of change
Footnote updated to remove wording about “on 
days of BI 836845 administration”
 
 
 
 
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Footnote 19
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
FLOW CHART –Phase II Randomised Trial: 
Footnote 20
Description of change
Footnote updated to state that all lesions 
identified at screening should be followed by 
imaging throughout the trial.
Footnote updated to state that bone scans must be 
performed at screening and then if clinically 
indicated and every 12 weeks until start of new 
anti-cancer therapy if clinically indicated
Footnote was also updated to clarify the imaging 
timelines from randomisation. Imaging time 
points will be calculated from randomisation as
PFS is calculated from randomisation.
Rationale for change
Clarification on imaging timelines and 
requirements.
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Section to be changed
FLOW CHART – Phase II Randomised Trial: 
Randomisation: Footnote 27
Description of change
An additional bullet point has been added to state 
that cycle 1 day 1 must start as soon as possible 
after randomisation but at least 3 days after.
Rationale for change
This change allows sites more flexibility for 
starting treatment. Per protocol patients should 
take enzalutamide early in the morning. By doing 
the randomisation on a day before the start of 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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treatment it enables the patient to start treatment 
in the morning.
Section to be changed
Abbreviations
Description of change
New abbreviations have been added for 
recommended phase II dose, 
 
and functional assessment of 
cancer therapy – prostate. EOT corrected to End 
of Treatment rather than End of Trial.
Rationale for change
Administrative changes
Section to be changed
Section 1.1 Medical Background
Description of change
The following paragraph was added: These data 
were more recently confirmed in the PREVAIL 
trial, investigating Enzalutamide in metastatic 
prostate cancer before chemotherapy: 
Enzalutamide significantly decreased the risk of 
radiographic progression and death and delayed 
the initiation of chemotherapy.
Rationale for change
Addition of more recent clinical trial data on 
enzalutamide.
Section to be changed
Section 1.2.2: Drug Profile - Enzalutamide
Description of change
The version date of the SmPC for Enzalutamide 
was removed from the protocol.
Rationale for change
The SmPC is updated regularly and investigators 
and site staff must refer to the most recent version 
of the SmPC
Section to be changed
Section 2.1: Rationale for Performing the Trial
Description of change
The following paragraph was removed: Whilst 
there is a lack of preclinical data for synergistic 
activity between IGF-targeting compounds and 
specifically enzalutamide thus far, there is a 
strong theoretical (mechanistic) rationale.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose (RP2D).
The section has been updated to clarify that 
patients require a rise in PSA in order to be 
eligible for phase Ib expansion and the words 
“failing on this  treatment” have been removed.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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The wording has been updated to clarify that 
patients must not have received any taxane 
therapy in order to be eligible to enter the Phase 
Ib expansion cohort.
Rationale for change
The paragraph was removed as this is no longer 
correct.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose (RP2D) to be consistent throughout 
protocol and other protocols in 1280 program 
within Boehringer Ingelheim.
Patients require a rising PSA “biological 
progression” to enter the trial but have not been 
considered to have “failed” treatment. The words 
failing treatment have therefore been removed.
Inclusion of the USA as country for Phase Ib 
expansion required that only patients not pre-
treated with taxane-based therapy may enter the 
cohort.
Section to be changed
Section 2.2: Trial Objectives
Description of change
Primary Objectives: Primary objectives updated 
to clarify the treatment regimens that patients 
must/must not have received prior to entering the 
trial. 
 
Rationale for change
Primary Objectives: The USA is being added as
an additional country for the Phase Ib expansion 
cohort and this added the requirement to make the 
expansion group of patient’s pre taxane -based 
therapy only. The other two cohorts (phase Ib 
escalation and phase II) have been updated to 
clarify the difference in the 3 cohorts. 
 
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Section 2.3: Benefit-Risk Assessment
Description of change
The requirement for the DMC to review the 
Phase Ib expansion part of the trial was removed. 
The phase Ib expansion will instead be 
continuously supervised and monitored by the BI 
study team and investigators.
Rationale for change
The phase Ib expansion part of the trial is being 
reviewed by BI in an open label manner and 
would therefore be better monitored by the BI 
study team during regular review of the data as 
well as by the investigators during 
teleconferences.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
In the first paragraph in the section  the words 
“two drugs” were replaced with BI 836845 in 
combination with enzalutamide.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose (RP2D) to be consistent throughout 
protocol and other protocols in 1280 program 
within BI.
The words “at the start of each treatment cycle” 
were removed from the sentence: “BI 836845 will 
be administered weekly in 28 day cycles of 
treatment, as per the flow chart, by a one hour 
intravenous infusion at the start of each treatment 
cycle.”
Figure 3.1:1 updated to clarify that only patients
who are pre taxane-based therapy may enter the 
expansion cohort. Also the words “at least” were 
added in front of 21 patients to be consistent with 
other places in the protocol (also in paragraph 
below).
Section updated to clarify that patients require a 
rise in PSA in order to be eligible for phase Ib 
expansion and the words “and be failing” have 
been removed.
This section has been updated so that fresh 
tumour biopsy is mandatory at baseline and cycle 
1 day 15 and optional at end of


Boehringer Ingelheim                                                                                                    06 Jun 2022
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treatment/progression time point for patients in 
the phase Ib expansion part of the trial.
Phase II: optional at each time point.
The section has been updated to clarify that soft 
tissue lesions are to be assessed using modified 
RECIST and bone lesions are to be assessed using
PCCTWG2 guidelines.
The word “and” was removed from the following 
sentence: Patients should be kept on trial until 
radiological or and symptomatic progression is 
documented with or without confirmed PSA 
progression.
 
Rationale for change
The words “two drugs” in the first paragraph in 
the section were updated to be consistent with 
other wording in rest of protocol.
The terminology for MTD/recommended phase II 
dose was updated to be consistent throughout 
protocol and other protocols in 1280 program 
within Boehringer Ingelheim.
The words “at the start of each treatment cycle” 
were removed as treatment is given weekly.
Figure 3.1:1 was updated because the USA is 
being added an additional country for the Phase 
Ib expansion cohort. This added the requirement 
to make the expansion group of patient’s pre 
taxane-based therapy only.  Also the words “at 
least” were added in front of 21 patients to be 
consistent with other places in the protocol.
Patients require a rising PSA “biological 
progression” but have not been considered to 
have failed treatment so the words failing 
treatment have been removed.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section has been updated based on updated 
requirements for serial tissue biopsies. New 
schedule is more flexible for patients.
Section on assessment of imaging updated to 
clarify how the different types of lesions are 
assessed. 
The word “and” was removed from the following 
sentence: Patients should be kept on trial until 
radiological or and symptomatic progression is 
documented with or without confirmed PSA 
progression. Patients may be removed from the 
trial due to symptomatic progression.
 
Section to be changed
Section 3.1.1 Administrative structure of the trial
Description of change
This section has been updated to state that trial 
drugs (only when required) will be provided by 
BI or a CRO appointed by BI.
The words “steering committee were removed 
from the following sentence: ”During phase Ib 
dose escalation phase of the study, regular 
teleconference will be held between the 
investigators and BI study team (steering 
committee) for review of safety data, decisions 
over dose escalation, discussions of on-going 
patients, and discussion
This section has been updated to clarify the 
review that will take place for each part of the 
trial: the phase Ib escalation part, phase Ib 
expansion part, and phase II.
Review of the Phase Ib escalation and expansion 
cohort data will be performed by the BI study 
team. A new paragraph has been added to 
confirm the review performed for the phase Ib 
expansion part of the trial and clarification has 
been provided in paragraph about the review of 
the data for the phase Ib escalation part of the 
trial.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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The section has also been updated to confirm that 
the decision to move to the phase II part of the 
trial as well as the phase Ib expansion will be 
discussed between the investigators and BI study 
team.
Rationale for change
The section relating to provision of trial drugs 
was updated as in the USA enzalutamide will be 
provided by the trial sites as it is standard of care.
The wording steering committee has been removd
from the section as there is no official steering 
committee on the trial.
It has been agreed that the phase Ib expansion 
part of the trial (a single arm cohort) would be 
better monitored during regular review of the data 
by the BI study team as well as by the 
investigators. The DMC (an internal but 
independent group of experts at BI) will review 
the phase II data randomised data.
The safety data from the Phase I escalation cohort 
will be reviewed by BI and Investigators in order 
to determine Phase II dose as well as the Phase Ib 
expansion dose.
Section to be changed
Section 3.2 Discussion of Trial Design, Including 
Choice of Control Groups
Description of change
This section has been updated to clarify that 
patients require a rise in PSA in order to be 
eligible for phase Ib expansion and the words 
“failing on this  treatment” have been removed
This section has been updated to clarify that only 
patients who are pre taxane-based therapy may 
enter the expansion cohort.
This section has been updated to clarify that soft 
tissue lesions are to be assessed using modified 
RECIST and bone lesions to be assessed using
PCCTWG2 guidelines.
The naming convention of the escalation cohort 
has been updated from safety and tolerability 
phase to escalation cohort.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Patients require a rising PSA “biological 
progression” but have not been considered to 
have failed treatment so the words failing on the 
treatment have been removed.
The USA is being added an additional country for 
the Phase Ib expansion cohort. This added the
requirement to make the expansion group of 
patient’s pre taxane-based therapy only.
The section on assessment of imaging has been 
updated to clarify how the different types of 
lesions are assessed. 
Naming convention of escalation phase updated 
to be consistent throughout protocol.
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
The words “at least” were added in front of 21 
patients in this section.
Additional wording has been added to clarify that 
that the safety and tolerability phase of the trial is 
called the escalation cohort. 
The number of centres taking part has been
updated to specify how many centres are taking 
part in each phase of the trial. Up to 8 centres for 
the phase Ib expansion part of the trial and 25-30 
centres for the phase II part of the trial.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose (RP2D) to be consistent throughout 
protocol and other protocols in 1280 program 
within BI.
Rationale for change
The words “at least” were added in front of 21 
patients in this section to be consistent with other 
places in the protocol.
Escalation part added as administrative change to 
make wording consistent throughout the protocol. 
Number of centres updated based on updated 
feasibility.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Section 3.3.1 Main diagnosis for study entry
Description of change
The word “dose” has been added to the 
paragraph: For the phase Ib dose escalation 
cohort and phase II cohort patients must have 
received and progressed after docetaxel-based 
chemotherapy…..
Section updated to clarify the allowed pre-
treatments before entering the trial. Patients in the 
phase Ib escalation and phase II must have 
received a docetaxel-based therapy. Patients 
entering phase Ib expansion cohort must be pre-
taxane and abiraterone therapy.
Section also updated to clarify that patients 
require a rise in PSA in order to be eligible for 
phase Ib expansion and the words “failing on this  
treatment” have been removed.
Rationale for change
The word dose was added as an administrative 
change.
Clarification on pre-treatments based on addition 
of USA into phase Ib expansion cohort. 
Patients require a rising PSA “biological 
progression” to enter the trial but have not been 
considered to have failed treatment. Therefore the 
words failing treatment have been removed.
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
Several inclusion criteria updated:
Inclusion 14: INR changed to 1.4 for inclusion 
into trial
Inclusion 18: 5 removed from wording in bullet 
point b as incorrect
Inclusion 19: The words “and be failing treatment 
prior to entering the study” have been removed.
The word “dose” was added into the following 
header: Inclusion criteria only for patients 
entering phase Ib dose escalation and phase II:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
INR changed based on discussions with 
investigators and reassessment of safety for the 
patient. 
Number 5 removed from bullet 18b as inserted in 
error.
Patients require a rising PSA “biological 
progression” to enter the trial but have not been 
considered to have failed treatment. Therefore the 
words failing treatment have been removed.
The word dose was added as an administrative 
change.
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Exclusion 1 and 2: These were removed as they
were relevant for patients being treatment with 
docetaxel. This is no longer applicable for the
Phase Ib expansion phase. The exclusion criteria 
are now added in subsection of exclusion for the 
Phase Ib escalation and Phase II only.
Exclusion 6: The list of potential medications to 
be excluded and wash-out time has been updated
in the exclusion criteria to be in line with the 
current enzalutamide summary of product 
characteristics. Strong CYP2C8 and inducers and 
inhibitors must be stopped within 2 weeks of 
starting trial treatment.
Exclusion 19: Updated to clarify that patient must 
not be pre-treated with any taxane- based 
therapies in the expansion cohort
Additional exclusion criteria added: 
21: Exclusion regarding previous or concomitant 
malignancies added
22: Added for patients entering Phase Ib
escalation or Phase II – amended wording from 
original exclusion 1. Amended to clarify number 
of regimens of docetaxel that patient can have 
had
23: Added for patients entering Phase Ib 
escalation or Phase II – original exclusion 2 but 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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moved due to change in requirements for patients 
entering Phase Ib expansion cohort. Patients 
entering phase Ib escalation or phase II must not 
have received abiraterone or taxane treatment 
within 4 weeks of starting treatment.
The word “dose” was added into the following 
headers: Exclusion criteria only for patients 
entering phase Ib dose escalation and phase II: 
and  Only for patients entering phase Ib dose
escalation and phase II cohorts:
Rationale for change
The exclusion criteria were updated due to 
changes in pre-treatment allowed (patients in 
phase Ib expansion cohort must now be pre-
taxane therapy), review of inclusion/exclusion 
criteria vs current summary of product 
characteristics for Enzalutamide and the missing 
requirement for patient not to have previous or 
concomitant malignancies.
The word dose was added as an administrative 
change.
Section to be changed
Section 3.3.4.2 Discontinuation of the trial by the 
sponsor
Description of change
Bullet 4: spelling error corrected
Rationale for change
Administrative change
Section to be changed
Section 4.1.2 Method of assigning patients to 
treatment groups
Description of change
The word “dose” was added into the following 
bullet point: At least 9-12 eligible patients will be 
entered into the safety and tolerability phase Ib, 
dose escalation……
Escalation part added to sentence to confirm that 
the safety and tolerability phase of the trial is the 
same as the escalation part of the trial.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose (RP2D) to be consistent throughout 
protocol and other protocols in 1280 program 
within BI.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Administrative change to ensure consistent 
terminology throughout protocol.
Section to be changed
Section 4.1.3 Selection of doses in the trial
Description of change
Escalation part added to sentence to confirm that 
the safety and tolerability phase of the trial is the 
same as the escalation part of the trial.
Rationale for change
Administrative change to ensure consistent 
terminology throughout protocol.
Section to be changed
Section 4.1.3.2 Enzalutamide
Description of change
Tablets changed to capsules as enzalutamide is 
supplied in capsules
Rationale for change
Administrative change
Section to be changed
Section 4.1.3.3 Determination of the dose of BI 
836845 in combination with enzalutamide
Description of change
Escalation part added to sentence to confirm that 
the safety and tolerability phase of the trial is the 
same as the escalation part of the trial.
The terminology for MTD/recommended dose 
was updated to MTD and/or recommended phase 
II dose (RP2D) to be consistent throughout 
protocol and other protocols in 1280 program 
within BI.
The paragraph “All safety aspects… randomised 
trial will commence” was removed from the 
protocol and instead the section refers to section 
5.2.4 where MTD and recommended dose for 
Phase II is described.
A statement is added to confirm that the 
recommended phase II dose will be used for 
phase Ib expansion cohort.
Rationale for change
Administrative change to ensure consistent 
terminology throughout protocol.
Section to be changed
Section 4.1.3.4 Exploratory Expansion cohort
Description of change
Section updated to clarify that only patients who 
are pre taxane-based therapy may enter the phase 
Ib expansion cohort.
Section also updated to clarify that patients 
require a rise in PSA in order to be eligible for 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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phase Ib expansion and the words “failing on 
enzalutamide…” have been removed.
Section updated to remove the detail of how 
supplies specifically for the study will be 
dispensed at cycle 1 day 1 in the expansion 
cohort. 
The terminology for MTD and/or recommended 
dose in the exploratory expansion cohort and 
phase II was updated to MTD and/or 
recommended phase II dose (RP2D). The phase 
Ib expansion will also be treated at this same 
dose.
Rationale for change
The USA is being added as an additional country 
for the Phase Ib expansion cohort. This added the
requirement to make the expansion group of 
patients pre taxane-based therapy only.
Patients require a rising PSA “biological 
progression” to enter the trial but have not been 
considered to have failed treatment. The words 
failing enzalutamide have therefore been 
removed.
The section on enzalatamide being supplied in 
from cycle 1 day 1 specifically for the study has 
been removed as the US sites will provide their 
own enzalutamide for the phase Ib expansion 
cohort.
The terminology for MTD and/or recommended 
dose in the exploratory expansion cohort and 
phase II was updated to MTD and/or 
recommended phase II dose (RP2D) to be 
consistent throughout protocol and other 
protocols in 1280 program within BI. The dose 
for phase Ib expansion cohort and phase II is 
described in section 5.2.4 of the protocol.
Section to be changed
Section 4.1.4.1 Phase I tolerability/safety and 
dose finding phase
Description of change
The terminology for MTD and/or recommended 
dose in the exploratory expansion cohort and 
phase II was updated to MTD and/or 
recommended phase II dose (RP2D). The phase 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Ib expansion will also be treated at this same 
dose.
Rationale for change
The terminology for MTD and/or recommended 
dose in the exploratory expansion cohort and 
phase II was updated to MTD and/or 
recommended phase II dose (RP2D) to be 
consistent throughout protocol and other 
protocols in 1280 program within BI.
Section to be changed
Section 4.1.4.2 BI 836845 (Phase Ib and Phase II 
– Arm A)
Description of change
Wording MDT (maximum tolerated dose) and/or 
recommended phase II added with regard to the 
dose that BI 836845 will be given in Phase Ib 
expansion cohort and Phase II.
Rationale for change
The phase Ib escalation part of the trial will 
determine either the MDT and/or recommended 
dose for Phase Ib expansion and Phase II. As only 
two dose levels are being explored it is not 
possible to know if the MDT will be reached.
Section to be changed
Section 4.1.4.3 Enzalutamide (Phase Ib and Phase 
II- Arm A and B)
Description of change
Section updated to change the wording for the 
supply of enzalutamide in Phase Ib expansion 
cohort. For countries where enzalutamide is 
supplied….
Rationale for change
The US sites will provide own enzalutamide for 
phase Ib expansion cohort.
Section to be changed
Section 4.1.4.4 Temporary treatment interruption 
and dose reduction for BI 836845 and 
enzalutamide during phase Ib and phase II
Description of change
The end of the following paragraph was updated 
to state permanently stopped and the patient 
discontinued rather than just stopped: In both 
phase Ib and phase II, the patient will be kept on 
study until both BI 836845 and enzalutamide are
permanently stopped and the patient is 
discontinued.
A new table has been added (Table 4.1.4.4:1 
Dose Interruption/reduction scheme by AE type 
and CTCAE (Phase I and II) as well as text 
amended in this section to clarify the list of 
adverse events requiring dose adjustment. The 
action that should be taken for unrelated adverse 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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events has also been added. Previously the 
terminology DLT was used all through this 
section to describe the adverse events requiring 
dose adjustment.
Table 4.1.4.4:1 Dose reduction scheme BI 
836845 and enzalutamide has been renamed to 
Table 4.1.4.4:2 Allowed dose reductions for BI 
836845 and enzalutamide.
Rationale for change
The words permanently stopped and patient is 
discontinued were added as administrative 
change.
As the trial is a phase Ib/II study the terminology 
DLT is not applicable for all the trial. DLT is 
only applicable for the phase Ib escalation part of 
the trial. DLTs are still referred to in section 5.2.3 
and these will be used to determine the MDT/
recommended dose from the phase Ib escalation 
cohort. 
Section 4.1.4.4 lists those adverse events whereby 
an action is needed by investigator to either pause 
or reduce the study treatments.
Original table 4.1.4.4:1 renamed to 4.1.4.4:2 due 
to new table 4.1.4.4:1 
Section to be changed
Section 4.1.4.5 Additional cycles of treatment
Description of change
The word “in phase Ib” in the title of the section 
has been removed as this section is relevant for 
phase Ib and phase II.  An additional paragraph
has been added to clarify the additional cycles of 
treatment for patients in phase II
Rationale for change
Administrative change
Section to be changed
Section 4.1.4.6 Preparation of BI 836845
Description of change
Language around administration of BI 836845 
was corrected to: …at this temperature they must 
be administered within 24 hours. Infusion bags 
stored at room temperature must be administered 
within 6 hours. Previously the protocol had stated 
that the medication could be stored for these 
periods whereas it administration should be 
completed within these timelines.
Rationale for change
Correction of the language to match the Summary 
of Product Information for BI 836845. Product 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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must be administered within 24 hours if stored at 
2-8C or within 6 hours if stored at room 
temperature.
Section to be changed
Section 4.1.6 Packaging, labelling, and resupply
Description of change
The words where required have been added into 
the paragraph about supply of trial drugs. The 
trial drugs, BI 836845 and enzalutamide, where 
required will be…
Rationale for change
In the USA for the phase Ib expansion part of the 
trial the enzalutamide will be supplied by the 
centres.
Section to be changed
Section 4.1.8 Drug accountability
Description of change
This section has been changed to apply to the 
supplies provided by Boehringer Ingelheim.
Rationale for change
In the USA for the phase Ib expansion part of the 
trial the enzalutamide will be supplied by the 
centres. 
Section to be changed
Section 4.2.1 Rescue medication, emergency 
procedures, and additional treatment(s)
Description of change
Change to the number of days post elective 
surgery that patient may restart treatment from 12 
days to 3 days.
Details of the supply of enzalutamide for the 
phase Ib expansion cohort has been updated to 
state that only in countries where enzalutamide is 
provided, clinical trial supplies will be provided 
on cycle 1 day 1
Rationale for change
Following review of the safety profile of BI 
836845 there is not considered to be any effect on 
wound healing. It was therefore considered to be 
more beneficial for patient to be able to restart 
treatment sooner.
Wording on the supply of enzalutamide from 
cycle 1 day 1 has been updated as in USA 
enzalutamide will be supplied by the trial sites.
Section to be changed
Section 4.2.1.1 Management of Infusion 
Reactions
Description of change
Section and table updated to section 4.2.1.1 from 
4.2.2.1
Rationale for change
Administrative change


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Section 4.2.1.2 Management of potential 
hyperglycaemia
Description of change
Section updated to section 4.2.2.2 from 4.2.1.2
Rationale for change
Administrative change
Section to be changed
Section 4.2.2.1 Restrictions regarding 
concomitant treatment
Description of change
This section has been updated to match the 
requirements for restricted medications in the 
Summary of Product Characteristics for 
Enzalutamide. 
Rationale for change
The protocol originally had a very exhaustive list 
of medications that should be discussed and 
agreed with BI in case patient wanted to stay on 
the concomitant medication (appendix 10.3). This 
section was not in line with the SPC for 
enzalutamide. After review with the investigators 
this section was revised to be more in line with 
Summary of Product Characteristics for 
enzalutamide and allow investigators to make 
clinical decisions on the best concomitant 
treatments for their patients.
The Summary of Product Characteristics for 
enzalutamide was also updated and included a 
new CYP substrate that has interactions with 
enzalutamide. Language refers investigator back 
to Summary of Product Characteristics for 
treatment related decisions to always ensure that 
Investigator is considering most current update.
Section to be changed
Section 5.1.1.1 Endpoint(s) of efficacy (anti-
tumour activity): Phase Ib Expansion Cohort
Description of change
Primary endpoint:
PSA Response – decline in PSA value must be 
confirmed by a second value 3-4 weeks later 
rather than more than 3 weeks later
Secondary Endpoints:
Radiological progression endpoint updated to add 
that bone lesions are assessed using PCCTWG2 
guidelines.
Changes in circulating T cells response updated to 
change terminology for the decrease in CTC 
count from fall to decline. Secondary endpoint –


Boehringer Ingelheim                                                                                                    06 Jun 2022
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decline by at least 30% of CTC counts was 
removed.
Rationale for change
PSA response endpoint updated according to the 
PCCTWG2 guidelines (in fact the PCCTWG1 
because no new definition in the PCCTWG2 
guidelines)
Radiological progression endpoint updated to 
clarify that soft tissue lesions are to be assessed 
using modified RECIST and bone lesions using 
PCCTWG2 guidelines.
Administrative change to better define the 
assessment of decrease in circulating tumour 
cells. Decline of 30% CTC counts removed as no 
longer considered a required secondary endpoint.
Section to be changed
Section 5.1.1.2 Endpoint(s) of efficacy (anti-
tumour activity): Phase II Randomised Trial
Description of change
Primary endpoint:
Radiological progression endpoint updated to add 
that bone lesions are assessed using PCCTWG2 
guidelines.
Secondary Endpoints:
Percentage change in PSA endpoint updated to 
specify that this must be percentage change at 
week 12.
PSA Response – decline in PSA value must be 
confirmed by a second value 3-4 weeks later 
rather than more than 3 weeks later
Changes in circulating T cells response updated to 
change terminology for the decrease in CTC 
count from fall to decline.
Rationale for change
Radiological progression endpoint updated to 
clarify that soft tissue lesions are to be assessed 
using modified RECIST and bone lesions using 
PCCTWG2 guidelines.
Clarification in the label of the Percentage change 
in PSA endpoint, already defined in section 5.1.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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PSA response endpoint updated for the 
confirmation timeframe according to the 
PCCTWG2 guidelines (in fact the PCCTWG1 
because no new definition in the PCCTWG2 
guidelines)
Administrative change to better define the 
assessment of decrease in circulating tumour 
cells.
Section to be changed
Section 5.1.2.1 Assessment of tumours and bone
Description of change
Section updated to included references to the
PCCTWG2 guidelines 
Section updated to remove the requirement to 
confirm tumour progression with a CT scan 6 
weeks later if progression is seen at the first scan.
Clarification that bone lesions should be reported 
on the assessment of bone metastases CRF page 
and not on the response to therapy RECIST 
assessment page.
The section has been updated to state that bone 
scans must be performed at screening and then if 
clinically indicated thereafter.
Section on bone scanning updated to clarify that 
bone scans must be performed if clinically 
indicated every 12 weeks to assess bone lesions.
Rationale for change
The reference to PCCTWG2 has been added as 
administrative change. 
The CT scan to confirm progression has been 
removed from the protocol as not in line with 
RECIST 1.1.
Clarification on where to record bone lesions in 
the CRF has been added as administrative change.
It is important to ensure that a bone scan is 
performed at screening to check for any bone 
lesions not known
Per PCCTWG2 guidelines for assessing bone 
lesions in prostate cancer, bone imaging should be 
performed. Information about imaging (CT/MRI 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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or X-ray) to assess bone destruction vs healing is 
covered in paragraph below.
Section to be changed
Section 5.1.2.2 Assessment of PSA
Description of change
This section has been updated to clarify when a
patient should be removed from the trial. Patients
should be kept on the trial until radiological 
and/or symptomatic progression is documented 
with or without PSA progression. 
Rationale for change
Patient does not need to have PSA progression to 
be removed from the trial.
Section to be changed
Section 5.1.2.3 Circulating tumour cell (CTC) 
assessments
Description of change
The following statement was removed: Based on 
the results of the CTC analysis in phase Ib of the 
study, the merits of continuing the CTC collection 
and analysis in the phase II randomised will be 
reviewed and adapted accordingly.
This section has been updated to change the
terminology used to describe the change in 
circulating tumour cells from fall to decline.
Rationale for change
CTC will be analysed as secondary endpoint in 
phase II part of trial.
Administrative correction to change the
terminology to describe decline in CTC. 
Section to be changed
Section 5.1.3 Central Imaging
Description of change
Two reference links have been added to the
section: Firstly a link to the section in the protocol 
regarding the assessment of tumours and bone
(section 5.1.2.1). Secondly a link to the imaging 
appendix (appendix 10.4)
Rationale for change
Administrative change
Section to be changed
Section 5.2.1 Endpoints of Safety
Description of change
Addition of the word endpoints in title “Primary 
endpoints (Phase Ib Escalation)
Rationale for change
Administrative change
Section to be changed
Section 5.2.2 Assessment of adverse events
Description of change
This section has been updated to match the
current protocol template for the assessment of 
adverse events in Boehringer Ingelheim trials. 
Reporting requirements for adverse events 
considered on treatment and in follow up were 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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clarified as not consistent in previous version of 
protocol between sections 5 and 6.
Rationale for change
Update to new template of Boehringer Ingelheim 
protocols and to clarify adverse event reporting 
requirements.
Section to be changed
Section 5.2.3 Dose Limiting Toxicity (DLT) 
definitions
Description of change
This section has been updated to clarify that DLTs 
are only applicable for the phase Ib escalation part 
of the trial to determine the MDT/recommended 
dose.
Rationale for change
Administrative change
Section to be changed
Section 5.2.4 Maximum Tolerated Dose (MTD) 
and Recommended Phase II Dose (RP2D)
Description of change
The title of this section is updated to include 
recommended phase II dose and the section has 
been updated to explain the review that will take 
place prior to opening recruitment in the phase II 
and phase Ib expansion parts of the trial. 
The sentence “the maximum tolerated dose in this 
study is defined as the highest protocol dose level 
of BI 836845 in combination with enzalutamide” 
was updated to include word protocol,
Rationale for change
This section was updated to confirm definition of 
phase II dose. The phase Ib expansion cohort will 
also proceed at the MTD and/or recommended 
phase II dose.
The definition of MTD was updated to clarify that 
this will be the maximum dose as given in the 
protocol.
Section to be changed
Section 5.2.5 Assessment of safety laboratory 
parameters
Description of change
The section was updated to change the fasting 
requirements for patients on day 1 of each cycle. 
The requirement was changed from at least 12 
hours to midnight the night before.
Rationale for change
Change implemented as more reasonable for 
patients and still considered to be a suitable 
fasting time to accurately measure the fasting
glucose and HbA1C levels
Section to be changed
Section 5.3.1 Other endpoint(s)


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
Rationale for change
Section to be changed
Description of change


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Section to be changed
Description of change
Rationale for change


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Boehringer Ingelheim                                                                                                    06 Jun 2022
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The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose.
Rationale for change
Administrative changes


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Section to be changed
Section 6.1.2 Treatment Visits
Description of change
The following words were removed from first 
sentence in the section: “Following assignment to 
a dose cohort in Phase Ib escalation or 
randomisation in phase II…
The section was updated to clarify the imaging 
timelines.
Rationale for change
Wording in the protocol was not correct as it is 
did not mention what should be done for the


Boehringer Ingelheim                                                                                                    06 Jun 2022
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phase Ib expansion part of the trial. As wording 
not required it was removed.
The section was updated to clarify the imaging 
timelines from baseline to be consistent with 
flowcharts. Imaging time points will be calculated 
from start of treatment/randomisation.
Section to be changed
6.1.3 Follow up period and trial completion
Description of change
Reference to AE and SAE reporting timelines 
removed from figure 6.1.3:1 
Rationale for change
All safety requirements are covered in section 5 of 
protocol and considered better not to have 
duplication
Section to be changed
6.1.3.2 Residual effect period (REP)
Description of change
The REP has been changed from 42+7 days from 
discontinuation of trial medication to 42 days 
from discontinuation of trial medication.
The word “also” has been added to paragraph. All 
AEs collected during this period will also be 
considered as “on treatment”.
Rationale for change
The REP for the treatments is 42 days. If the 
patient comes in for first follow up visit at day 
42+7 (allowance for visit window) REP will still 
only be considered as 42 days.
Word also added as on treatment does not only 
apply to AEs in follow up period.
Section to be changed
Section 6.1.3.4 Observation Period
Description of change
Removal of the sentence regarding reporting of 
adverse events in the follow up phase of the trial:
After the end of FU contact….not yet recovered 
at the last FU visit will continue.
Rationale for change
Adverse event requirements are all covered in 
section 5 of the protocol and so it was decided not 
to duplicate these in section 6.1.3.4
Section to be changed
Section 6.2.1 Screening Period
Description of change
A sentence has been added to state that patients 
who failed screening may repeat screening after 
discussion between investigator and sponsor.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Safety laboratory: Link to section of the protocol 
updated to 5.2.5
Tumour assessment and bone scans/skeletal 
assessment section: A reference link to the
prostate cancer clinical trials working group 
(PWCG2) criteria has been added
Tumour assessment and bone scans/skeletal 
assessment section: The timelines/requirements 
for bone scan assessment has been removed as 
this is covered in section 5.1.2.1
Rationale for change
Following discussion internally and with 
investigators it was decided that re-screening of 
patients can be considered so this has been 
detailed in protocol.
Safety laboratory: Administrative error to correct 
link for safety laboratory.
Tumour assessment and bone scans
 
 section: The Reference link has been
added to refer back to main section in the 
protocol for the tumour assessment section.
Tumour assessment and bone scans/
 
 section: The language for bone scan 
requirements has been removed for this section as 
covered in detail in 5.1.2.1
Section to be changed
Section 6.2.2 Treatment Period
Description of change
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose.
Randomisation: Allowance of 3 day window to 
randomise patient in IXRS
 
 
Safety laboratory: Link to section of the protocol 
updated to 5.2.5


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Tumour assessment and bone scans/
 
section: A reference link to the 
prostate cancer clinical trials working group 
(PWCG2) criteria has been added
Tumour assessment and bone scans/
 
 section: The timelines/requirements 
for bone scan assessment has been removed as 
this is covered in section 5.1.2.1
Rationale for change
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose to be consistent throughout the 
protocol.
Randomisation: Allowance of window to help 
sites manage logistics of registering patient in 
IXRS, receiving medication number and having 
IP prepared by pharmacy. Ideally patient should 
start treatment early in morning for PK sampling 
and this enables site to start treatment earlier on 
C1D1.
 
 
Safety laboratory: Administrative error to correct 
link for safety laboratory.
 
 
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Tumour assessment and bone 
 
 section: The Reference link has been 
added to refer back to main section in the 
protocol.
Tumour assessment and bone scans/
 
section: The language for bone scan 
requirements has been removed for this section as 
covered in detail in 5.1.2.1
Section to be changed
Section 6.2.3 End of treatment 
Description of change
 
 
Safety laboratory: Link to section of the protocol 
updated to 5.2.5
Tumour assessment and bone scans
 
section: A reference link to the 
prostate cancer clinical trials working group 
(PWCG2) criteria has been added. The 
terminology skeletal events was also added as 
these will be collected in CRF at EOT.
Tumour assessment and bone scans/
 
section: The timelines/requirements 
for bone scan assessment has been removed as 
this is covered in section 5.1.2.1. 
Tumour biopsy: Wording regarding whether fresh 
tissue biopsy are mandatory or optional were 
removed and reference made to section 5.6.3.4 for 
details.
Rationale for change
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Safety laboratory: Administrative error to correct 
link for safety laboratory.
Tumour assessment and bone scans/
 
 section: The Reference link has been 
added to refer back to main section in the 
protocol.
Tumour assessment and bone scans
 
 section: The language for bone scan 
requirements has been removed for this section as 
covered in detail in 5.1.2.1
Tumour biopsy: Section changed as fresh tissue 
biopsy is no longer mandatory at EOT in the
phase I expansion cohort.
Section to be changed
Section 6.2.3 Follow up period 
Description of change
Safety laboratory: Link to section of the protocol 
updated to 5.2.5
The section about tumour assessment
 
was added to follow up period.
Rationale for change
Administrative error to correct link for safety 
laboratory.
Tumour assessment and bone scans
 
 section: Tumour assessments may still 
be performed during follow- up period. Skeletal 
events are collected up to FU1.
Section to be changed
Section 7.1 Statistical Design-Model
Description of change
This section has been updated to correct number
the of cohorts in the trial to three (escalation, 
expansion and phase II)
Rationale for change
Administrative change
Section to be changed
Section 7.3 Planned Analyses
Description of change
Exploratory was removed from the sentence and 
phase II was added :
This MTD, and/or recommended phase II dose 
will be used in the phase Ib exploratory 
expansion….


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Phase Ib escalation was removed from the 
paragraph about efficacy analyses. It has also 
been clarified that for the phase Ib expansion 
cohort, progression free survival will be 
summarised at the cohort level.
Rationale for change
The word exploratory was removed as an 
administrative change to be consistent with other 
wording used in the protocol. The wording phase 
II was added to MTD and/or recommended phase 
II dose to be consistent throughout the protocol.
The phase Ib escalation was removed from this 
section as there will be no efficacy analyses for 
the phase Ib escalation cohort.
Section to be changed
Section 7.3.1 Primary analysis
Description of change
The section has been updated to refer to the
prostate cancer clinical trials working group 
(PWCG2) criteria for the assessment of bone 
lesions
The section has been updated to change the 
definition of PSA response from needing to be 
confirmed by a second value 3 or more weeks 
later to needing to be confirmed by a second 
value 3-4 weeks later.
Rationale for change
The section about PWCG2 guidelines was 
updated as an administrative change to ensure this 
was consistent throughout the trial.
The PSA response endpoint was updated 
according to the PCCTWG2 guidelines (in fact 
the PCCTWG1 because no new definition has 
been provided in the PCCTWG2 guidelines)
Section to be changed
Section 7.3.2 Secondary analyses
Description of change
The following sentence was changed from:
Kaplan-Meier estimates of overall survival will 
be plotted by treatment group, overall and within 
strata.
To:
Kaplan-Meier estimates of overall survival will 
be plotted by treatment group.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Additional paragraph added stating that 
exploratory analyses will be performed to 
investigate if PFS or circulating tumour cell 
decline are potential surrogate endpoints for 
overall survival.
Rationale for change
Administrative change - there are no strata in this 
trial.
Additional detail of the planned secondary 
analyses looking at the correlation between 
overall survival and radiographic progression free 
survival and circulating tumour cell decline.
Section to be changed
Section 7.3.3 Safety analyses
Description of change
Hyperlink corrected to refer only to section 5.2.4 
MDT and recommended phase II dose
Rationale for change
Administrative change 
Section to be changed
Section 7.3.4 Interim analyses
Description of change
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose.
Clarification that the phase Ib expansion part of 
the trial will be continuously monitored by the BI 
study team and investigators.
Additional statement added in this section to state
that the phase Ib expansion and phase II results 
will be analysed separately but be part of the 
same clinical trial report.
Rationale for change
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose to be consistent throughout the 
protocol.
Phase Ib expansion part of the trial is a single arm 
part of the trial and will not be reviewed by BI 
study team in blinded manner. Review of safety 
will be performed as part of the BI standard 
review of patient via medical quality review 
meetings. DMC review is not needed.
Administrative change to confirm how the results 
will be analysed.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Section 7.5 Randomisation
Description of change
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose.
Rationale for change
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose to be consistent throughout the 
protocol.
Section to be changed
Section 7.6 Determination of Sample Size
Description of change
The words “at least” were added in front of 21 
patients in the section.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose.
Rationale for change
The words “at least” were added to be consistent 
with other parts of the protocol.
The terminology for MTD and/or recommended 
dose was updated to MTD and/or recommended 
phase II dose to be consistent throughout the 
protocol.
Section to be changed
Appendix 10.3
Description of change
Appendix simplified to only list examples of 
CYP3A4 substrates.
Rationale for change
Investigators are referred to look at most current 
summary of product characteristics for 
enzalutamide. As this is likely to change 
throughout course of the trial it was decided the 
best approach would be to refer directly to SPC 
rather than maintain a separate list of medications 
that have possibility to interact with enzalutamide 
metabolism.
Section to be changed
Appendix 10.4
Description of change
Appendix updated to clarify that bone lesions 
should be assessed on the assessment of bone 
metastases CRF page and not the response to 
therapy RECIST assessment CRF page.
Additional criteria for bone lesion assessments 
removed from appendix 10.4
Rationale for change
Administrative change to inform sites where bone 
lesions should be entered.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Criteria for assessing bone lesions using Prostate 
Cancer Clinical Trials Working Group (PWCG2) 
guidelines is removed from appendix 10.4 as 
appendix is covering modified RECIST and bone 
lesions are assessed separately using the PWCG2 
guidelines.
Section to be changed
Appendix 10.7
Description of change
The wording protocol specified was removed 
from AESI.
Rationale for change
Change in terminology of AEs of special interest


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Number of global amendment
3
Date of CTP revision
09 April 2015
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate 
Cancer (CRPC) Following Disease Progression 
on Docetaxel-Based Chemotherapy and 
Abiraterone
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
Section 3.3.3 Exclusion Criteria
Description of change
Exclusion 1: Exclusion criterion 1 is not 
applicable for patients enrolled after protocol 
version 3 is approved. 
Was changed to: Exclusion criterion 1 is not 
applicable for patients enrolled after protocol 
version 3 (or subsequent versions) are
approved. 
Exclusion 2: Exclusion criterion 2 is not 
applicable for patients enrolled after protocol 
version 3 is approved. 
Was changed to: Exclusion criterion 2 is not 
applicable for patients enrolled after protocol 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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version 3 (or subsequent versions) are
approved. 
Exclusion 4: Patients that have been treated with 
any of the following within 4 weeks of starting 
trial treatment: chemotherapy, immunotherapy, 
biological therapies, molecular targeted, hormone 
therapy (except LHRH agonists), radiotherapy 
(except in case of localized radiotherapy for 
analgesic purpose or for lytic lesions at risk of 
fracture which can then be completed within 2 
weeks prior to study 
Was changed to: Patients that have been treated 
with any of the following within 4 weeks of 
starting trial treatment: chemotherapy, 
immunotherapy, biological therapies, molecular 
targeted therapy, hormone therapy (except 
LHRH agonists), radiotherapy (except in case of 
localized radiotherapy for analgesic purpose or 
for lytic lesions at risk of fracture which can then 
be completed within 2 weeks prior to study 
The wording following exclusion criterian 20 
was changed from: After approval of protocol 
version 3 the additional following exclusion 
criteria apply:
To: After approval of protocol version 3 (or 
subsequent versions) the additional following 
exclusion criteria apply:
Exclusion 22: Patients who have received at least 
1 but not more than 2 cytotoxic chemotherapy 
regimens for Metastatic Castration-Resistant 
Prostate Cancer (mCRPC). At least one regimen 
must have contained docetaxel. If docetaxel-
containing chemotherapy was used more than 
once, those regimens containing docetaxel would 
be considered as one regimen in total.
Was changed to: Patients who have received 
more than 2 prior non-docetaxel-containing 
cytotoxic chemotherapy regimens for Metastatic 
Castration-Resistant Prostate Cancer (mCRPC). 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Exclusion 1, 2 and the wording following 
exclusion criterian 20 were updated as protocol 
version 3 might not be approved at all sites due to 
protocol version 4 being released soon after. 
Exclusion 4 was updated as administrative 
change.
Exclusion criterian 22 was re-written in protocol 
version 3 (formally exclusion criterian 1) as the 
original wording in protocol version 1 was 
considered unclear. In error the new language 
was worded as an inclusion criterian rather than 
an exclusion criterian. This has been corrected in 
version 4 of the protocol.
Section to be changed
Adverse event and serious adverse event 
reporting, section 5.2.2.2
Description of change
The following paragraph has been updated from:
These lab findings constitute a hepatic injury alert 
and the patients showing these lab abnormalities 
need to be followed up according to Appendix 
10.7 of the protocol and the “DILI checklist” 
provided in the ISF
To: 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
Rationale for change
Investigators should refer to the current version of 
the DILI checklist which is provided to sites in 
the investigator site file. Appendix 10.7 has been 
removed from the protocol.
Section to be changed
Appendix 10.7
Description of change
Appendix 10.7 has been removed from the 
protocol.
Rationale for change
Investigators should refer to the current version of 
the DILI checklist which is provided to sites in 
the investigator site file. 
Number of global amendment
4
Date of CTP revision
15 September 2015
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Number of global amendment
4
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
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 – Phase II 
Randomised Trial Endpoints
Description of change
The primary endpoint has been changed from:
Radiological progression free survival (PFS) 
based on central review
To:
Radiological progression free survival (PFS) 
based on investigator assessment.
An additional secondary endpoint has been added:
Radiological progression free survival (PFS) 
based on central review
Rationale for change
Based on the discrepancy rates seen in previous 
prostate cancer trials between investigator 
assessment and central imaging review there is a 
concern that the original primary endpoint of 90 
events by central imaging will not be met.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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As this is an open label phase II trial tumour 
assessment by central imaging is not required as a 
primary endpoint. The primary endpoint has been 
updated to PFS by investigator assessment.
Section to be changed
 
Section to be changed
Flow Chart # Phase Ib Escalation /Expansion 
Cohort – Footnote 15
Description of change
The timing of the CTC samples has been updated. 
Originally a CTC sample was performed at C4D1 
but this has been replaced with two samples on 
C3D1 and C5D1 instead. Clarification also that a 
CTC sample is performed at EOT.
Rationale for change
The scheduling of CTC samples has been updated 
in line with imaging assessments so that efficacy 
assessments can be performed on CTC samples 
and imaging in parallel.
Section to be changed
Flow Chart # Phase Ib Escalation /Expansion 
Cohort – Footnote 16
Description of change
The timing of the PSA samples has been updated. 
An additional PSA sample is now being 
performed at C3D1. PSA samples are now 
collected at screening, C1D1 and then day 1 of 
every cycle from cycle 3.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
The scheduling of PSA samples has been updated 
in line with imaging assessments so that efficacy 
assessments can be performed on both PSA and 
imaging at week 8 in parallel.
Section to be changed
Flow Chart # Phase Ib Escalation /Expansion 
Cohort – Footnote 19
Description of change
Reference to section 5.1.2.1 has been added.
The timing of the imaging assessments (CT/MRI 
and bone scans) has been updated. Imaging will 
now be performed at 8 weekly intervals (starting 
at cycle 3 day 1) up until week 24 and then at 12 
weekly intervals thereafter.
It has been clarified that a bone scan must be 
performed at each tumour assessment:
“A bone scan should be performed at screening 
and, prior to the start C3D1 and onwards
according to schedule below.”
Rationale for change
The imaging schedule has been updated during the 
early part of the patient’s participation on trial. 
Data is available that shows patients’ with 
advanced prostate cancer having received multiple 
lines of treatment (including abiraterone and 
docetaxel) have an estimated median PFS of 
around 3 months on enzalutamide alone. The 
median PFS in combination arm (BI 836845 + 
enzalutamide) is expected to be between 4.3-4.6 
months.
As the primary endpoint of the trial is progression 
free survival by imaging it is important to ensure 
that the imaging assessments are scheduled to be 
able to capture any early imaging progressions.
Bone lesion progression must be assessed by bone 
scan and not by CT/MRI. 
Section to be changed
Flow Chart # Phase Ib Escalation /Expansion 
Cohort – Footnote 20
Description of change
Footnote 20 has been changed from:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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In cases of discontinuation from treatment due 
to progression, the tumour assessment at EOT
will not be necessary if the previous evaluation 
was performed within 4 weeks of EOT. 
To:
All patients should have a tumour 
assessment/bone scan at EOT visit regardless of 
the reason for discontinuation, unless the last 
evaluation was performed within 4 weeks of 
EOT
Rationale for change
This footnote has been updated to clarify that all 
patients at the end of treatment visit should have 
an imaging assessment unless they have had an
imaging assessment within the last 4 weeks.
Section to be changed
Section to be changed
Flow Chart # Phase II Randomised Trial –
Footnote 16
Description of change
The timing of the CTC samples has been 
updated. Originally a CTC sample was 
performed at C4D1 but this has been replaced 
with two samples on C3D1 and C5D1 instead.
Clarification also that a CTC sample is 
performed at EOT.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
The scheduling of CTC samples has been 
updated in line with imaging assessments so that 
efficacy assessments can be performed on CTC 
and imaging in parallel.
Section to be changed
Flow Chart # Phase II Randomised Trial –
Footnote 17
Description of change
The timing of the PSA samples has been 
updated. An additional PSA sample is now being 
performed at C3D1. PSA samples are now 
collected at screening, C1D1 and then day 1 of 
every cycle from cycle 3.
Rationale for change
The scheduling of PSA samples has been updated 
in line with imaging assessments so that efficacy 
assessments can be performed on both PSA and 
imaging at week 8 in parallel.
Section to be changed
Flow Chart # Phase II Randomised Trial –
Footnote 20
Description of change
Reference to section 5.1.2.1 has been added.
The timing of the imaging assessments (CT/MRI 
and bone scans) has been updated. Imaging will 
now be performed at 8 weekly intervals (starting 
at cycle 3 day 1) up until week 24 and then at 12 
weekly intervals thereafter.
It has been clarified that a bone scan must be 
performed at each tumour assessment where 
patient has bone metastases:
“A bone scan should be performed at screening 
and, prior to the start C3D1 and onwards
according to schedule below.”
Rationale for change
The imaging schedule has been updated during 
the early part of the patient’s participation on 
trial. 
Data is available that shows patients’ with 
advanced prostate cancer having received 
multiple lines of treatment (including abiraterone 
and docetaxel) have an estimated median PFS of 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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around 3 months on enzalutamide alone. The 
median PFS in combination arm (BI 836845 + 
enzalutamide) is expected to be between 4.3-4.6 
months.
As the primary endpoint of the trial is 
progression free survival by imaging it is 
important to ensure that the imaging assessments 
are scheduled to be able to capture any early 
imaging progressions.
Bone lesion progression must be assessed by 
bone scan and not by CT/MRI. 
Section to be changed
Flow Chart # Phase II Randomised Trial –
Footnote 21
Description of change
Footnote 21 has been changed from:
In cases of discontinuation from treatment due 
to progression, the tumour assessment at EOT
will not be necessary if the previous evaluation 
was performed within 4 weeks of EOT. 
To:
All patients should have a tumour 
assessment/bone scan at EOT visit regardless of 
the reason for discontinuation, unless the last 
evaluation was performed within 4 weeks of 
EOT
Rationale for change
This footnote has been updated to clarify that all 
patients at the end of treatment visit should have 
an imaging assessment unless they have had an
imaging assessment within the last 4 weeks.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Abbreviations
Description of change
CTC added as abbreviation
Rationale for change
Administrative change
Section to be changed
1.2.1 Drug profile – BI 836845
Description of change
The following sentence was changed from:
BI 836845 is a fully human IgG1 monoclonal 
antibody that binds to and neutralises the 
function of IGF-1 and IGF-2. 
To:
BI 836845 is a humanised IgG1 monoclonal 
antibody that binds to and neutralises the 
function of IGF-1 and IGF-2. 
In addition the following sentence was changed 
from:
It is known that human IgGs like BI 836845 
are mainly cleared by catabolism
To:
It is known that humanised IgGs like BI 
836845 are mainly cleared by catabolism
Rationale for change
Administrative change based on discussions with 
the WHO around the INN.
Section to be changed
2.2 Trial objectives
Description of change
PSA doubling time was removed from the 
statement about other trial endpoints.
Rationale for change
This was an error in previous version of protocol
Section to be changed
2.3 Benefit – RISK Assessment
Description of change
The following paragraph was changed from:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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BI 836845 is a fully humanised antibody given 
intravenously. Infusion reactions and immune 
responses cannot be excluded; however, thus 
far, neither of these events have been reported 
in two ongoing phase I studies. Any infusion 
reactions that might occur will be carefully 
evaluated and appropriate preventive and/or 
corrective action implemented……
To:
BI 836845 is a humanised antibody given 
intravenously. Infusion reactions and immune 
responses cannot be excluded; and have been 
reported. Any infusion reactions that occur will 
be carefully evaluated and appropriate 
preventive and/or corrective action 
implemented…..
Rationale for change
Fully humanized was changed to humanized as 
administrative change based on discussions with 
the WHO around the INN.
After this section was originally initially written 
in the protocol, infusion reactions have been seen 
in other trials with the compound.
Section to be changed
3.1 Overall Trial Design and Plan. Phase I and 
Phase II: Figure 3.1:1
Description of change
Figure 3.1:1 was updated to only allow patients 
with an ECOG of 0-1 in Phase Ib expansion and 
Phase II parts of trial. 
Rationale for change
Only patients ECOG 0 and 1 should be 
considered for trial to ensure that they are fit 
enough to manage the weekly visits and to stay 
on treatment long enough to benefit from it.
Section to be changed
3.1 Overall Trial Design and Plan. Phase I and 
Phase II:
Description of change
The following sentence was changed from:
Patients that withdraw from the trial and do not 
have progressive disease, or have not started 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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another anti-cancer therapy, will continue with 
limited follow-up visits at scheduled tumour 
assessments, until start of progressive disease, or 
start of other anti-cancer therapy.
Patients that withdraw from treatment and do 
not have progressive disease, or have not started 
another anti-cancer therapy, will continue with 
limited follow-up visits at scheduled tumour 
assessments, until start of progressive disease, or 
start of other anti-cancer therapy.
The following paragraph was changed from:
Soft tissue tumour assessment by imaging…..
according to modified Response Evaluation 
Criteria for Solid Tumours (RECIST) version 1.1 
(R09-0262 and appendix 10.4), as well as bone 
scans according to Prostate Cancer Clinical 
Trials Working Group 2 (PCWG2) (R13-1642
and section 5.1.2.1), at baseline and after every 
three cycles as per the Flow Chart…..
To:
Soft tissue tumour assessment by imaging 
according to modified Response Evaluation 
Criteria for Solid Tumours (RECIST) version 1.1 
(R09-0262 and appendix 10.4), as well as bone 
scans according to Prostate Cancer Clinical 
Trials Working Group 2 (PCWG2) (R13-1642
and section 5.1.2.1), at baseline, every two
cycles until week 24 and then every three 
cycles thereafter as per the Flow Chart. 
Rationale for change
The imaging schedule has been updated during 
the early part of the patient’s participation on 
trial. 
Data is available that shows patients’ with 
advanced prostate cancer having received 
multiple lines of treatment (including abiraterone 
and docetaxel) have an estimated median PFS of 
around 3 months on enzalutamide alone. The 
median PFS in combination arm (BI 836845 + 
enzalutamide) is expected to be between 4.3-4.6 
months.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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As the primary endpoint of the trial is 
progression free survival by imaging it is 
important to ensure that the imaging assessments 
are scheduled to be able to capture any early 
imaging progressions.
Section to be changed
3.3 Selection of Trial Population
Description of change
The following sentence was corrected:
In phase II of the study, 120 patients will be
randomised onto one of the two study arms, with 
60 patients randomised to each arm (Arm A=60, 
Arm B=60).  
Originally Arm B was mentioned twice.
Rationale for change
Administrative change
Section to be changed
3.3.2 Inclusion criteria 
Description of change
The following inclusion criteria were changed:
6. Eastern Cooperative Oncology Group 
performance status (ECOG PS) 0 or 1. 
ECOG score of 2 is no longer allowed.
7. Cardiac left ventricular function with resting 
ejection fraction ≥50% as determined by ECHO 
or MUGA
>50% was changed to ≥50% 
Rationale for change
Only patients ECOG 0 and 1 should be 
considered for trial to ensure that they are fit 
enough to manage the weekly visits and to stay 
on treatment long enough to benefit from it.
An LVEF measurement above 50% is considered 
normal.
Section to be changed
3.3.3 Exclusion criteria 
Description of change
The following exclusion criterion was removed:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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11. Patients with poorly controlled diabetes 
mellitus. Patients with a history of diabetes are 
allowed to participate, provided that their blood 
glucose is within normal range (fasting < 160 
mg/dL or below ULN) and that they are on a 
stable dietary or therapeutic regimen for this 
condition
Rationale for change
This exclusion criterion is not required based on 
the presence of inclusion criterion 15. The 
additional wording in exclusion 11 caused 
confusion and has therefore been removed. 
Inclusion criterion 15 requires the patient to have 
a fasting plasma glucose < 8.9 mmol/L (< 160 
mg/dL) and HbA1c < 8.0.%. This automatically 
excludes patients with poorly controlled diabetes.
Section to be changed
3.3.5 Replacement of patients
Description of change
The following section was changed from:
For phase Ib expansion cohort and phase II:
Patients who withdraw after assignment (phase 
Ib expansion), or randomisation (phase II),
but before start of therapy will be replaced:
to: 
For phase Ib expansion cohort:
Patients who withdraw after assignment but 
before start of therapy will be replaced.
Rationale for change
For the phase II part of trial an intent-to-treat 
analysis will be performed and replacing patients 
will not have an impact on the analysis. 
Therefore no patients will be replaced and only 
60 patients per arm should be randomized.
Section to be changed
4.1.1 Treatments to be administered: Identity of 
BI investigational product and comparator 
product(s)
Description of change
The following was changed from:
BI 836845 human monoclonal antibody


Boehringer Ingelheim                                                                                                    06 Jun 2022
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To:
BI 836845 humanised monoclonal antibody
Rationale for change
Administrative change
Section to be changed
4.1.4.2 BI 836845 (Phase In and Phase II - Arm 
A)
Description of change
The following sentence was changed from:
A one hour observation period is recommended 
following each infusion. See section 4.2.1.1.
To: 
A one hour observation period is recommended 
following each infusion for the first 3 cycles of 
treatment and at least a 15 minute 
observation period is recommended following 
subsequent infusions. See section 4.2.1.1.
The following sentence was added to the section:
Infusion reactions will not be reported on the 
standard AE page but will be reported on a 
separate page specifically for infusion reactions 
in the CRF.
Rationale for change
Infusion reactions seen to date in patients infused 
with BI 836845 have been during treatment. 
After the first 3 cycles the patient will have 
received 12 infusions of BI 836845 and so to 
make the trial less time consuming for the patient 
the recommendation that the patient stays in for 
one hour after the infusion has been reduced to at 
least 15 minutes.
A new page is being added into the CRF to 
collect additional information about infusion
reactions.
Section to be changed
4.1.4.4 Temporary treatment interruption and 
dose reduction for BI 836845 and enzalutamide 
during phase Ib and phase II


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
The bolded wording was added to the following 
paragraph:
Drug-related DLTs or those adverse events 
requiring dose adjustment, will be managed by a 
pause in treatment followed by a subsequent 
dose reduction of the relevant medication
according to tables 4.1.4.4:1 and 4.1.4.4:2.
Rationale for change
To ensure that it is clear in protocol that only the 
medication considered relevant to the adverse 
event is required to be reduced.
Section to be changed
4.2.1.1 Management of Infusion Reactions
Description of change
The following sentence was changed from:
A one hour observation period is recommended 
following each infusion. 
To: 
A one hour observation period is recommended 
following each infusion for the first 3 cycles of 
treatment and at least a 15 minute 
observation period is recommended following 
subsequent infusions. 
The following sentence was added to the section:
Infusion reactions will not be reported on the 
standard AE page but will be reported on a 
separate page specifically for infusion reactions 
in the CRF.
Rationale for change
Infusion reactions seen to date in patients infused 
with BI 836845 have been during treatment. 
After the first 3 cycles the patient will have 
received 12 infusions of BI 836845 and so to 
make the trial less time consuming for the patient 
the recommendation that the patient stays in for 
one hour after the infusion has been reduced to at 
least 15 minutes.
A new page is being added into the CRF to 
collect additional information about infusion 
reactions.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
The wording in extremities was removed from the 
following paragraph:
For symptom control palliative radiotherapy may 
be permitted for bone metastases in extremities 
after discussion with the sponsor provided that
radiotherapy does not affect the target lesions, and 
the reason for the radiotherapy does not reflect 
progressive disease.
New wording: 
For symptom control palliative radiotherapy may 
be permitted for bone metastases after 
discussion with the sponsor provided that 
radiotherapy does not affect the target lesions, and 
the reason for the radiotherapy does not reflect 
progressive disease.
The following paragraph was added to the 
section:
Exceptions for patients in Phase Ib expansion:
In order to effectively assess the potential for 
pharmacokinetic drug interaction between 
enzalutamide and BI 836845 and to investigate 
potential alterations of pharmacokinetics during 
co-administration, strong and moderate 
CYP2C8 inhibitors/inducers and CYP3A4 
inhibitors/inducers are prohibited during the 
periods specified below in the Ph Ib expansion 
cohort:
∀from Day -7 of the screening period till 
visit 1 of treatment course 1 (C1V1) and
∀from visit 4 of the first treatment course 
(C1V4) till visit 2 of treatment course 2 
(C2V2)
A list of examples is provided in appendix 10.3.2. 
Switching to a different class of drug that is not a 
strong or moderate CYP2C8 inhibitor/inducer or 
CYP3A4 inhibitor/inducer is recommended.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Outside the above time periods, follow the 
respective drug package insert/SPC when 
considering concomitant treatment with CYP2C8 
inhibitors/inducers and CYP3A4 
inhibitors/inducers.
Rationale for change
Palliative radiotherapy will be allowed for all 
bone metastases so long as any target lesions are 
not affected by the field of radiotherapy. This 
change is in line with the PCWG2 guidelines. This 
must be discussed with medical team at sponsor.
An exceptions section with regard to co-
medications for patients in the phase Ib expansion 
has been added. This covers the time frame of the 
drug-drug-interaction assessment for each patient. 
Any of these co-medications may influence the 
exposure of enzalutamide during this period.
Section to be changed
5.1.1.1 Endpoints of efficacy: Phase Ib expansion 
cohort
Description of change
The reference to the prostate cancer working 
group 2 (PCWG2 guidelines) has been removed 
from the primary endpoint PSA response
Rationale for change
PSA response is not considered any more by 
PCWG2 guidelines.
Section to be changed
5.1.1.2 Endpoints of efficacy: Phase II 
Randomised trial
Description of change
The primary endpoint has been changed from:
Radiological progression free survival (PFS) -
defined as time from randomisation to disease 
progression based on central review:
To:
Radiological progression free survival (PFS) -
defined as time from randomisation to disease 
progression based on investigator assessment:
An additional secondary endpoint has been added:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Radiological progression free survival (PFS) -
defined as time from randomisation to disease 
progression based on central review:
o
in bone based on the prostate cancer 
clinical trials working group (PCWG2) 
criteria, (R13-1642) (see section 5.1.2.1)
o
or soft tissue based on modified RECIST 
1.1 (R09-0262) where applicable (see 
Appendix 10.4)
o
or death 
The reference to the prostate cancer working 
group 2 (PCWG2 guidelines) has been removed 
from the secondary endpoint PSA response
Rationale for change
Based on discrepancy rates seen in previous 
prostate cancer trials between investigator 
assessment and central imaging review there is a 
concern that the original primary endpoint of 90 
events by central imaging will not be met.
As this is an open label phase II trial tumour 
assessment by central imaging is not required as 
primary endpoint.
PSA response is not considered any more by 
PCWG2 guidelines.
Section to be changed
5.1.2.1 Assessment of tumours and bone
Description of change
The following sentence has been added to the 
section on soft tissue lesions:
If a patient presents with marginal or equivocal 
tumour progression at their first RECIST 
assessment, confirmation by a second scan 6 or 
more weeks later, after continued treatment, is 
recommended.
The section on assessment of the bone lesions was 
updated in line the imaging schedule being 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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updated to 8 weekly for up to week 24 and then 
12 weekly.
Changed from:
A bone scan should be performed at screening 
and if clinically indicated every 12 weeks
throughout the trial at scheduled scan assessment 
visits until disease progression and/or new 
anticancer therapy is started.
Radiographic progression on bone scans is 
defined by the following criteria (as per the 
Prostate Cancer Clinical Trials Working Group 
(R13-1642)):
∀
≥ 2 new bone lesions consistent with 
progression
∀
If the first scan was performed < 12 
weeks from randomization, then it 
requires ≥ 2 new bone lesions plus 2 
additional at confirmation (“2 + 2”) on 
a second bone scan ≥ 4 weeks later. The 
date of progression is the date of the 
first scan that shows the change.
Any changes in bone imaging should be evaluated 
radiographically by CT scan, MRI, or X-ray to 
ascertain the presence of bone destruction versus 
a healing reaction. As such, the first protocol-
defined imaging assessment is scheduled at the 
end of week 12 of treatment (end of cycle 3 
tumour assessment, within 7 days prior to Cycle 4 
Day 1).
∀
If this assessment shows definitive 
evidence of ≥ 2 new bone lesions 
consistent with progression, then 
patient should discontinue from study.
∀
Alternatively, if bone scan does not show 
new lesions OR new lesions are not
       consistent with progression, then patient 
should continue study protocol and 
continue dosing until the next tumour
To:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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A bone scan should be performed at screening, at 
8 week intervals until week 24 (i.e. weeks 8, 16 
and 24) and then at 12 week intervals 
thereafter (i.e. weeks 36, 48 etc.) throughout the 
trial at until disease progression and/or new 
anticancer therapy is started. 
Radiographic progression on bone scans is 
defined by the following criteria (as per the 
Prostate Cancer Clinical Trials Working Group 2
(R13-1642)):
∀
≥ 2 new bone lesions on bone scan 
performed within the flare window plus 
≥ 2 additional at confirmation (“2 + 2”) 
on a second bone scan ≥ 6 weeks later. 
The date of progression is the date of 
the first scan that shows the change.
∀
≥ 2 new bone lesions on bone scans 
performed after the flare window, 
disease progression is determined at 
that assessment. 
∀
If bone scan does not show new lesions 
OR new lesions are not consistent with 
progression, then patient should continue 
on study protocol and continue dosing 
until the next tumour assessment, as 
clinically indicated, until radiographic 
disease progression.
The flare window is considered as 12 weeks 
from randomization for patients in phase II 
and 12 weeks from start of treatment for 
patients in phase Ib escalation and expansion.
Any changes in bone imaging should be evaluated 
radiographically by CT scan, MRI, or X-ray to 
ascertain the presence of bone destruction versus 
a healing reaction. 
For examples of bone scan progression using 
the prostate cancer clinical trials working 
group guidelines (PCWG2), see appendix 10.7


Boehringer Ingelheim                                                                                                    06 Jun 2022
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The following paragraph in the general rules on 
imaging was also updated from:
Assessments will be performed at screening, or if 
valid results are available as part of routine  
clinical practice and are within 28 days prior to 
start of study treatment, repeat imaging will not 
be required. Imaging will be every 3 cycles (12 
weeks) from baseline and prior to the start of 
cycle 4, 7, 10 onwards. Tumour assessments may 
be performed up to 7 days prior to the scheduled 
date for start of the relevant cycle/assessment 
date.
To:
Assessments will be performed at screening, or if 
valid results are available as part of routine 
clinical practice and are within 28 days prior to 
start of study treatment, repeat imaging will not 
be required. Imaging will be at baseline and 
then every 2 cycles (8 weeks) up to week 24 and 
then every 3 cycles (12 weeks) thereafter i.e. 
prior to the start of cycles 3, 5, 7, 10 onwards. 
Tumour assessments may be performed up to 7 
days prior to the scheduled date for start of the 
relevant cycle/assessment date.
Rationale for change
The soft tissue lesion section has been updated to 
add an example of where an investigator can 
chose to keep patient on treatment if equivocal or 
marginal tumour progression is seen at the first 
imaging assessment at week 8.
The bone imaging section has been updated due to 
the fact that the first imaging assessment for bone 
lesions now falls within the flare window. A 
confirmation scan would therefore always be 
required if new lesions were seen on the first bone 
scan.
The section has also been updated to confirm the 
new timelines for all imaging assessments.
Reference to a new appendix 10.7 has been added


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
5.1.2.2 Assessment of PSA
Description of change
The timing of PSA assessments has been 
amended to assess at PSA 8 weeks after the start 
of treatment, at the start of cycle 3 and then every 
cycle thereafter. Originally PSA was first 
assessed after 12 weeks (start of cycle 4).
Rationale for change
The scheduling of PSA samples has been updated 
in line with imaging assessments so that efficacy 
assessments can be performed on both PSA and 
imaging in parallel.
Section to be changed
5.1.3 Central Imaging
Description of change
The following sentence was removed from this 
section:
The data will also be reviewed by an oncologist 
who will provide a final assessment of each 
patient
Rationale for change
This was an error in previous version of protocol. 
Images will only be reviewed by radiologists to 
evaluate and confirm response and progression. 
An oncologist will not perform an overall 
assessment.
Section to be changed
5.2.2.1  Definitions of Adverse Events
Description of change
The following paragraph has been added in the 
section on definitions of AEs:
An AE does not meet the SAE criteria for 
hospitalisation if:
∀
The subject was treated in the emergency 
room but was not admitted for an 
overnight stay
∀
Hospitalisation due to pre-planned 
treatments or procedures
∀
Hospitalisation due to social 
circumstances or administrative reasons
∀
Hospitalisation for diagnostic reasons 
without AE


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
By adding examples that are not SAEs it means 
that unnecessary reporting of events (for example 
planned procedures) will be avoided.
Section to be changed
5.2.2.1  Definitions of Adverse Events
Description of change
A section on exemptions to (S)AE reporting has 
been added regarding disease progression.
Rationale for change
This section is based on a language from new 
oncology standard template at Boehringer 
Ingelheim so that investigators are not required to 
report all disease progressions but instead report 
only ones where there is evidence suggesting a 
causal relationship between study drug and 
underlying malignancy.
Section to be changed
6.1.3.5 Treatment visits


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
The following paragraph has been updated from:
Tumour assessments, including bone scans, will 
be performed as per the Flow Chart at week 12, 
week 24, week 36 and every 12 weeks thereafter. 
All tumour assessment visits may be within 7 
days prior to the start of the respective cycle of 
treatment.
Tumour assessments, including bone scans, will 
be performed as per the Flow Chart at week 8, 
week 16, week 24, week 36 and every 12 weeks 
thereafter. All tumour assessment visits may be 
within 7 days prior to the start of the respective 
cycle of treatment.
Rationale for change
Updated as per change to imaging schedule.
Section to be changed
6.1.3.5 Patient completion
Description of change
The following bullet has been added to reasons 
for patient completion in the trial:
∀
Withdrawal to be followed-up
Rationale for change
In case patients withdraw consent from follow up 
they will be considered to have completed the 
study.
Section to be changed
6.2.2 Treatment Period – Circulating tumour cells 
(CTCs)
Description of change
The timing of the CTC samples has been changed 
from C4D1 to C3D1 and C5D1. All other samples 
remain the same.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
The scheduling of CTC samples has been updated 
in line with imaging assessments so that efficacy 
assessments can be performed on CTC and 
imaging in parallel.
Section to be changed
6.2.2 Treatment Period – Prostate serum Antigen 
(PSA)
Description of change
The timing of the PSA samples has been changed. 
An additional PSA sample is now being 
performed at C3D1.
Rationale for change
The scheduling of PSA samples has been updated 
in line with imaging assessments so that efficacy 
assessments can be performed on both PSA and 
imaging in parallel.
Section to be changed
 
Section to be changed
6.2.2 Treatment Period – Tumour assessments 
and bone scans
Description of change
The timing of the imaging assessments has been 
changed. Imaging will now be performed at 8 
weekly intervals up until week 24 and then at 12 
weekly intervals thereafter.
Rationale for change
The imaging schedule has been updated during the 
early part of the patient’s participation on trial. 
Data is available that shows patients’ with 
advanced prostate cancer having received multiple 
lines of treatment (including abiraterone and 
docetaxel) have an estimated median PFS of 
around 3 months on enzalutamide alone. The 
median PFS in combination arm (BI 836845 + 
enzalutamide) is expected to be between 4.3-4.6 
months.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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As the primary endpoint of the trial is progression 
free survival by imaging it is important to ensure 
that the imaging assessments are scheduled to be 
able to capture any early imaging progressions.
Section to be changed
6.2.3 End of trial and follow-up period - Tumour 
assessments and bone scans/
Description of change
The following statement was added to the section:
All patients should have a tumour 
assessment/bone scan at EOT visit regardless of 
the reason for discontinuation, unless the last 
evaluation was performed within 4 weeks of EOT
Rationale for change
This footnote has been updated to clarify that all 
patients at the end of treatment visit should have 
an imaging assessment unless they have had an
imaging assessment within the last 4 weeks.
Section to be changed
7.3.1 Primary Analyses
Description of change
The following paragraph has been changed:
The primary analysis of PFS for the phase II will 
be conducted and reported when approximately 
90 patients (75% of all randomised patients) 
have progressed according to independent 
review or died. Any additional information 
collected after the data cut-off for the primary 
analysis will be part of a revised report.
To:
The primary analysis of PFS for the phase II will 
be conducted and reported when approximately 
90 patients (out of 120 randomised patients) 
have progressed or died. However, it may be 
performed with fewer events after
approximately 23 months of the first patient 
being randomized in the Phase II part. Any 
additional information collected after the data cut-
off for the primary analysis will be part of a 
revised report.
Rationale for change
This section has been changed as independent 
review is no longer the primary endpoint. There is 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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also an allowance that the data may be analysed 
even if 90 events are not reached after 23 months. 
This has been added in the case that more patients 
than expected come off the trial due to 
symptomatic progression and therefore 90 events 
are not obtainable.
Section to be changed
7.3.1 Secondary Analyses
Description of change
The following sentence was added to the start of 
this section:
The analysis of PFS based on independent review 
data will be performed in the same way as the 
primary evaluation on investigator assessments.
Rationale for change
Analysis of PFS by central imaging review has 
now been added as a secondary endpoint.
Section to be changed
7.6 Determination of Sample Size
Description of change
Table 7.6:2 has been updated ….
The following paragraph was changed from 
Assuming the true hazard ratio is 0.65, and 
given 90 events, the probability of observing a 
hazard ratio of less than 0.8 is sufficiently high at 
0.84. In comparison, if the true hazard ratio is 1.0 
(i.e. no treatment effect) and given 90 events, the 
probability of observing a hazard ratio of less than 
0.8 is sufficiently low at 0.14. 
To:
Assuming the true hazard ratio is between 0.65 
and 0.70, and given 90 events, the probability of 
observing a hazard ratio of less than 0.8 is 
sufficiently high, between 0.84 and 0.75. In 
comparison, if the true hazard ratio is 1.0 (i.e. no 
treatment effect) and given 90 events, the 
probability of observing a hazard ratio of less than 
0.8 is sufficiently low at 0.14. 
The following paragraphs were added:


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Due to the inherent difficulties 
determining…….observing a HR of 0.8 is still 
sufficiently low with 0.19
Due to the patients’ advanced condition and 
previous treatment……in the combination arm of 
BI836845 + enzalutamide.
Assuming recruitment rates of 10-13 patients per 
month for a period of A months….after the first 
patient was randomized in the phase II part.
Table 7.6:3 was added.
Rationale for change
Table 7.6: 2 has been updated to take into account
more assumptions with regard to true HR. Details 
have been added to the descriptions to account for 
potential discrepancies between investigator and 
independent review assessment. As there is now 
the possibility of not waiting for the 90 events, it 
has also been described in this section how the 
minimum duration of the trial has been calculated.
Table 7.6:3 has been added to provide examples 
of expected time to reach primary endpoint of 90 
events.
Section to be changed
10.6 Appendix: Examples of CYP 3A4 and 
CYP2C8 INHIBITORS, INDUCERS AND
CYP3A4 substrates
Description of change
The list has been updated to include examples of 
CYP2C8 inhibitors and inducers and CYP3A4 
inhibitors and inducers.
Rationale for change
Updated based on new language in section 4.2.2 
of protocol.
Section to be changed
 
 
 
 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
Appendix added
Rationale for change
To provide real examples of bone progressions 
according to PCWG2 guidelines
Number of global amendment
5
Date of CTP revision
19 November 2015
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Title of protocol
A Phase Ib/II, Multicentre, Open Label,
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, in 
Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
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
Protocol Synopsis: Number of patients:
Description of change
At least 21 patients changed to approximately 25 
patients
Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an 
evaluable patient is that patient can be assessed for 
primary endpoint.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Figure 3.1:1 Removal of “at least” from Phase Ib 
expansion cohort, addition of “approximately” 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an
evaluable patient is that patient can be assessed for 
primary endpoint.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
The following sentence was changed from: 
An exploratory expansion cohort will be pursued 
in at least 21 enrolled patients at the MTD, 
and/or recommended phase II dose (RP2D) 
determined in the escalation part of phase Ib 
described above.
To:
An exploratory expansion cohort will be pursued 
in approximately 25 enrolled patients to ensure 
21 evaluable patients at the MTD, and/or 
recommended phase II dose (RP2D) determined in 
the escalation part of phase Ib described above. A 
patient is considered evaluable if data for the 
assessment of the primary endpoint is
available.
Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an 
evaluable patient is that patient can be assessed for 
primary endpoint.
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
At least 21 patients was changed to approximately 
25 patients.
Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an 
evaluable patient is that patient can be assessed for 
primary endpoint.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
3.3.3 Exclusion Criteria 
Description of change
Addition of Exclusion criteria 24 for patients in 
phase Ib expansion cohort only, “Patients that are 
in immediate need of chemotherapy (e.g., for 
visceral disease, or intractable pain) should be 
excluded.”
Rationale for change
Updated based on feedback from the FDA 
Section to be changed
Section 4.1.2 Method of Assigning 
Patients to Treatment Groups
Description of change
At least 21 patients was changed to approximately 
25 patients.
Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an 
evaluable patient is that patient can be assessed for 
primary endpoint.
Section to be changed
Section 4.1.3.4 Exploratory Expansion 
Cohort 
Description of change
At least 21 patients was changed to approximately 
25 patients.
Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an 
evaluable patient is that patient can be assessed for 
primary endpoint


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Section 7.6 Sample Size
Description of change
The following paragraph was changed from:
The phase Ib exploratory expansion cohort consists 
of one cohort treated at the MTD and/or 
recommended phase II dose. In this cohort, at least 
21 additional patients will be treated. ….. a 
sample size of 21 patients …..
If the true PSA response rate……. the chosen 
sample size of 21 patients.
The probability of a false positive signal is…. a 
sample size of 21 patients…..
To:
The phase Ib exploratory expansion cohort consists 
of one cohort treated at the MTD and/or 
recommended phase II dose.In this cohort,
approximately 25 additional patients will be 
treated to ensure 21 evaluable patients….. a 
sample size of 21 evaluable patients …
If the true PSA response rate ….the chosen sample 
size of 21 evaluable patients. In the phase Ib 
expansion part of the study an evaluable patient 
is defined as a patient where data for the 
assessments if the primary endpoint is available.
The probability of a false positive signal is…. a 
sample size of 21 evaluable patients…..
Rationale for change
The number of patients was updated as per FDA 
request. Approximately 25 patients will be 
enrolled to ensure that 21 evaluable patients are 
available for analysis. The definition of an 
evaluable patient is that patient can be assessed 
for primary endpoint.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Boehringer Ingelheim                                                                                                    06 Jun 2022
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Number of global amendment
6
Date of CTP revision
31 May 2016
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
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
TITLE PAGE
Description of change
Change of Trial Clinical Monitor
Rationale for change
Change of Trial Clinical Monitor
Section to be changed
Protocol Synopsis: Number of patients
Description of change
Approximately 160 patients (all parts of the 
study) was changed to 120.
Rationale for change
New sample size to be used, and as a consequence 
of the sample size reduction in Phase II part of the 
trial.
Section to be changed
Protocol Synopsis: Number of patients
Description of change
60 patients to be included in each Arm of Phase II 
changed to 40 patients per treatment arm.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Sample size reduction in Phase II as a 
consequence of new statistical estimations and a 
project level decision.
Section to be changed
FLOW CHART- Phase Ib Escalation/Expansion 
cohort
Description of change
Addition of 1 day window in first visit of each 
treatment course.
Rationale for change
Changed to allow flexibility in visit schedule and 
according to project standards.
Section to be changed
FLOW CHART- Phase II
Description of change
Addition of 1 day window in first visit of each 
treatment course.
Rationale for change
Changed to allow flexibility in visit schedule and 
according to project standards.
Section to be changed
Figure 3.1.1 – Illustration of study design – Phase 
II
Description of change
Change of sample size for Phase II from 120 
patients (60 per treatment arm) to 80 (40 per 
treatment arm).
Rationale for change
Sample size reduction in Phase II as a 
consequence of new statistical estimations and a 
project level decision.
Section to be changed
Section 3.3. Selection of trial population
Description of change
Change of sample size for the whole trial from 
160 to 120 patients. And change Phase II 
recruitment from 120 patients (60 per treatment 
arm) to 80 (40 per treatment arm).


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Sample size reduction in Phase II as a 
consequence of new statistical estimations and a 
project level decision.
Section to be changed
Section 3.3.2 Inclusion criteria #4
Description of change
Change of inclusion criteria for PSA from > 20 
ng/mL to >5 ng/mL
Rationale for change
Revision of the globally accepted ranges of PSA 
to determine CRPC and adaptation of the 
inclusion criteria to these parameters.
Section to be changed
Section 3.3.2 Inclusion criteria #14
Description of change
Change of INR limit for inclusion from 1.4 to 2
Rationale for change
Adaptation of this criteria to the BI 836845 
project standards.
Section to be changed
Section 3.3.2 Inclusion criteria #19
Description of change
Inclusion of the number of the affected criteria to 
the description.
Rationale for change
To clarify that only inclusion criteria #19 is  
applicable to Phase Ib expansion cohort.
Section to be changed
Section 3.3.3 Exclusion criteria #4
Description of change
Addition of LHRH antagonists as accepted 
concomitant treatment during the trial.
Rationale for change
To update the protocol according to CRPC 
treatment standards.
Section to be changed
Section 5.2.5 Assessment of safety laboratory
parameters
Description of change
Second paragraph was changed from:
Fasting serum samples (fasting state from 
midnight the night before) should be collected as 
per the time points specified in the Flow Chart.  
Further samples may be taken throughout the 
course of the study when deemed appropriate by 
the investigator. All analyses are to be performed 
by the local clinical laboratory.
TO:
Blood samples, including fasting serum samples 
(fasting state from midnight the night before), 
will be collected up to one day prior to the 
scheduled time points as specified in the Flow 
Chart and analysed in a laboratory facility at (or 
close to) the


Boehringer Ingelheim                                                                                                    06 Jun 2022
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investigational site. Safety laboratory 
examinations include hematology, biochemistry, 
coagulation and urine examination. See Table 
5.2.5: 1 for details. Futher samples may be taken 
throughout the course of the study when deemed 
appropriate by the investigator. All analyses are 
to be performed by the local clinical laboratory.
Rationale for change
During the course of the trial it was detected that 
performing blood drawn, analysis and lab results 
review on the same day of the drug administration 
could cause treatment delays and patient should 
be at the hospital for more time than strictly 
needed. This, together with the fact that blood 
parameters do not suffer from major changes in 
less than 24 hours, lead the clinical team to allow 
blood sampling (even for fasting parameters) on 
the day before drug adminitration.
Section to be changed


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Boehringer Ingelheim                                                                                                    06 Jun 2022
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Section to be changed
Section 7.3.1 Primary analyses
Description of change
The following text was changed:
The primary analysis of PFS for the phase II will 
be conducted and reported when approximately 
90 patients (out of 120 randomised patients) have 
progressed or died.
To
The primary analysis of PFS for the phase II will 
be conducted and reported when approximately 
60 patients (out of 80 randomised patients) have 
progressed or died.
Rationale for change
Change of the primary analysis timepoint 
according to new statistical estimations and a 
project level decision.
Section to be changed
Table 7.6:2
Description of change
Rows with more than 70 events were removed 
from the table. 
Rows for 40 events have been added in the table.
Footnote 3 added: 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Note that 70 events out of 80 patients can only 
be seen if the number of permanently censored 
patients is very low.
Rationale for change
New statistical estimations and sample size 
calculations gives no sense to calculations over 70 
events. Less patients  imply less events therefore 
calculations for less events (40) have been added.
Section to be changed
Section Table 7.6, determination of sample size
Description of change
The following text was changed from:
Assuming the true hazard ratio is between 0.65
and 0.70, and given 90 events, the probability of 
observing a hazard ratio of less than 0.8 is 
sufficiently high, between 0.84 and 0.75. In 
comparison, if the true hazard ratio is 1.0 (i.e. no 
treatment effect) and given 90 events, the 
probability of observing a hazard ratio of less 
than 0.8 is sufficiently low at 0.14. 
(…)
From Table 7.6: 2 it can be seen that having a 
discordance rate of going up to 33% – leaving 
potentially only 60 independent review events –
still gives a probability of between 0.79 and 0.70 
(corresponding true underling HR of between 0.65 
and 0.70) of observing a HR of less than 0.8 in the 
evaluation of the independent review as well. If the 
true underlying HR should be 1.0, then the 
probability of observing a HR of 0.8 is still 
sufficiently low with 0.19.
(…)
Therefore, the primary analysis is targeted when 
90 PFS events by investigator’s assessment are 
observed or 23 months after the first patient was 
randomized in the phase II part.
To:
Assuming the true hazard ratio is between 0.65
and 0.70, and given 60 events, the probability of 
observing a hazard ratio of less than 0.8 is 
sufficiently high, between 0.70 and 0.79. In 
comparison, if the true hazard ratio is 1.0 (i.e. no 
treatment effect) and given 60 events, the 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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probability of observing a hazard ratio of less 
than 0.8 is sufficiently low at 0.19. 
(…) 
From Table 7.6: 2 it can be seen that having a 
discordance rate of going up to 33% – leaving 
potentially only 40 independent review events –
still gives a probability of between 0.66 and 0.74
(corresponding true underling HR of between 0.65 
and 0.70) of observing a HR of less than 0.8 in the 
evaluation of the independent review as well. If the 
true underlying HR should be 1.0, then the 
probability of observing a HR of 0.8 is still 
sufficiently low with 0.24.
(…)
Therefore, the primary analysis is targeted when 
60 PFS events by investigator’s assessment are 
observed or 23 months after the first patient was 
randomized in the phase II part.
Rationale for change
Text updated according to new statistical 
estimations, a project level decision, and sample 
size calculations.
Section to be changed
Table 7.6:3
Description of change
Change of table title and column title from
Study duration until targeted number of 90 PFS 
events from 120 randomised patients are observed 
for different possible underlying scenarios
And
Drop out rate
To:
Study duration until targeted number of 60 PFS 
events from 80 randomised patients are observed 
for different possible underlying scenarios
And
Rate of permanently censored patients
Rationale for change
To adapt the table to new statistical estimations, a 
project level decision, and project standards.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Number of global amendment
7
Date of CTP revision
06 Feb 2018
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
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
TITLE PAGE
Description of change
Change of Trial Clinical Monitor
Rationale for change
Change of Trial Clinical Monitor
Section to be changed
Section 3.3.4 Removal of patients from therapies 
or assessments
Description of change
The following bullet point was added:
Investigator and patient (following discussion) 
consider it in the patient’s best interest to remove 
the patient from BI 836845 following results of 
the phase II trial.
Rationale for change
Following the phase II results the decision was 
made to inform patients of results and allow them 
and investigator the chance to stay on 


Boehringer Ingelheim                                                                                                    06 Jun 2022
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enzalutamide only if considered best for patient. 
This was considered as a non substantial change 
to the protocol.
Number of global amendment
8
Date of CTP revision
15 Jul 2019
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
Global amendment due to urgent 
safety measures
Global amendment
Section to be changed
Flow Chart – Phase Ib escalation/expansion and 
Phase II
Description of change
Additional flow chart added for all patients still 
on treatment or in follow up after approval of 
protocol version 9. Reduced procedures will be 
performed. 
Rationale for change
All required data has been collected. Patients will 
be required to have only certain trial procedures 
in order to continue with trial treatment.
Section to be changed
Section 1.2 Drug Profile
Description of change
Link to IB updated
Rationale for change
Administrative change
Section to be changed
Section 2.2 Trial Objectives
Description of change
Statement added that after protocol version 9 
there will be reduced data collection
Rationale for change
Sufficient data has been collected to answer 
primary and secondary endpoints for the trial. 
Patients still benefiting on treatment should have 
reduced trial procedures, only those required to 
ensure treatment can be continued.
Section to be changed
Section 3.1 Overall Trial and Design


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
After approval of protocol version 9, fresh tissue
biopsies will no longer be collected, survival 
follow up will not be performed, and follow up 
will be reduced to the residual effect period (42 
(+7 ) days after last study treatment)
Rationale for change
Sufficient data has been collected to answer 
primary and secondary endpoints for the trial.
Section to be changed
Section 5.1.3 Central Imaging
Description of change
Clarification that images are sent to central 
provider only until primary analysis
Rationale for change
Administrative change
Section to be changed
Section 5.2.5 Assessment of safety laboratory 
parameters
Description of change
Safety lab assessments should be done per flow 
chart.
Rationale for change
Following approval of protocol version 9 safety 
labs should be done as per standard of care
Section to be changed
Section 6.1.3.3 Follow up period
Description of change
After approval of protocol version 9, only FU1 
visit is required
Rationale for change
Sufficient data has been collected to answer 
primary and secondary endpoints for the trial
Section to be changed
Section 6.1.3.4 Observation period
Description of change
After approval of protocol version 9, no further 
survival data will be collected


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Sufficient data has been collected to answer 
primary and secondary endpoints for the trial
Section to be changed
Section 6.2.2 Treatment period
Description of change
Section updated to clarify that procedures should 
be done per flow chart to allow for reduced 
procedures after approval of protocol version 9
Rationale for change
Sufficient data has been collected to answer 
primary and secondary endpoints for the trial
Section to be changed
Section 6.2.3 End of trial and follow up period
Description of change
Section updated to clarify that procedures should 
be done per flow chart to allow for reduced 
procedures after approval of protocol version 9
Rationale for change
Sufficient data has been collected to answer 
primary and secondary endpoints for the trial
Section to be changed
Section 9.2 Unpublished references
Description of change
Reference for IB updated
Rationale for change
Administrative change
Section to be changed
Appendix 10.6
Description of change
Added statement that this is only applicable until 
after approval of protocol version 9
Rationale for change
Administrative change
Number of global amendment
9
Date of CTP revision
13 Sep 2019
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
Global amendment due to urgent 
safety measures
Global amendment
Section to be changed
Flowcharts and Sections 2.2, 3.1 5.6.3.4, 6.1.3.3, 
6.2.2, 6.2.3, 10.6


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Number of global amendment
9
Description of change
Wording protocol version 9 updated to protocol 
version 10
Rationale for change
Protocol version 9 was rejected by a health 
authority due to the reduced collection of safety 
laboratory data. It was determined that as patients 
are on experimental therapy the safety laboratory 
tests should be clearly defined in the protocol 
rather than being per standard of care. Protocol 
version 9 was therefore not implemented by any 
sites with ongoing patients. Instead it was agreed 
that the protocol should be updated to protocol 
version 10 to include safety lab testing on day 
one of every cycle for all patients ongoing on trial 
treatment.  
Protocol version 9 included statements as to 
which procedures should be performed before 
and after the implementation of protocol version 
9. These statements have been updated 
throughout the protocol to state which procedures 
should be performed before or after 
implementation of protocol version 10. 
Protocol version 9 was not implemented by any 
sites with ongoing patients.
Section to be changed
Flow Chart
Description of change
Table updated to include safety labs.
Pharmacogenetics samples removed.
Rationale for change
Safety laboratory tests should be done as part of 
trial procedures. Pharmacogenetic tests not
required for protocol version 10.
Section to be changed
Section 2.2 Trial Objectives
Description of change
Paragraph amended to remove statement that only 
AEs and SAEs would be collected.
Rationale for change
Safety laboratory tests results will be collected on 
the CRF page. Any findings will still be entered 
on the AE/SAE form as per standard procedure.
Section to be changed
Section 5.2.2.2 Assessment of adverse events 
Description of change
The section was updated to remove the wording 
that SAE forms must be faxed.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
In the future SAEs may be sent by other methods 
e.g via BI system and therefore wording is more 
flexible.
Section to be changed
Section 5.2.5 Assessment of safety laboratory 
parameters
Description of change
Section updated to specify which tests should be 
performed before and after approval of protocol 
version 10.
Rationale for change
Safety laboratory parameters will be reduced for 
patients after approval of protocol version 10 to 
ones required to ensure safety of the patient.
Section to be changed
Section 6.2.3 End of trial and follow up period
Description of change
Section updated to clarify that safety labs will be 
performed in patients after approval of protocol 
version 10
Rationale for change
Safety laboratory parameters will be reduced for 
patients after approval of protocol version 10 to 
ones required to ensure safety of the patient.
Number of global amendment
10
Date of CTP revision
11 Aug 2020
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
Global amendment due to urgent 
safety measures
Global amendment
Section to be changed
TITLE PAGE
Description of change
Change in Trial Clinical Monitor.
Rationale for change
Change in Trial Clinical Monitor.
Section to be changed
Section 2.3 BENEFIT – RISK ASSESSMENT
Description of change
Update to benefit-risk to include assessment of 
COVID-19 pandemic.


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Rationale for change
Evaluation of the benefit-risk in relation to the 
COVID-19 pandemic.
Section to be changed
Section 4.1.1 Identity of BI investigational 
product and comparator product(s)
Description of change
Pharmaceutical form of enzalutamide (Xtandi®)
updated to include film-coated tablets.
Rationale for change
SPC has been updated to include enzalutamide 
40mg and 80mg film-coated tablets.
Section to be changed
Section 4.1.3.2 Enzalutamide
Description of change
The recommended dose of enzalutamide updated 
to include four 40mg tablets or two 80mg tablets.
Rationale for change
SPC has been updated to include enzalutamide 
40mg and 80mg film-coated tablets.
Section to be changed
Section 4.1.4.3 Drug assignment and 
administration of doses for each patient
Description of change
A direct shipment from site to patient may 
happen provided that the shipment occurs with a 
courier approved by the Sponsor in order to 
ensure correct conditions of shipments, if allowed 
by country regulations. 
Rationale for change
The COVID-19 pandemic requires additional 
guidance to ensure patient’s safety by decreasing 
in-patients visits to the sites if needed. 
Section to be changed
Section 5.2.5 Assessment of safety laboratory 
parameters
Description of change
If blood sampling at the trial site is not possible, 
safety lab analyses can be performed at a local 
lab.
Rationale for change
The COVID-19 pandemic requires additional 
guidance to ensure patient’s safety by decreasing 
in-patients visits to the sites if needed. 
Section to be changed
Section 6.1.2 Treatment Visits
Description of change
Possibility for a patient unable or unwilling to 
attend a clinic visit to have the evaluation 
performed by a remote visit if deemed safe by the 
investigator, after agreement with the sponsor.
Rationale for change
The COVID-19 pandemic requires additional 
guidance to ensure patient’s safety by decreasing 
in-patients visits to the sites if needed.
Number of global amendment
11
Date of CTP revision
06 Jun 2022


Boehringer Ingelheim                                                                                                    06 Jun 2022
BI Trial No.: 1280.8
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Number of global amendment
11
EudraCT number
2013-004011-41
BI Trial number
1280.8
BI Investigational Product(s)
BI 836845
Title of protocol
A Phase Ib/II, Multicentre, Open Label, 
Randomised Study of BI 836845 in Combination 
With Enzalutamide, versus Enzalutamide alone, 
in Metastatic Castration-Resistant Prostate Cancer 
(CRPC) Following Disease Progression on 
Docetaxel-Based Chemotherapy and Abiraterone
Global amendment due to urgent 
safety measures
Global amendment
Section to be changed
Flow Chart – Phase Ib escalation/expansion and 
Phase II
Description of change
Additional flow chart added for all patients still 
on treatment or in follow up after approval of 
Protocol Version 12. Tumour assessment and 
bone scans performed as per standard of care. 
Rationale for change
All required data has been collected. Patients will 
be required to have only standard of care imaging
to continue with trial treatment.
Section to be changed
1.2.2 Enzalutamide
Description of change
Information on the new special safety warnings, 
second primary malignancies and hypersensitivity 
reactions added. 
Rationale for change
New safety warnings included in updated 
enzalutamide SmPC.
Section to be changed
Section 2.3 BENEFIT – RISK ASSESSMENT
Description of change
Section updated to include the top-line results 
from the 1280-0022 trial.
Information on the new special safety warnings, 
second primary malignancies and hypersensitivity 
reactions added.
Rationale for change
All oncology development of xentuzumab has 
now been terminated by Boehringer Ingelheim.
New safety warnings included in updated 
enzalutamide SmPC.
Section to be changed
Section 3.3.4.1 Removal of individual patients


Boehringer Ingelheim                                                                                                    06 Jun 2022
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Description of change
Addition of point 8 to confirm that patients must 
discontinue trial drug(s) if the trial is terminated 
for any of the reasons listed in Section 3.3.4.2.
Rationale for change
Individual patients must discontinue therapy with 
the trial drug(s) if the trial is discontinued by the 
sponsor.
Section to be changed
Section 3.3.4.2 Discontinuation of the trial by the 
sponsor
Description of change
Point 4 updated to include the rationale for 
discontinuation of the clinical development 
program with xentuzumab in CRPC, including 
how the trial will proceed towards termination.
Rationale for change
The clinical development of xentuzumab was 
discontinued by Boehringer Ingelheim in 
oncology generally including in CRPC.
Section to be changed
Section 6.2.2 Treatment period
Description of change
Sentence added to tumour assessments and bone 
scans section to confirm they can be performed as 
per standard of care following implementation of 
Protocol Version 12.
Rationale for change
All required data has been collected. Patients will 
be required to have only standard of care imaging 
to continue with trial treatment.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F
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SAP_001.pdf: 
 
Trial Statistical Analysis Plan 
c02577053-02
BI Trial No.:
1280.8
Title:
A Phase Ib/II, Multicentre, Open Label, Randomised Study of BI 
836845 in Combination with Enzalutamide, versus Enzalutamide 
alone, in Metastatic Castration-Resistant Prostate Cancer (CRPC) 
Following Disease Progression on Docetaxel-Based Chemotherapy 
and Abiraterone
Including Protocol Amendment 6 [c02304008-09] 
Investigational
Product(s):
Xentuzumab, BI 836845
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
28 SEP 2017 REVISED
Version:
Revised
Page 1 of  76
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1
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................5
2
LIST OF ABBREVIATIONS ...............................................................6
3
INTRODUCTION................................................................................11
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.......12
4.1
ADDITIONS/NEW ANALYSES......................................................................12
4.2
CHANGES..........................................................................................................12
4.3
CLARIFICATIONS...........................................................................................12
4.4
CLARIFICATIONS TO THE PRIMARY ANALYSIS.................................13
5
ENDPOINTS ........................................................................................14
5.1
PRIMARY ENDPOINTS..................................................................................14
5.1.1
Phase Ib escalation ........................................................................................14
5.1.2
Phase Ib expansion cohort............................................................................14
5.1.3
Phase II...........................................................................................................15
5.2
SECONDARY ENDPOINTS............................................................................18
5.2.1
Key secondary endpoints..............................................................................18
5.2.2
Other secondary endpoints...........................................................................19
5.2.2.1
Phase Ib escalation......................................................................................19
5.2.2.2
Phase Ib expansion cohort ..........................................................................19
5.2.2.3
Phase II .......................................................................................................19
6
GENERAL ANALYSIS DEFINITIONS...........................................33
6.1
TREATMENTS..................................................................................................33
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................33
6.3
PATIENTS SETS ANALYSED........................................................................37
6.5
POOLING OF CENTRES ................................................................................41
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................41
6.6.1
AEs..................................................................................................................42
6.6.2
Laboratory values at baseline ......................................................................42
6.6.3
PK parameters / biomarkers........................................................................42
6.6.4
Randomisation and stratification (Interactive Response Technology 
(IRT) versus CRF) (only for phase II).........................................................43
6.6.5
ECG ................................................................................................................43
6.6.6
FACT-P questionnaire and BPI-SF questionnaire ....................................43


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6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................44
6.7.1
Baseline...........................................................................................................44
6.7.2
Time windows for every tumour assessment ..............................................44
6.7.3
Time schedule of ECG recordings and related PK blood sampling .........45
7
PLANNED ANALYSES......................................................................46
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........47
7.1.1
Disposition of patients...................................................................................47
7.1.2
Important protocol violations ......................................................................47
7.1.3
Demographic and other baseline characteristics........................................47
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................47
7.3
TREATMENT COMPLIANCE .......................................................................47
7.4
PRIMARY ENDPOINTS..................................................................................48
7.4.1
Phase Ib escalation ........................................................................................48
7.4.2
Phase Ib expansion cohort............................................................................48
7.4.3
Phase II...........................................................................................................48
7.5
SECONDARY ENDPOINTS............................................................................51
7.5.1
Key secondary endpoints..............................................................................51
7.5.2
Other secondary endpoints...........................................................................51
7.5.2.1
Phase Ib escalation......................................................................................51
7.5.2.2
Phase Ib expansion cohort ..........................................................................51
7.5.2.3
Phase II .......................................................................................................52
7.7
EXTENT OF EXPOSURE................................................................................55
7.8
SAFETY ANALYSES........................................................................................55
7.8.1
Adverse events ...............................................................................................55
7.8.2
Laboratory data.............................................................................................57
7.8.2.1
Laboratory data...........................................................................................57
7.8.2.2
Laboratory values of special interest ..........................................................58
7.8.3
Vital signs.......................................................................................................58
7.8.4
ECG ................................................................................................................58
7.8.5
Others .............................................................................................................61
7.9
STATISTICAL BIOMARKER AND PK/PD ANALYSES ...........................61
7.9.1
Potentially prognostic biomarkers...............................................................61
7.9.2
Purely exploratory biomarkers....................................................................62
7.9.3
Biomarker measurements taken over time.................................................62
7.9.4
Potential surrogate biomarkers ...................................................................62
7.9.5
Potential predictive biomarkers...................................................................63
7.9.6
Statistical evaluations of pharmacological endpoints ................................63
7.9.7
Exposure- and biomarker-efficacy analyses...............................................64
7.9.8
Immune response (ADA) ..............................................................................64
8
REFERENCES.....................................................................................65


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HISTORY TABLE...............................................................................76


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LIST OF TABLES
Table 5.1.3: 1
Derivation rules for PFS.............................................................................16
Table 5.2.2.3: 1
Derivation rules for OS..........................................................................20
Table 5.2.2.3: 2
Derivation rules for time to PSA progression........................................21
Table 6.2: 1
Important protocol violations..........................................................................33
Table 6.6: 1
Rules for imputations of missing or incomplete dates ....................................41
Table 6.7.2: 1
Nominal time-points and windows for imaging.........................................45
Table 7.8.1: 1
Adverse events by user defined AE categories ..........................................57
Table 10: 1
History table ....................................................................................................76


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2
LIST OF ABBREVIATIONS
Term
Definition / description
(e)CRF
(electronic) Case Report Form
(m)RNA
(messenger) RiboNucleic Acid
(T)SAP
(Trial) Statistical Analysis Plan
ADA
Anti-Drug Antibody
ADS
Analysis Data Set
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALKP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANOVA
Analysis Of Variance
AR-V7
Androgen Recept Variant 7
AST
Aspartate Transaminase
ATC
Anatomical, Therapeutic, Chemical (classification system)
AUC
Area Under the plasma concentration-time Curve
AUCτ,ss
Area under the plasma concentration-time curve over the dosing interval 
at steady state
AUEC
Area Under the Effect Curve
BB
Blood Biomarker Set
BI
Boehringer Ingelheim
BIcMQ
BI customised MedDRA Queries
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BLQ
Below lower Limit of Quantification
BMI
Body Mass Index
BPI-SF
Brief Pain Inventory Short Form
BRPM
Blinded Report Planning Meeting
BS
Biomarkers Set
BSA
Body Surface Area
C
Cycle
cfDNA
cell-free DNA (DeoxyriboNucleic Acid)
Cmax,ss
Maximum measured plasma concentration at steady state


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Term
Definition / description
Cpre,ss
Pre-dose plasma concentration at steady state
CR
Complete Response
CRPC
Castration-Resistant Prostate Cancer
CSAP
Cumulative Statistical Analysis Plan
CSD
Company Standard Displays
CT
Concomitant Therapy
CTC
Circulating Tumour Cell
CTCAE
Common Terminology Criteria for Adverse Events  
CTCb
CTC biomarker set
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DC
Disease Control
DCS
Downstream Cascade Set
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DMS
Data Management and Statistics
ECG
Electrocardiogram
ECG-PK
ECG-PK analysis set
ECGS
ECG Set
Emax
Emax model (PD/PD model)
ENR
Enrolled Set
EOT
End of Treatment
EOT(V)
End of Treatment (Visit)
EWB
Emotional Well-Being (subscale score)
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-G
Functional Assessment of Cancer Therapy - General
FACT-P
Functional Assessment of Cancer Therapy - Prostate
FDA
Food and Drugs Administration
FFPE
Formalin Fixed Paraffin Embedded
FU
Follow-up


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Term
Definition / description
FWB
Functional Well-Being (subscale score)
HR
Hazard Ratio / heart rate
ICH
International Conference on Harmonisation
IGF
Insulin Growth Factor
IGF-1
Insulin Growth Factor 1
IGF-2
Insulin Growth Factor 2
IGFBP-3
Insulin Growth Factor Binding Protein 3
IHC
Immunohistochemistry
IPV
Important Protocol Violation
IRT
Interactive Response Technology 
ITT
Intent-to-Treat
LLOQ
Lower Limit of Quantification
LLT
Lowest Level Term
LS Means
Least-Squares Means
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MMRM
Mixed-effects Model for Repeated Measures
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
mRNAS
mRNA set
MS
MTD Set
MSb
Mutational status biomarker set
MTD
Maximum Tolerated Dose
NCA
Noncompartmental Analysis
NCI
National Cancer Institute
ND
No Disease
NE
Not Evaluable
OS
Overall Survival 
pAkt
phosphor Akt
PCS
Prostate Cancer Subscale score


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Term
Definition / description
PCWG2
Prostate Cancer Clinical Trials Working Group 2
PD
Progressive Disease / Pharmacodynamic (as applicable)
PES
Protein Expression Set
PFS
Progression Free Survival
PK
Pharmacokinetics
PKS
Pharmacokinetics Set
PPS
Per Protocol Set
PR
Partial Response
PR interval
ECG interval from the onset of the P wave to the beginning of the QRS 
complex
PRP
Platelet-Rich Plasma
PSA
Prostate-Specific Antigen 
PT
Preferred Term
PTEN
Phosphatase and Tensin Homolog
PV
Protocol Violation
PWB
Physical Well-Being (subscale score)
Q1
25th percentile
Q3
75th percentile
QOL
Quality of Life
QRS
Combination of the Q, R and S waves
QT
ECG interval from the beginning of the QRS complex to the end of the 
T wave
QTc
Generic term for QTcF and QTcB intervals
QTcB
QT interval, corrected by Bazett’s formula
QTcF
QT interval, corrected by Fridericia’s formula
RD
Reference Document
RECIST
Response Criteria In Solid Tumours
REP
Residual Effect Period
RP2D
Recommended Phase II Dose
RPM
Report Planning Meeting
RS
Randomised Set
SAE
Serious Adverse Event


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Term
Definition / description
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Stable Disease / Standard Deviation
SIR
Synoptic Interim Report
SMQ
Standardised MedDRA Queries
SOC
System Organ Class
SOP
Standard Operating Procedure
SPOP
Speckle-type POZ Protein
ss
Steady state
SWB
Social/Family Well-Being (subscale score)
TCM
Trial Clinical Monitor
tmax
The time after dosing when Cmax occurs
TMCP
Translational Medicine and Clinical Pharmacology
TOI
FACT-P Trial Outcome Index
TS
Treated Set
UDAEC
User Defined Adverse Events Categories
ULN
Upper Limit of Normal
URPM
Unblinded Report Planning Meeting
V
Visit
VT
Virtual Twins
WHO-DD
World Health Organisation Drug Dictionary


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3
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (5), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP (see in section “Statistical Methods and 
Determination of Sample Size”). Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation. 
This TSAP follows Boehringer Ingelheims (BI) internal reference (1).
The trial consists of three parts, the phase Ib including the dose escalation part and the 
expansion cohort and phase II including the randomised part.
The TSAP describes the analysis for all parts of the trial. After the phase I escalation part, 
safety analyses were performed and documented in a Synoptic Interim Report (SIR) (see 
Section 9.1).
In general, study or trial medication refers to the combination of xentuzumab with 
enzalutamide, as well as the monotherapy of the aforementioned medications.
Statistical Analysis System (SAS) Version 9.4 or later version will be used for all analyses 
unless otherwise specified.


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4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
4.1
ADDITIONS/NEW ANALYSES
Skeletal events are analysed by investigator assessment and by central review assessment. 
Only the endpoint "time to first skeletal event" related to investigator assessment was planned 
in the protocol. The endpoint associated to central review assessment has been added in the 
further endpoints.
The endpoint Disease Control (DC) has been added in further endpoints.
4.2
CHANGES
There is one change in the assessment of target lesions according to Response Criteria In 
Solid Tumours version 1.1 (RECIST 1.1) (R09-0262) which is applied by the central review 
in this trial and which is described in the imaging charter. More details can be found in 
Section 5.2.2.3 of this TSAP.
Several criteria are used to analyse CTCs. The following one was not planned in the protocol, 
but will be analysed along with the other CTC criteria: "CTC status at week 12".
Prostate-Specific Antigen (PSA) endpoints (response, progression): definitions in this TSAP 
might be slightly different as the ones from the protocol. They have been reworked using the 
Prostate Cancer Clinical Trials Working Group 2 (PCWG2) guidelines (R13-1642), previous 
studies and medical knowledge. They are therefore more accurate and include more details in 
the TSAP.
4.3
CLARIFICATIONS
The following points warrant further clarification:
∀
If not stated otherwise, date of randomisation will be replaced by first treatment 
administration of any study medication in the outputs  for the Phase Ib part of this 
trial.
∀
The terms “progression”, “progressive disease” (PD) and “disease progression” will 
be used interchangeably within this document.
∀
The terms “treatment cycle” or “treatment course” will be used interchangeably 
throughout this document.
∀
The terms “study medication” and “trial medication” will be used interchangeably 
throughout this document. These terms may be used for the combination of 
enzalutamide and xentuzumab, or any of these medications alone. Clarification is 
given when necessary.
∀
According to the current TSAP template, “Other endpoints” described in the CTP are 
now named “Further endpoints”.


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4.4
CLARIFICATIONS TO THE PRIMARY ANALYSIS
The protocol (Section 7.3.1) mentions that the primary analysis will be conducted 
approximately 23 months after first patient was randomized in phase II part, in case 60
Progression Free Survival (PFS) events are not reached. According to the Table 7.6:3 from 
the protocol, the calculated duration was actually 22.5 months. The impact of this difference 
in terms of PFS events is negligible, and it has therefore been decided and agreed to perform 
this primary analysis 22.5 months after first patient randomized, in case 60 events are not 
reached.
The protocol (Section 4.1.5.1) states as well that “the BI study team will be blinded for the 
aggregated phase II data at the treatment level until the trial database lock”. The trial and 
project team clarified and agreed that it is meant until the trial database lock (DBL) of the 
primary analysis. Indeed, there is no additional blinded team planned for this trial and almost 
all patients will be off-treatment at that time. The BI study team will therefore be completely 
unblinded after DBL of the primary analysis.


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5
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Best overall response to trial medication will be determined separately according to RECIST 
version 1.1 (see Appendix 10.4 of the CTP) and to PCWG2 criteria, recorded from first 
administration of trial medication until the earliest of disease progression, death or last 
adequate tumour assessment before new anti-cancer therapy. Details about derivation of best 
overall response are given in Section 5.4.7.
5.1.1
Phase Ib escalation
The primary endpoint is the maximum tolerated dose (MTD) of trial medication based on the 
occurrence of dose limiting toxicity (DLT) during the first treatment course. The planned 
treatment course consists of 28 days.
MTD:
MTD is defined as the highest dose level examined of trial medication, at which no more than 
1 out of 6 patients experienced a DLT during the MTD evaluation period. The MTD 
evaluation period is defined as the time from the first administration of xentuzumab up to 
start of cycle 2. That means that the exact duration of this period will be derived for each 
patient. If the patient does not start cycle 2, a fixed duration of 28 days will be used.
The MTD and the safety profile (including DLTs occurring after first treatment course), will 
be the basis to define the recommended phase II dose (RP2D) to be used for further parts of 
this trial as well as further trials in the development of xentuzumab in combination with 
enzalutamide.
5.1.2
Phase Ib expansion cohort
The primary endpoint of the phase Ib expansion cohort is the PSA response.
A PSA response in a patient is defined as a decline in PSA value >50% compared to baseline 
(which is confirmed by the next available value occurring at least 3 weeks later) (R13-1642). 
The confirmatory value should be at least 50% lower than the baseline, but may be higher 
than the first PSA value taken into account for response. However the confirmatory value 
may not be 50% higher than this first PSA. If it is >= 50% higher than the first PSA, the next 
available sample should be taken to determine if response has been achieved. The date of 
response is the date that the first 50% (or greater) decline is observed. 
Patients without baseline or post-baseline assessments are considered as missing.
Patients presenting with a PSA value showing response but without any confirmatory value
will be defined as "unconfirmed responders".
The percentage change from baseline in PSA will be calculated as follows:
∀
100*(PSA value post-baseline - PSA value at baseline)/PSA value at baseline
A negative percentage change from baseline shows a decline in PSA.


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Some particular data patterns may lead to a patient having PSA progression and PSA 
response at the same timepoint. Data will be carefully checked in order to detect such 
assessments. In case further rules are needed, these will as well be discussed at a Blinded 
Report Planning Meeting (BRPM) or added in a revision of the TSAP.
5.1.3
Phase II
The primary endpoint for the phase II part of the study is PFS based on investigator 
assessment.
PFS is defined as the time from randomisation until radiological tumour progression in bone 
(based on PCWG2 criteria) or soft tissue (based on modified RECIST 1.1) or death from any 
cause, whichever occurs earlier. 
Tumour assessments will be performed at screening, week 8, week 16, week 24 and then 
every 12 weeks thereafter (more details in CTP Flow Chart).
For each follow-up (FU) imaging time-point an overall tumour response will be determined 
for soft tissue according to modified RECIST 1.1 (R09-0262 and Appendix 10.4 of the CTP) 
and for bone according to the prostate cancer clinical trials working group (PCWG2) criteria 
(R13-1642). The overall tumour response for each imaging time-point according to modified 
RECIST 1.1 will be selected from the following categories: Complete Response (CR); Partial 
Response (PR); Stable Disease (SD); No disease (ND); Progressive Disease (PD); Non-
CR/Non-PD; Not Evaluable (NE). The overall tumour response for each imaging time-point 
(if clinically indicated) for bone lesion will be selected from the following categories: Non-
progressive disease (Non-PD); Progressive disease (PD); Not Evaluable (NE).
Some patients enter the trial without any target or non-target lesion according to RECIST 1.1. 
Until new lesions appear and a progression is reported for this patient, the response 
assessment for such patients will be set to No Disease (ND) (see also Section 5.4.7).
For details on the imaging process and RECIST evaluation, see Section 5.1.2 and Section 
10.4 of the CTP.
Derivation of endpoint PFS
Derivations below are described in days. However, the endpoints below will be presented in 
months in the outputs produced for the Clinical Trial Report (CTR).
For patients with 'event' as an outcome for PFS:  (according to modified RECIST version 1.1 
or PCWG2)
∀
PFS [days] = date of outcome - date of randomisation + 1.
For patients with 'censored' as an outcome for PFS: (according to modified RECIST version 
1.1 or PCWG2)
∀
PFS (censored) [days] = date of outcome - date of randomisation + 1.
The censoring rules for PFS (i.e. outcome and date of outcome) are given in Table 5.1.3: 1. 
Clinical disease progression will not be considered for determination of a PFS event, unless 
the outcome of the progression is death.


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If patients would have their radiological examinations over a number of days, i.e. target 
lesions assessed on day x, non-target lesions assessed on day y and new lesion (if applicable) 
on day z, the following rules will be applied: 
∀
If the overall response is PD, the earliest date of multiple assessments will be taken.
∀
If the overall response is SD, Non-CR/Non-PD, Non PD, PR, CR or NE, the latest of 
multiple assessment dates will be taken, i.e. in the case of SD, Non-CR/Non-PD, Non 
PD, PR, CR, the latest of multiple dates will be used to censor the patients.
For PFS according to RECIST and PCWG2, the date of overall response will be determined 
for RECIST and PCWG2 separately. In case both RECIST and PCWG2 show PD then the 
date of PD will be the earliest date of these two. When either RECIST or PCWG2 show PD, 
then the date of outcome will be the date of PD. In case none of RECIST or PCWG2 shows 
PD then the latest date of RECIST and PCWG2 will be used for censoring.
Imaging assessments for which NE is assigned as the overall response at an imaging time-
point are considered to be missed assessments. Please note that NE does not indicate lack of 
progression.
Table 5.1.3: 1 Derivation rules for PFS
Situation
Outcome 
(event or 
censored)
Date of outcome
No baseline radiological assessment
Patient with death on or 
before the second 
planned radiological 
assessment
Event 
Date of death
Patient without death or 
patient with death after 
second performed 
radiological assessment
Censored
Date of randomisation (or first 
treatment administration, in non-
randomised trials)
Without post-baseline radiological assessments
Vital status is unknown 
or patient is known to be 
alive
Censored
Date of randomisation  (or first 
treatment administration, in non-
randomised trials)
Death prior or on the 
second planned 
radiological assessment
Event
Date of death


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Table 5.1.3: 1 Derivation rules for PFS (cont.)
Situation
Outcome 
(event or 
censored)
Date of outcome
Death beyond the second 
planned radiological 
assessment
Censored
Date of randomisation  (or first 
treatment administration, in non-
randomised trials)
With baseline and post-baseline radiological assessments BUT no other anti-cancer 
therapy
Alive and not 
progressed, no more than 
one consecutively missed 
radiological assessments
Censored
Date of last radiological assessment
Alive and not 
progressed, two or more 
consecutively  missed 
radiological assessments
Censored
Date of last radiological assessment 
prior to missed radiological 
assessments
Progressed, zero or one 
missed radiological 
assessment prior to 
progression 
Event
Date of radiological assessment of 
progression
Progressed, but two or 
more consecutively  
missed radiological 
assessments prior to 
progression
Censored
Date of last radiological assessment 
prior to missed assessment
Death but no 
progression, zero or one 
missed radiological 
assessment prior to death
Event
Date of death


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Table 5.1.3: 1 Derivation rules for PFS (cont.)
Situation
Outcome 
(event or 
censored)
Date of outcome
Death without 
progression, but two or 
more consecutively  
missed radiological 
assessments prior to 
death
Censored
Date of last radiological assessment 
prior to missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer 
therapy started before 
progression or death
Censored
Date of last radiological assessment 
before subsequent anti-cancer therapy
No baseline and post-
baseline imaging and 
subsequent-anti cancer 
therapy started prior to a 
death
Censored
Date of randomisation (or first 
treatment administration, in non-
randomised trials)
Data will be carefully checked in order to detect missing assessments. In case further rules 
are needed, these will be discussed at a BRPM and added in a revision of the TSAP.
In order to identify that consecutive imaging time-points are missing for a given patient, a 
nominal time point [8, 16, 24, and then every 12 weeks thereafter] will be assigned to the 
assessments. This is achieved by creating windows for every assessment. The windows are 
defined in Table 6.7.2: 1.
Last evaluable imaging
An evaluable radiological image for the censoring of PFS is an image for which an overall 
response assessment of SD, Non-PD, Non-CR/Non-PD, PR or CR has been assigned. This is 
used for censoring of patients without progression at end of trial, or censoring prior to missed 
assessments or censoring prior to subsequent anti-cancer therapy. If the bone and the soft 
tissue assessment have been done at different dates, the date of the first assessment will be 
the date of censoring.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.


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5.2.2
Other secondary endpoints
5.2.2.1
Phase Ib escalation 
There are no secondary endpoints.
5.2.2.2
Phase Ib expansion cohort
Progression-free survival (PFS) based on investigator assessment
The rules are the same as the ones described in Section 5.1.3.
Please note that the date of randomisation will be replaced by the date of the first treatment 
administration of any study medication. 
Changes in CTC response
This is defined as a decline in CTC value from ≥5 to <5 cells per 7.5mL blood (called 
“specimen volume” within this section and Section 7.5.2.2 (R14-0865), for at least one post-
baseline time-point. 
Patients with a CTC value <5 cells per 7.5 ml blood at baseline, or with missing baseline 
value, are not taken into consideration for this endpoint. Patients with no post baseline value 
are considered as missing for this endpoint. 
5.2.2.3
Phase II
Progression-free survival (PFS) based on central review
The rules are the same as the ones described in Section 5.1.3, except the rule defined below. 
Instead of investigator assessment, the assessment based on central review will be used.
It should be referred to the imaging charter for more details regarding the assessment of 
response. However, there is one important change to RECIST 1.1 in the assessment of target 
lesions based on central review. In case one patient has the following:
∀
PR at last assessment
∀
more than 20% increase from nadir in the sum of longest diameters of target lesions, 
but less than 5 mm absolute increase from nadir.
In this case the assessment of PR should be carried forward to PR. This difference will not 
affect the endpoint PFS of this trial.
Overall survival (OS)
OS is defined as the time from randomisation until death from any cause.
For patients with ‘event’ as an outcome for overall survival:
∀
Overall survival [days] = date of outcome – date of randomisation + 1.
For patients with ‘censored’ as an outcome for overall survival:
∀
Overall survival (censored) [days] = date of outcome – date of randomisation + 1
The censoring rules for OS (i.e. outcome and date of outcome) are given in Table 5.2.2:3: 1.


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Table 5.2.2.3: 1
Derivation rules for OS
Status at time of analysis
Outcome (event or 
censored)
Date of outcome
Patient died and the date of 
death is known 
event
Date of death
Patient died and date of 
death is unknown
event
Date of last contact when the patient is 
known to be alive + 1 day
Patient alive
censored
Date of last contact when the patient is 
known to be alive
Unknown
censored
Date of last contact when the patient is 
known to be alive
The date when the patient was last known to be alive will be derived using the following data 
sources:
∀
Patient status: date of patient status obtained (if patient status is alive), last date 
patient known to be alive (in case patient is lost to follow-up), date of refusal (in case 
the patient actively refused to be followed up)
∀
Tumour assessment and/or radiological imaging data (date of imaging target lesions, 
date of imaging non-target lesions, date of detection of new lesion, date of assessment 
of bone lesions)
∀
Trial medication administration pages (including dates of start and end of 
administration, and termination of trial medication page)
∀
Onset and/or end dates of Adverse Events (AEs)
∀
Vital signs and/or physical examination dates
∀
Dates of subsequent anti-cancer therapy
Imputed AE dates as well as imputed subsequent anti-cancer therapy dates will not be used 
for the derivation of the last contact date.
Time to PSA progression
For the definition of time to PSA progression, the following rules are used:
∀
If there is a decline from baseline in PSA before increasing: Time to PSA progression 
is defined as the time from the date of randomisation until the date where a 25% or 
greater increase in PSA and an absolute increase of 2 ng/mL (=ug/L, unit collected in 
the trial) or more from the nadir, is documented (which is confirmed by the next 
available value occurring at least 3 weeks later) (R13-1642). The date of the 
progression is the first date where the increase is observed.
∀
If there is no decline from baseline in PSA: Time to PSA progression is defined as the 
time from the date of randomisation until the date where a 25% or greater increase in 
PSA and an absolute increase of 2 ng/mL (=ug/L, unit collected in the trial) or more 


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from baseline, is documented. However, only values after 12 weeks of therapy (i.e. 
starting at day 84) are considered. In this case no confirmation is needed. (R13-1642)
The percentage change from nadir/baseline will be calculated as follows:
∀
100*(PSA value at assessment - PSA value at nadir/baseline)/ PSA value at 
nadir/baseline
Derivations below are described in days. However, the endpoint will be presented in months 
in the statistical tables produced for the CTR.
For patients presenting with PSA progression, time to PSA progression is computed by:
∀
Time to PSA progression [days] = date of PSA progression - date of randomisation + 
1.
For patients not presenting with PSA progression or being lost to follow-up, time to PSA 
progression (censored) is computed by:
∀
Time to PSA progression (censored) [days] = date of censoring - date of 
randomisation + 1.
See Table 5.2.2.3: 2 for more details about time to PSA progression rules and derivation of 
date of censoring. 
Table 5.2.2.3: 2
Derivation rules for time to PSA progression
Situation
Outcome (event or 
censored)
Date of PSA progression or 
censoring
No baseline PSA value
censored
Date of randomisation 
No post-baseline PSA value
censored
Date of randomisation
No PSA progression, 
irrespective of missed 
assessments
censored
Date of last evaluable PSA 
value 
PSA progression, 
irrespective of missed 
assessments
event
Date of PSA progression 
In the case when confirmation of progression is needed, the censoring rules are defined 
irrespective of the duration between the first assessment of progression and the confirmatory 
assessment which only needs to be the next available assessment more than 3 weeks after the 
first one. In this case, a patient without confirmation of progression will not be considered a 
progressor. 
Data will be carefully checked in order to detect missing assessments. In case further rules 
are needed, these will be discussed at a BRPM and added in a revision of the TSAP.


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Some particular data patterns may lead to a patient having PSA progression and PSA 
response at the same timepoint. Data will be carefully checked in order to detect such 
assessments. In case further rules are needed, these will as well be discussed at a BRPM and 
added in a revision of the TSAP.
Maximum decline in PSA
The maximum decline in PSA is defined as the change in PSA between the baseline PSA 
value and the minimum post-baseline PSA value. The change from baseline is defined as:
∀
Change from baseline in PSA (ng/mL) = PSA value post-baseline - PSA value at 
baseline. 
Maximum decline in PSA is defined as:
∀
Maximum decline in PSA (ng/mL) = min(PSA value post-baseline) – PSA value at 
baseline.
Percentage decline will be calculated too (please refer to Section 5.1.2 for the computation). 
A negative change from baseline in PSA shows a decline in PSA.
Percentage change in PSA at week 12
Percentage change in PSA from baseline to week 12 of treatment is defined as:
∀
Percentage change in PSA (%) = 100*(PSA value at week 12 - PSA value at 
baseline)/PSA value at baseline
For this assessment, it is allowed to take a value:
∀
until one week later than week 12, in case the PSA assessment was delayed
∀
one day earlier due to the one day window allowed by the protocol 
Values from assessments between day 84 and day 92 after first treatment administration will 
therefore be taken into account (according to the protocol schedule for visits at week 12). 
In case there are several values within this timeframe (day 84 to 92), the closest value to Day 
85 will be taken.
In case there is no value within this timeframe (day 84 to 92), but the patient discontinued all 
treatments earlier than day 84, then the End of Treatment (EOT) value should be used. A 
PSA value will be taken as EOT value if the assessment was performed between the date of 
discontinuation of the last study medication until 7 days (included) after this date (according 
to the protocol schedule for the EOT visit (EOTV)).
In case there is no value within this timeframe (day 84 to 92), and the patient did not 
discontinue all treatments earlier than day 84, no earlier value will be taken as replacement, 
the assessment will be missing. 
PSA response
PSA response is defined as a decline in PSA value >50% (with confirmation at least 3 weeks 
later) (R13-1642). See Section 5.1.2. for more details. 


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Changes in CTC response
Changes in CTCs will be evaluated using the following criteria:
∀
CTC reduction is defined as a decline in CTC value from ≥5 to <5 cells per 7.5mL
blood (called “specimen volume” within this section and Section 7.5.2.3) (R14-0865),
for at least one post-baseline time-point. Patients with a CTC value <5 cells per 7.5 
mL blood at baseline, or with missing baseline value, are not taken into consideration 
for this endpoint.
∀
Maximum decline in CTC counts (in number of cells) compared to baseline that 
occurs at any point after treatment start, defined as the difference (absolute and 
percentage) between the minimum post-baseline CTC value and the baseline CTC 
value. Patients with missing baseline value are considered missing for this criterion.
∀
CTC status at week 12 (≥5 or <5 cells per 7.5mL blood)
Baseline value is the value collected before a patient starts treatment with trial medication. 
Patients with no post-baseline value are considered as missing for the three criteria. 
For the criterion “CTC status at week 12”, the nearest assessment to C4V1 (day 85) will be 
used, with following window:
∀
A later value, until one week after (day 92), can be used
∀
An earlier value, after four weeks in trial (day 29), can be used.
In case the patient discontinued the trial before the planned assessment, the EOT assessment 
will be used for this criterion in case it is the nearest to the target day. 
In case it is needed for descriptive tables, multiple entries for one single time point in a 
patient will be assessed as follows:
∀
If only one valid value (with acceptable specimen volume or imputable value) is 
available, this one will be used
∀
If several valid values are available, the value of the time point will be set as the mean 
of the available values


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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Phase I escalation and expansion parts: Patients will be analysed according to the cohort 
initially assigned. All planned analysis will be presented by this cohort, unless specified 
otherwise. Handling of patients where cohort assignment has not been followed will be 
handled on a case-by-case basis, to be agreed at report planning meetings or DBL meeting 
(but prior to DBL).
Phase II part: For safety analyses, treated patients will be analysed according to the treatment 
they actually received. For efficacy analyses, the intent-to-treat (ITT) approach will be used, 
i.e. patients will be analysed according to the treatment group they were randomised to. 
For safety summaries data recorded during the REP will be considered as on-treatment. For 
this trial, the length of the REP is 42 days.
The actual study periods and treatment codes are defined in a document entitled “8-7-other-
sdtm-trial-arms-trial-elements”, which can be found in Data Management and Statistics 
(DMS) folder, Section 8, within Boehringer Ingelheim Regulatory Documents for 
Submission (BIRDS).
Patients in phase I expansion part are on continuous enzalutamide treatment before the trial 
and during the screening period. For these patients, the on-treatment period is considered to 
start at the first intake of xentuzumab.
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol set (PPS) analysis will be performed for this study, hence, no patient will be 
excluded from the analyses (except those with missing informed consent or not adhering to 
age limit). However patients with potentially important protocol violations (IPVs) will be 
documented. The following list of potentially IPVs in Table 6.2: 1 will be used; note that this 
is a working list and may not be finalised until the final Blinded Report Planning Meeting 
(BRPM) or DBL meeting (but prior to DBL for the primary analysis). Potentially important 
protocol violations will be handled according to BI standards (7).
During the study conduct, protocol deviation should be monitored and guidance for 
improving / teaching the respective sites should be discussed during the study Medical 
Quality Review Meetings (MQRMs).
Table 6.2: 1
Important protocol violations
Category/
Code
Description
Requirements
Excluded 
from
A 
[1]
Entrance criteria not met
A1
Diagnosis of trial disease 
questionable
Inclusion criteria* IN1, IN3, IN4
not met
None


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
A2
Prohibited baseline 
condition, diagnosis or 
treatment
Inclusion criteria* IN5, IN6, IN7 or 
IN16, IN17, IN18 (phase Ib 
escalation and phase II only) or 
IN19, IN20 (phase Ib expansion 
cohort only) not met 
or
Exclusion criteria* EX1-EX10 or 
EX13-EX17 or EX21 or 
EX18, EX22, EX23 (phase Ib 
escalation and phase II only) or
EX19 (phase Ib expansion cohort 
only) met 
None
A3
Laboratory result 
indicating inadequate 
organ function at 
screening
Inclusion criteria* IN8 to IN15 not 
met
or
Exclusion criterion* EX12 met
None
A4
Adequate archival tumour 
tissue not available
Not applicable
None
A5
Relevant medical history 
available for patients 
undergoing tumor biopsy 
only
Exclusion criterion* EX20 met
None
B 
[1]
Legal Criteria
B1
Informed consent not 
available / not done
Informed consent date missing
All
B2
Informed consent too late
Informed consent date was after 
Screening Visit date
None
B3
Age limit for patient 
inclusion not adhered to
Inclusion criteria IN2 not met or, 
Calculate age given the date of 
birth and date of informed consent: 
patients must be ≥ 18 years old
All


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
C 
Trial medication and 
randomisation
C1
[2]
Time window violation for 
procedures performed at 
screening
Screening imaging earlier than 28 
days to first drug intake or later 
than first drug intake;
Safety labs, ECG performed earlier 
than 28 days to, or later than first 
drug intake;
Timeframe > 4 days between 
randomisation and first drug intake.
None
C2
[2]
Trial medication not given 
according to protocol
Dose reduction scheme not 
followed (see CTP Section 4.1.4.4);
Administration of trial 
medication(s) not compliant. 
Indicated by medical review (i.e. 
where Administration of 
xentuzumab according to the 
protocol = ‘No’ and associated 
comments, or compliance data from 
Enzalutamide with associated 
comments)
Please note: This excludes the 
investigational treatment given 
outside the boundaries specified in 
the CTP (covered in Category C3)
None


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
C3
[1]
Infusion time for the 
investigational treatment 
outside of CTP specific
boundaries
Infusion duration of xentuzumab 
given < 50 minutes or > 200 
minutes (Infusion time should be 
from 60 to 180 minutes, but the 
thresholds above are accepted). 
The exact duration of the infusion 
should be calculated taking 
interruptions into account. 
In case of missing administration 
times, the violation will not be 
considered important if 
administration according to 
protocol = ‘Yes’
None
C4
[2]
Patient assignment not 
followed
Patients do not receive the initial 
treatment they were randomised /
allocated to
None
C4.1
Randomisation not 
followed
This applies only for phase II part
of the trial
None
C4.2
Treatment allocation not 
followed
This applies for all non-randomized 
parts of the trial.
None
D 
[2]
Concomitant medication
D1
Prohibited treatment 
during trial conduct phase
Treatment taken during the 
treatment period as described in 
Section 4.2.2.1 of the CTP.
None
E 
[2]
Missing Data
E1
Imaging assessments not 
done according to CTP 
instructions
Imaging assessment should be
performed at Screening and several 
time points thereafter (see Section 
5.1.2.1 of the CTP, Section 6.7.2 of 
the TSAP).
None


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Table 6.2: 1
Important protocol violations (cont.)
F 
[2]
Trial Specific protocol 
violations
F1
Other protocol violations 
affecting patient rights or 
safety
Manual Protocol Violations (PVs)
will be collectively captured.
None
[1] IPV will be derived automatically 
[2] IPV will be identified via individual review at MQRM/RPM/DBL.
* During the amendments of CTP the inclusion and exclusion criteria were adapted. 
Therefore, the inclusion/exclusion criteria valid at subject’s enrolment have to be considered.
6.3
PATIENTS SETS ANALYSED
The following analysis sets will be defined for this trial:
∀
Enrolled set (ENR)
This patient set includes all patients with informed consent given. The enrolled set will be 
used for patient disposition tables.
∀
Treated set (TS)
This patient set includes all patients who are documented to have received and taken at least 
one dose of any study medication during the treatment cycles (from day 1).
In phase Ib escalation and expansion parts, the TS will be used for all planned safety and 
efficacy analyses, except for CTCs endpoints in phase Ib expansion part, for which the 
corresponding biomarker set (CTCb) will be used (see below). In phase II part, the TS will be 
used for all planned safety analyses.
∀
MTD Set (MS)
The MTD set defines the set of patients in the phase Ib escalation part of the trial that are 
fully evaluable for determination of the MTD in the first treatment course. The MTD set will 
be used for some safety analyses in the first part, this is specified in the technical TSAP.
Patients in the TS who were replaced within the MTD evaluation period in the first part of the 
trial will be excluded from the determination of the MTD. Replacement of patients in the first 
part of the study is defined in Section 3.3.5 of the CTP. The final list of replaced patients is 
supplied by the Trial Clinical Monitor (TCM) no later than the last report planning meeting
(RPM) before the DBL for the safety analysis.
∀
Randomised set (RS)
This patient set includes all randomised patients in the phase II of the trial, regardless of 
whether or not they have received treatment. Patients are assigned to xentuzumab in 
combination with enzalutamide or enzalutamide alone. The randomised set will be used for 
the efficacy analyses of patients in the phase II of the study, except for CTCs endpoints, for 
which the corresponding biomarker set (CTCb) will be used (see below).


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∀
Pharmacokinetic set (PKS)
This patient set includes all patients in the treated set who provide at least one PK parameter 
that was not excluded according to the description in Section 6.6.3 below. Thus, a patient will 
be included in the PKS, even if he contributes only one PK parameter value for one period to 
the statistical assessment.
∀
Biomarker Sets
A patient set will be defined for each biomarker, if the data is available.These sets include all 
patients in the treated set who have at least one evaluable baseline value for a biomarker.
o
BB: Blood Biomarkers - Baseline measurements of free, dissociable and total 
IGF-1, free, dissociable and total IGF-2, total IGFBP-3 in serum and IGF 
bioactivity in heparin plasma
o
MSb: Mutational status of archival FFPE tumor samples, at baseline
o
mRNAS: Messenger RNA (mRNA) expression of IGF pathway related genes, 
e.g. tumor IGF-1 and IGF-2, at baseline
o
DCS: Relevant biomarkers related to IGF-1 and IGF-2 Downstream Cascade 
(e.g. pAkt) in tumour tissue, at baseline
o
PES: Protein Expression Set of IGF-1/2 in FFPE tumour sample, at baseline
o
CTCb: CTC baseline measurement
Biomarker sets will be used for the corresponding biomarker analyses, and the CTCb set will 
be used as well for the analysis of the secondary and further endpoints related to CTC 
assessments. In case one of the biomarker sets is identical or contains <5% difference in 
number of patients with the randomized set (or treated set in the phase Ib expansion part), 
then the randomized set (or treated set in the phase Ib expansion part) will be used and 
biomarker sets will not be considered at all.
∀
ECG Set (ECGS)
This patient set includes all patients in the treated set who do not have artificial cardiac 
pacemakers and have at least one on-treatment value for at least one ECG variable.
∀
ECG-PK Set
This patient set includes all patients in the ECG set who are
o
in the comparator group (’enzalutamide’) or
o
in the ‘xentuzumab+enzalutamide’ groups and have at least one time-matching pair of 
valid xentuzumab plasma concentration and QTcF change from baseline (see 
Section 7.8.4).
The decisions whether
o
a concentration is considered valid or
o
a time deviation between PK blood sampling and ECG recording is acceptable
will be made no later than at the final BRPM before DBL.


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The analyses of ECG data will be based on the ECG set except those concerning the 
relationship between plasma concentrations and ECG variables which will be based on the 
ECG-PK set.
No per protocol population will be used for analyses. 


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6.5
POOLING OF CENTRES
This section is not applicable because there are no inferential statistics, and therefore there is 
no statistical model in which centre/country can be included.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, missing data will not be imputed, unless required for the following analyses and 
definitions. Then the rules as described below apply.
Missing dates that affect the evaluation of endpoints specified in previous sections of this 
TSAP will be imputed utilising a “worst case” approach, which will be applied on a case-by-
case basis (depending on the affected endpoint) and agreed to by the trial team members at 
the final BRPM before DBL at the latest.
The rules in the Table 6.6: 1 below have been agreed by the trial and project teams, and will 
be used in this trial, if applicable.
Table 6.6: 1
Rules for imputations of missing or incomplete dates
Date
Imputation rule
Date of birth
In case only the year is given: 31st of December
Date of death
Date last known to be alive.
If only year and month are given: this will be imputed with 1st  
of the month for the analysis of OS
Date of first histological 
diagnosis
1st of month if day is missing
1st of January if month also missing
Date of first appearance or 
recurrence of metastasis
1st of month if day is missing
1st of January if month also missing
Date of start of 
concomitant medication
No imputation required
Date of end of 
concomitant medication
No imputation required
Date of start of 
subsequent anti-cancer 
therapy (imputation 
required only for 
censoring of PFS)
If the day (respectively day and month) of the start date of 
subsequent anti-cancer therapy is missing, then the first of the 
month (respectively 1st January) will be imputed unless this date 
leads to a date before the stop date of study medications. In this 
case, the study medications stop date + 1 day will be imputed.
Additionally, all imputed start dates of subsequent anti-cancer 
therapy should be before death date if available.
Date of stop of subsequent 
anti-cancer therapy
No imputation required


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Table 6.6:1
Rules for imputations of missing or incomplete dates (cont.)
Date
Imputation rule
Date of end of treatment (only for patients still ongoing at time of 
snapshot/DBL)
Date of 
snapshot/DBL
6.6.1
AEs
Missing or incomplete AE dates are imputed according to BI standards (2).
6.6.2
Laboratory values at baseline
For missing laboratory data at Cycle 1 Visit 1 (before the very first administration of study 
medication) data from preceding visits will be used.
6.6.3
PK parameters / biomarkers
Missing data and outliers of PK data are handled according to BI standards (3).
Missing biomarker data may be imputed. The rules will be described in the Unblinded Report 
Planning Meeting (URPM) minutes and/or in the CTR.
Plasma concentration data and parameters of a subject will be included in the statistical PK 
analyses if they are not flagged for exclusion due to a protocol violation relevant to the 
evaluation of PK or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be
∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
∀
the subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),
∀
missing samples/concentration data at important phases of PK disposition curve.
Exclusion of PK parameters
The analysis data set (ADS) ADPP contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS are based on PK parameters with APEXC equal 
to “Included”, regardless of the analysis flag comment APEXCO.


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Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point) contains a column variable ACEXCO 
containing an analysis flag comment. Exclusion of a plasma concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’ the 
value can be used for further analyses based on actual times. If ACEXCO is set to ‘HALF 
LIFE’ the value will be excluded from half-life calculation only; the value is included for all 
other analyses.
Further details are given in (3), RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” and RD-03 “Description of Analytical 
Transfer Files and PK/PD Data Files”.
6.6.4
Randomisation and stratification (Interactive Response Technology (IRT) versus 
CRF) (only for phase II)
In general, the data as reported in the eCRF will be used for analyses. 
6.6.5
ECG
If replicate ECG recordings are missing, the arithmetic means per time point will be 
computed with the reduced (1 or 2) number of recordings.
If single cardiac cycles (also denoted as beats or waveforms) are missing, the arithmetic 
means per single ECG will be computed with the reduced (1 or 2) number of cardiac cycles.
If baseline is missing, a QTcF/QT interval > 500 msec at any time on treatment will be a 
notable finding. In case of a missing qualitative ECG finding at baseline, a finding observed 
on-treatment will be categorized as ’new onset’.
Exposure-response analyses
Missing xentuzumab plasma concentration data in the PK4+ (ADPC dataset) file identified 
with below lower limit of quantification (BLQ) will be replaced by zero if measured at 
baseline and by ½ lower limit of quantification (LLOQ) if measured at an on-treatment time 
point.
When the actual sampling time of the blood sample or of the ECG recording is not available, 
the pair of plasma concentration and time-matched ECG endpoint will be excluded from the 
analyses at the corresponding planned time point. Furthermore, all plasma concentrations 
flagged with ‘exclusion’ by the PKEXC variable of the PK4+ file (ADPC dataset) will be 
excluded from the exposure-response analyses.
6.6.6
FACT-P questionnaire and BPI-SF questionnaire
Handling of missing data for the FACT-P questionnaire is described in Sections 5.3 and 9.3.
Handling of missing data for the BPI-SF questionnaire is described in Section 5.3.


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6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
6.7.1
Baseline
The last measurement observed prior to start of trial medication will be assigned to baseline. 
Note that for some trial procedures (for example body weight, vital signs, laboratory tests) 
this may be the value measured on the same day trial medication was started. In these cases it 
will be assumed that the measurements were taken prior to the intake of any study 
medication. For tumour assessment, baseline evaluations must be based on Magnetic 
Resonance Imaging (MRI) or Computed Tomography scans performed no more than 28 days 
prior to start of trial medication.
Study days and visits will be labelled according to the flow chart of the CTP.
Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of any study medication. If this criterion is not fulfilled then no baseline will 
be derived, except in the following case: if a patient is entered (phase Ib escalation and 
expansion parts) or randomised (phase II part), but not treated, the last value we have for the 
patient is considered baseline.
Laboratory values:
Baseline is defined as the latest time-point before the very first administration of any study 
medication.
If any of these times are missing and the date of laboratory value is equal to the date of first 
study drug administration, then the laboratory assessment will be considered as according to 
protocol, i.e. as prior to first study medication.
ECG
Baseline values will be derived from the triplicate at the time-point closest to but prior to the 
first administration of study medication.
Quality of Life (QOL) questionnaires
BPI-SF questionnaire is assessed at screening and several time-points thereafter. Baseline 
assessment is the questionnaire assessment from screening, unless it is missing. In this case, 
the C1V1 assessment is considered baseline.
FACT-P questionnaire is assessed at several time-points starting at C1V1. Baseline 
assessment is considered as being the assessment from C1V1.
6.7.2
Time windows for every tumour assessment
In order to identify whether consecutive imaging time-points are missing for a given patient, 
a nominal time point [8, 16, 24, 36 weeks and every 12 weeks thereafter] will be assigned to 
each and every image. This is achieved by creating windows for every tumour assessment 
(modified RECIST 1.1 and bone). The windows are defined in Table 6.7.2: 1 below. Day 1 
corresponds to date of randomisation for the phase II part (for phase Ib expansion part it 
corresponds to the date of first drug intake of xentuzumab). Assigning time windows for 
images is only needed for phase Ib expansion part and phase II part. This will therefore not be 
done for phase Ib escalation part.


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Table 6.7.2: 1 Nominal time-points and windows for imaging
Nominal time-point [weeks 
from start of therapy]
Due date of imaging [days]
Window [days]
8
57
1 to =< 85
16
113
86 to =< 141
24
169
142 to =< 211
36
253
212 to =< 295
48
337
296 to =< 379
60
421
380 to =<463
every 12 week interval
etc (1)
etc (1)
(1) Due date of imaging = (nominal time point * 7) + 1. To calculate the lower bound of 
the window, use the middle point between the due date of the previous time point and 
the current due date + 1. To calculate the upper bound of the window, use the middle 
point between the due date of the next time point and the current due date.
If a patient does not have an image in one of the windows described above, he will be said to 
have 'missed an assessment' for that time-point. In case a patient has more than one 
assessment in one window, the assessment with the latest outcome will be used for the 
analysis unless a PD has been recorded earlier then PD will be used.
6.7.3
Time schedule of ECG recordings and related PK blood sampling
The scheduled time points of ECG recordings and PK blood sampling are described in the 
CTP, section 10.6.


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7
PLANNED ANALYSES
The labelling and display format of statistical parameters will follow BI standards (8).
Unless otherwise specified, outputs will be displayed separately for each part of the trial.
Descriptive statistics for continuous variables will generally contain number of patients in 
that patient set with non-missing values (N), Mean, Standard Deviation (SD), Minimum 
(Min), 25th percentile (Q1), Median, Q3 (75th percentile), Maximum (Max). In general, 
means, SDs, medians, Q1 and Q3 will be presented to one more decimal place than the raw 
data. Minima and maxima will be presented to the same number of decimal places as the raw 
data.
For time-to-event analysis tables, the set of statistics is: number of patients [N (%)], Number 
of patients with event [N (%)], Number of patients censored [N (%)], <Time to event> 
[months] followed by Q1 (25th percentile), Median, Q3 (75th percentile). If not specified 
otherwise, the duration as well as time to event will be displayed in months.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group total. Percentages will be rounded to one decimal place. In general 
a category “missing” will be displayed, if there are missing data for the corresponding 
variable. Percentages will also generally be based on all patients in the respective patient set 
whether they have non-missing values or not.
The primary analysis will include all treated (phase I escalation and expansion parts) or 
randomised patients (phase II part), following the ITT approach (as specified in Section 6.3).
Sort order for general categorical variables: If categories correspond to the collected 
categories on the eCRF and the table shells do not explicitly specify the ordering, the “default 
ordering” defined by the eCRF is to be used in such cases. If categories are derived the 
ordering as specified in the table shell document should be used; in general ordinal data (e.g. 
categorised continuous data) are to be displayed in ascending order.
The denominator of the main categories is defined by the number of patients in the used 
patient set. The main categories define the denominators of the subcategories. Subcategories 
should be indented and “[N (%)]” to be displayed only for the main category.
If a table includes only categorical data, “[N (%)]” is to be displayed in the column header.
In general, a “Total” column will be displayed in section 15.1 (trial subjects) of the CTR. In 
sections 15.2 and 15.3 of the CTR, a “Total” column will be displayed in phase I part outputs,
but not in phase II outputs.
Abbreviations (e.g., Wors.) or acronyms (e.g., PD) should not be displayed in tables and 
patients data listings without any explanation. They will be either spelled out in the table or 
explained in footnotes (whatever is more reasonable from the programming point of view).
If applicable, conversion from days to weeks, months and years will be as follows:
∀
Weeks = days ÷ 7
∀
Months = days × 12 ÷ 365.25


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∀
Years = days ÷ 365.25
In case a pooled analysis of 1280.4 and 1280.8 will be deemed appropriate, specifications of 
this analysis will be given in a separate CSAP before DBL.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.1.1
Disposition of patients
For patient disposition the standard descriptive table from the EOT/CSD (Company Standard 
Display) catalogue will be populated. Additionally, patients with discontinuations by initial 
treatment and the reasons will be listed and tabulated, overall and and for each treatment 
separately. The same output will also contain an overview of discontinued and non-
discontinued, as well as completed and non-completed patients. In Appendix 16.1.9.2, a 
disposition table by country will be produced.
7.1.2
Important protocol violations
A table and a listing of patients with important protocol violations based on Table 6.2: 1 will 
be created in Section 15.1.3 and Appendices 16.2.3 and 16.1.9.2.3 (if needed) respectively, of 
the CTR.
7.1.3
Demographic and other baseline characteristics
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demographic data, oncological history and baseline conditions.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Concomitant diseases will 
be coded similarly as adverse events based on the most current MedDRA version. 
Concomitant therapies (CT) will be coded according to World Health Organisation Drug 
Dictionary (WHO-DD). CT will be classified according to the Anatomical, Therapeutic, 
Chemical (ATC) classification system. The third ATC level will be used to categorise CTs by 
therapy type. In situations where a medical product may be used for more than one equally 
important indication, there are often several classification alternatives. As appropriate, 
patients receiving CTs with more than one possible ATC level-three category will be counted 
more than once; footnotes will clarify this possible double counting in tables.
Concomitant medications will be presented according to whether they are concomitant with 
the reception of study medication, or whether they were given prior to study medication. In 
case start and stop dates of the medications are completely missing, they are assigned as 
given prior to study medication.
7.3
TREATMENT COMPLIANCE
Compliance was not analysed separately by treatment received. The number of missed doses 
of any medication as recorded on the eCRF will be listed by patient.


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7.4
PRIMARY ENDPOINTS
7.4.1
Phase Ib escalation
The primary endpoints are the MTD and the occurrence of DLT. The MTD is determined 
from the occurrences of DLTs during the MTD evaluation period (this period is defined in 
Section 5.1.1). An overall summary of the DLTs (see CTP Section 5.2.3 for definitions of 
DLT) which occurred during the MTD evaluation period and the on-treatment period will be 
provided for each dose cohort.
Patients that were treated but replaced for the MTD evaluation (see CTP Section 3.3.5) will 
be excluded from the MTD determination. Replacement of patients will be determined on a 
case by case basis; exclusion of these patients from the MTD evaluation will be confirmed by 
the trial team at the RPM prior to DBL.
A listing of patients with DLTs by initial treatment will be performed. A plot with an 
overview of the phase I escalation part (showing the patients and their assigned doses, 
replaced patients and patients with DLT) will be displayed.
At the end of the dose escalation phase, a safety analysis will be performed to determine the 
RP2D. The results will be documented for internal use and communication with the 
participating investigators (see also Section 9.1).
7.4.2
Phase Ib expansion cohort
Descriptive statistics for PSA response will be provided for all treated patients. Confirmed as 
well as unconfirmed responses will be displayed.
7.4.3
Phase II 
The primary analysis for PFS based on investigator assessment will be conducted for all 
patients of the RS in the phase II part of this trial. PFS by investigator's assessment is the 
primary endpoint and will be assessed based on the Kaplan-Meier method for each treatment 
arm separately. Point estimates together with confidence intervals (based on Greenwood's 
method) will be provided for median PFS. An estimation of the effect on PFS of xentuzumab 
plus enzalutamide compared to the effect on PFS of enzalutamide will be given by the hazard 
ratio (HR) and its 95% confidence interval using a Cox proportional hazards model. The 
validity of the underlying assumptions of this model will also be checked. HR < 1 will favour 
treatment with xentuzumab plus enzalutamide; p-value from the two-sided log-rank test will 
be also displayed but it should be emphasised here that this is only to be understood in an 
exploratory way. The Breslow method for handling ties will be used. The censoring rules for 
PFS are as stated in Section 5.1.3.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Other secondary endpoints
7.5.2.1
Phase Ib escalation
This section is not applicable as no secondary endpoint has been specified in the protocol.
7.5.2.2
Phase Ib expansion cohort
PFS based on investigator's assessment
PFS based on investigator's assessment will be assessed based on the Kaplan-Meier method 
in the phase Ib expansion cohort. Point estimates together with confidence intervals (based on 
Greenwood's method) will be provided for median time to event and quartiles.
Changes in CTC response
The following imputation will be performed before the analysis, separately for each sample: 
o
If the amount of specimen volume is 7.5mL as planned, the measured cell 
count will be taken for the analysis
o
If the amount of specimen volume  is ≥5mL and <7.5, and number of cells is 
reported and is ≥10 then the expected number of cells for the planned 


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specimen volume will be imputed using linear transformation: expected cell 
count=7.5/(actual amount of blood in mL)*(measured cell count)
o
If the specimen volume amount of blood is ≥5mL and <7.5, and number of 
cells is missing or is <10, then no imputation will be done and the number of
cells will be set to missing for the analysis
Frequencies of patients with CTC reduction will be displayed.
The maximum decline (percentage) in CTC counts compared to baseline will be analyzed 
descriptively.
7.5.2.3
Phase II 
PFS based on central review
PFS based on central review will be analysed using the same methods as for the primary 
endpoint for phase II (see Section 7.4.3), including subgroup analyses, if deemed appropriate. 
OS
OS will be analysed using the same methods as for the primary endpoint for phase II (see 
Section 7.4.3), including subgroup analyses, if deemed appropriate. 
Time to PSA progression
Time to PSA progression will be analysed using a Cox proportional hazards model in the 
same way as the primary endpoint for phase II (see Section 7.4.3). 
Maximum decline in PSA
Descriptive statistics for maximum decline in PSA will be displayed. This endpoint will also 
be explored graphically by means of a waterfall plot (using the percentage decline). All PSA 
assessments will be displayed in a longitudinal plot.
Percentage change in PSA at week 12
Descriptive statistics for percentage change in PSA at week 12 will be provided. This 
endpoint will also be explored graphically by means of a waterfall plot. All percentage 
changes in PSA will be displayed in a longitudinal plot.
PSA response
Descriptive statistics for PSA response will be provided. Confirmed as well as unconfirmed 
responses will be displayed.
Changes in CTC response
Imputations as specified in Sections 5.2.2 and 7.5.2.2 will be performed before the analysis, 
separately for each sample.
Frequencies of patients with CTC reduction will be displayed.
The maximum decline (percentage) in CTC counts compared to baseline will be analyzed 
descriptively and also explored graphically by means of a waterfall plot. All CTC 
assessments will be displayed in an overtime plot per patient.


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Difference in proportions for week 12 status will be displayed by means of a contingency 
table, along with 95% confidence interval and a Fisher's exact test.


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7.7
EXTENT OF EXPOSURE
The variables defined in Section 5.4.2 will be summarised descriptively for each dose cohort 
(phase Ib parts) or treatment group (Phase II part).
7.8
SAFETY ANALYSES
All safety analyses will be performed on the TS (unless otherwise specified; for example, the 
MTD Set will be used for some safety outputs). Patients in the first part of the trial who were 
replaced within or before the first treatment cycle will be excluded from the determination of 
the MTD. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses will be based on the number 
of patients with AEs (not the number of AEs).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies: 
∀
All AE attributes are identical (LLT, CTCAE grade, action taken with trial 
medication, therapy required, seriousness, reason for seriousness, relationship, 
outcome, AESI)
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
For further details on summarisation of AE data, please refer to (2) and (4).
AEs will be coded with the most recent version of MedDRA. The severity of AEs will be 
scaled according to CTCAE (CTCAE version 4.03 (R10-4848)).
The analyses of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events with an onset between first treatment 
administration until end of the REP will be assigned as ‘on treatment’. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’; these AEs will 
be displayed in separate tables and listings. Adverse events will be displayed by the initial 
dose of study medication administered on the first day of treatment .
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary SOC and PT. Separate tables will 
be provided for patients with drug-related AEs, AEs leading to dose reduction, adverse events 
leading to discontinuation, SAEs, serious drug-related AEs, AEs leading to death, other 
significant AEs, AESI, and AEs fulfilling the DLT definition (for phase Ib escalation only).
Sorting order:
In tables presenting SOCs and PTs, SOCs will be sorted alphabetically and PTs (within SOC) 
by descending frequency.


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Reporting of CTCAE grades in tables:
In tables showing AEs by worst CTCAE grade, AEs with missing CTCAE grade will only be 
displayed under the category "All grades", but no category "Missing grade" will be displayed. 
Therefore the categories "Grade 1" to "Grade 5" might not add up to the category "All 
grades"; a footnote will explain this handling.
Displaying of CTCAE grades in AE tables (Section 15) will be “All grades”, “Grade 1”, 
“Grade 2”, “Grade 3”, “Grade 4”, and “Grade 5” separately. In the appendix (Section 
16.1.9.2), the categorisation “All grades”, “Grade 1/2”, “Grade 3/4/5”, will be used.
Listings of AEs
Adverse events will be reported with start and end day as calculated from the first day of 
treatment with study medication.
Incidence and severity of AEs
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and SAEs will be reported by severity according to CTCAE grades.
Other significant AEs
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
or permanent discontinuation of study medication. Their incidence will be reported by 
severity according to CTCAE grades.
A listing of patients who developed ‘other significant’ AEs will be provided and a flag for 
serious and non-serious will be included.
AEs leading to dose reduction or permanent discontinuation will include:
∀
AEs leading to dose reduction of xentuzumab
∀
AEs leading to dose reduction of enzalutamide
∀
AEs leading to permanent discontinuation of xentuzumab
∀
AEs leading to permanent discontinuation of enzalutamide
AEs leading to death
AEs leading to death during the on-treatment period will be tabulated in a separate table. In 
this table no CTCAE grades will be shown. For fatal AEs without CTCAE grade 5 or missing 
grade, the grade will be imputed as CTCAE grade 5. Reported fatal AEs that occurred in the 
post-treatment period will be listed within the listing containing all post-treatment AEs.
Protocol-specified AESI
AESIs are specified in the CTP Section 5.2.2.1. Their incidence will also be reported. DLTs 
are considered as AESIs only in the phase Ib escalation.
Adverse events by user defined AE categories (UDAEC)
UDAEC as defined on project level by the pharmacovigilance working group will be derived 
and the latest version will be used for the analysis. The categories will be taken as defined in 
the most recent signed version of the safety statistical analysis plan at the time of DBL. These 


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categories can also be found in Table 7.8.1:1. This document is entitled "8-02-sap-safety-
core", which can be found in the Project DMS folder, section 8 (project level), within BIRDS. 
Table 7.8.1: 1 Adverse events by user defined AE categories
Term
Group#
Hepatic impairment
SMQ: Drug related hepatic disorders – comprehensive 
search SMQ
Hyperglycaemia narrow
SMQ: Hyperglycaemia/new onset diabetes mellitus 
Narrow
Infusion related reaction
BIcMQ:
PT list of Infusion related reaction 
AND
SMQ Hypersensitivity Narrow 
Non-infectious pneumonitis
SMQ: Interstitial lung disease Narrow 
Renal insufficiency
SMQ: Acute renal failure Broad 
Weight loss
BIcMQ:
Weight loss - Broad
Neutropenia
SMQ: Haematopoietic leukopenia – Narrow
Stomatitis
BIcMQ:
Stomatitis PT list
Asthenia
BIcMQ:
Asthenic conditions – Narrow
Anemia
SMQ: Haematopoietic erythropenia
Thrombocytopenia
SMQ: Haematopoietic thrombocytopenia 
#
This column indicates whether the Term(s) provided in the first column are MedDRA preferred terms 
(PT), Standardised MedDRA Queries (SMQ) or BI customised MedDRA Queries (BIcMQ).
The incidence of AE by UDAEC will be analysed.
7.8.2
Laboratory data
7.8.2.1
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6). The same on-treatment periods as considered for the analysis of AEs will be 
applied for laboratory values except for that the baseline laboratory value will be included in 
the 'on-treatment' period. Patients having at least one post-baseline laboratory value will be 
displayed in the descriptive analyses.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.03 (R10-4848). The 
following outputs will be presented:
∀
Worst CTCAE grade experienced during the on-treatment phase.


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∀
Transitions of CTCAE grade from baseline to worst laboratory value, from worst to 
last laboratory value during the on-treatment phase, and from baseline to last 
laboratory value.
Patients with missing CTCAE grade at baseline or no baseline value but post baseline values 
will be displayed in the category “Missing CTCAE grade at baseline”. Laboratory values 
without CTCAE grading will be compared to their reference ranges and frequency tables will 
be provided for the number of patients within and outside the reference range at baseline and 
the last measurement on treatment.
Analysis of potentially clinically significant abnormal laboratory values, and handling of 
CTCAE grade -1 and -9 laboratory parameters, are described in the SOP for "Display and 
analysis of laboratory data" (6), RD 9.
7.8.2.2
Laboratory values of special interest
Hepatic enzyme elevations (potential Hy’s law cases):
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of alanine aminotransferase (ALT) and/or aspartate transaminase
(AST) > 3 Upper Limit of Normal (ULN) with total bilirubin ≥ 2ULN and alkaline 
phosphatase (ALKP) < 2 ULN. The events can occur in any order, but must occur within 14 
days of the previous event, i.e. the second event must occur within 14 days of the first event, 
and the third event must occur within 14 days of the second event, etc.
Patients with missing laboratory values for liver enzymes will be excluded from these 
analyses but will be presented separately in a listing. Tabulations of hepatic enzyme 
elevations and liver laboratory values (see Section 5.2.2.1 of the CTP), including flags of true 
DILI (Drug-Induced Liver Injury) cases, are created in accordance with the Food and Drug 
Administration (FDA) DILI guidance (P09-12413).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
All ECG analyses will be performed using the ECG Set, except those concerning the 
relationship between plasma concentrations and ECG endpoints which will be based on the 
ECG-PK set.
Descriptive analyses (separate analysis of first and second parts)
Descriptive analyses of continuous and categorical endpoints will be performed. The QTcB 
interval as well as the percentage changes for PR interval and QRS complex will only be 
displayed in Listings (Appendix 16.2.8 of the CTR)
Absolute values and change from baseline in QTcF interval, QT interval, heart rate, PR 
interval, and QRS complex will be summarized descriptively by initial treatment, cycle, day 
and planned time.
Frequency tables will be provided for all categorical endpoints including notable findings and 
qualitative ECG assessments. Frequencies of the increases in QTcF and QT intervals above 


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thresholds such as 450 msec, 480 msec, and 500 msec between baseline and on-treatment 
values will be displayed in two-way shift tables by initial treatment.
Patients in the TS who have notable findings but are excluded from the ECG Set will be 
listed in separate listings which will be presented in Section 15 of the CTR.
Additional statistical analyses will be performed as described in the following.
Repeated measures analyses (Phase II part only)
The following analyses will only include the ECG interval data of both arms of the Phase II 
part.
The endpoint ‘change in QTcF interval between baseline and on-treatment’ will be analysed
by a linear mixed-effects model for repeated measures (MMRM). This model will include the 
fixed, categorical effects of ‘treatment’ and ‘timepoint’, the ‘treatment-by- timepoint’ 
interaction, as well as the continuous, fixed covariate ‘baseline’ and the ‘baseline-by-
timepoint’ interaction. An unstructured covariance structure will be used to model the within-
patient measurements. The SAS® procedure MIXED will be used, involving the restricted 
maximum likelihood estimation method, and the Kenward-Roger method will be applied to 
adjust standard errors and estimate denominator degrees of freedom. The model is detailed in 
Section 9.2.2.
Timepoints will only be included as long as evaluable data in ‘change in QTcF between 
baseline and on-treatment’ from at least 30 patients are still available in any of the treatment 
groups. The choice of 30 patients is relatively arbitrary and is conceived as a compromise, i.e. 
balancing out between precision of the estimates and receiving preliminary information over 
time on the other hand. The analyses of heart rate, QT, PR and QRS endpoints will be aligned 
to the respective QTcF analyses.
For the pairwise comparisons of ’xentuzumab + enzalutamide’ versus ’enzalutamide’, the 
treatment differences at each timepoint will be estimated by the difference in the 
corresponding Least-Squares Means (LS Means). Two-sided 90% confidence intervals based 
on the t-distribution will also be computed. Having estimated the treatment difference at each 
timepoint by the analysis described above, the timepoint at which the difference is largest 
will be identified.
This analysis will also be performed using the corresponding endpoints based on the QT 
interval, heart rate, PR interval and QRS complex, respectively.
The repeated-measures analysis will also be applied to the absolute on-treatment QTcF 
interval, heart rate, QT interval, PR interval and QRS complex values, respectively. Least 
squares means of ‘treatment-by-timepoint’ and two-sided 95% confidence intervals based on 
the t-distribution will be computed.
Sensitivity analysis
In the model described above, a covariance structure of type ‘unstructured’ will be used to 
model the covariances of the within-patient measurements. This model does not consider the 
particular underlying time structure, being consecutive pairs of within-day measurements 
(pre- and post-dose measurements approximately 1 hour apart) separated by one (or more) 
week(s). To account for this particular time structure, a modified covariance structure will be 
used in the sensitivity analysis: A two-by-two unstructured covariance matrix will be used to 


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model the within-patient measurements on each day (pre- and post-dose measurements). A 
second two-by-two unstructured covariance matrix will be used to model the within-patient 
measurements between days; this matrix will be the same for all combinations of days. 
Hence, in this second analysis the number of necessary covariance parameter estimates will 
not depend on the number of included timepoints. The sensitivity analysis will be restricted to 
the endpoints based on the QTcF interval. The model is detailed in Section 9.2.2.
Exposure-response analyses (Phase I and Phase II parts pooled)
The exposure-response analyses will be based on the ECG-PK set. The analyses will include 
the pooled data of the Phase I and Phase II parts. Patients in the expansion cohort of the 
Phase I part will be excluded as they are pre-treated with enzalutamide. Data of patients 
receiving enzalutamide alone (Phase II part) will be included with xentuzumab plasma 
concentrations set to zero (see R17-0553).
Pairs of xentuzumab plasma concentrations and QTcF changes from baseline that are not 
time-matched (i.e. a time deviation between PK blood sampling and ECG recording that is 
not acceptable, see Section 6.6.5) will be excluded from the analyses. When the collecting 
time of the blood sample or the ECG recording is not available, the pair will also be 
excluded. The decisions to exclude pairs from the analyses will be made no later than at the 
final BRPM before DBL (for further details see also Sections 6.3 and 6.6.5).
The relationship between xentuzumab plasma concentrations and QTcF change from baseline 
will be explored using a random coefficient model including a categorical variable 
‘treatment’ with the two levels ‘xentuzumab+enzalutamide’ and ‘enzalutamide’ to estimate 
the adjusted mean difference between ‘xentuzumab + enzalutamide’ and ‘enzalutamide’ in 
QTcF change from baseline and its 90% confidence interval at clinically relevant plasma 
concentrations, which are the geometric means of the C1D11h, C2D81h and C3D11h values of 
the RP2D. The model is detailed in Section 9.2.3. For visualization, plasma concentration 
against QTcF changes from baseline will be plotted, as well as the (fixed effect) regression 
line, its 90% confidence interval and the geometric means of C1D11h, C2D81h and C3D11h.
The assumption of a linear relationship will be checked by visual inspection of diagnostic 
plots (presented in Section 16.1.9.2 of the CTR). If linearity is not given, the concentrations 
may be log-transformed prior to the analysis.
To inspect (graphically) whether the peaks of the time-profiles for xentuzumab plasma 
concentrations and QTcF interval changes from baseline coincide, figures of the individual 
time profiles of xentuzumab plasma concentrations and QTcF interval changes from baseline 
will be generated for each patient (presented in Appendix 16.1.9.2 of the CTR), as well as for 
the means of the group treated at RP2D/MTD (presented in Section 15 of the CTR). Mean 
time profiles from the patients treated with enzalutamide alone will be displayed as well.
These analyses will also be performed using the corresponding endpoints based on the QT 
interval and heart rate.
Furthermore, a first sensitivity analysis will be performed using the random coefficient model 
described above including the categorical effect ‘day’, and a second sensitivity analysis will 
be done including the categorical effect ‘time’ with the two levels pre- and post-dose, instead. 
These analyses will only be applied to the QTcF changes from baseline.


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Appropriateness of QT interval correction methods for heart rate
To evaluate the appropriateness of the heart rate correction methods of QT interval, slopes of 
the relationship of QT, QTcF, and QTcB interval versus RR interval (values log-transformed 
using the natural logarithm) will be estimated by applying a random coefficient model (see
Section 9.2.4) separately for the treatments ‘xentuzumab+enzalutamide’ and ‘enzalutamide’. 
These analyses will be based on the on-treatment single ECGs (i.e. three values per time 
point). A table of the resulting (fixed effect) slopes will be displayed together with two-sided 
95% confidence intervals in Appendix 16.1.9.2 of the CTR.
7.8.5
Others
Not applicable.
7.9
STATISTICAL BIOMARKER AND PK/PD ANALYSES
The biomarkers collected in different parts of the trial will be analyzed and reported 
separately for each part of the trial.
As statistical biomarker analyses are purely exploratory, there will be no strict error control in 
a confirmatory sense.
If data is available, the following biomarkers will be evaluated and reported in the CTR:
7.9.1
Potentially prognostic biomarkers
∀
Baseline measurements of free, dissociable and total IGF-1, free, dissociable and total 
IGF-2, total IGFBP-3 in serum and IGF bioactivity in heparin plasma
∀
Mutational status of archival FFPE tumour samples
∀
mRNA expression of IGF pathway related genes, e.g. tumour IGF-1 and IGF-2
∀
Relevant biomarkers related to IGF-1 and IGF-2 downstream cascade (e.g. pAkt) in 
tumour tissue
∀
IGF-1/2 protein expression in FFPE tumour sample.
∀
CTC baseline measurement
∀
cfDNA baseline measurement
Statistical analyses for prognostic biomarkers
A Kaplan-Meier analysis (including median, 95% confidence interval, Q1 and Q3 statistics) 
plus corresponding plot will be conducted for PFS.
The categorised/binary biomarker variables for the biomarkers mentioned above will be the 
group determining factors. Categorisations will be data-driven and described in the URPM 
minutes and/or in the CTR. For mutational status the focus will be on mutations with known 
functional impact. For mutational status, mRNA and cfDNA the categorisations defined in 
the Biomarker SAP (c09122174-01) will be used as starting point for this exploratory 
analysis.


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Cox proportional hazard analysis will additionally be conducted for biomarker-efficacy 
relationship. The validity of the underlying assumptions will be checked.
Corresponding sensitivity analyses, such as modelling with continuous biomarker variable 
may also be conducted. Further analyses may be carried out in an explorative approach and 
results will be discussed in the context of pharmacokinetic, efficacy, and safety data of 
xentuzumab in combination with enzalutamide.
7.9.2
Purely exploratory biomarkers
The following biomarkers will be listed in the CTR:
∀
Ki67 expression level in fresh tumour biopsies taken before and after treatment with 
xentuzumab
∀
Other exploratory biomarkers measured in fresh tumour biopsies
7.9.3
Biomarker measurements taken over time
Time series analyses will be performed on the following biomarkers:
∀
For relevant IGF down-stream cascade biomarkes measured in PRP, total IGF-1, total 
IGF-2, dissociable IGF-1, dissociable IGF-2, free IGF-1, free IGF-2, IGF bioactivity, 
as well as IGFBP-3 measured in peripheral blood overtime plots and descriptive 
statistic tables for the measured values and absolute changes from baseline will be 
created. Baseline values will be derived and all pre-dose values will be flagged. 
Correlation plots will be shown, Pearson and Spearman correlation coefficients will 
be calculated. If feasible, exploratory analyses including (non-)linear function fits
such as population Emax model will be applied. Further details will be provided in the 
CTR.
∀
cfDNA concentrations from patient plasma samples assessing mutational profiling at 
baseline and monitoring mutational status over time of treatment. Exploratory 
analyses including nonlinear function fits and AUECs (Area Under the Effect Curve)
will be performed if feasible (for the calculation, the linear trapezoidal method is 
used, as described in (3), RD_01). The measures will be compared between the 
treatments.
∀
CTC measures over time (overdispersed count data). Exploratory analyses including 
nonlinear function fits and AUECs will be performed in order to quantify the time for 
which the cell counts remain under 5 cells per 7.5ml for each patient. The measures 
will be compared between the treatments.
7.9.4
Potential surrogate biomarkers
If and only if PFS or OS study results are statistically significant, the CTC status at week 12 
alone and in combination with lab parameters will be evaluated as potential surrogate for 
either PFS or OS using Prentice Criteria (R16-0801). The alpha level will be increased to 
20% in order to account for the study size. The following lab parameters and their pairwise 
combinations will be investigated, if data allows: albumin, alkaline phosphatase, hemoglobin, 
lactate dehydrogenase. The time points for lab measures will be selected as close as possible 


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to the CTC status measure and must be on treatment. Details of the analyses are as in R16-
0801 and will be described further in Cumulative Statistical Analysis Plan (CSAP).
7.9.5
Potential predictive biomarkers
The statistical analyses for potentially predictive biomarkers will be reported outside of the 
CTR and described in the Translational Medicine and Clinical Pharmacology (TMCP) SAP.
This SAP can be found in BIRDS, on substance level, DMS folder, Section 8 and is entitled 
“8-02-sap-predictive-biomarkers”.
7.9.6
Statistical evaluations of pharmacological endpoints
If data are sufficient and calculation of the PK parameters AUCτ,ss and Cmax,ss of enzalutamide 
is feasible, these PK parameters at steady state (ss) in absence and presence of xentuzumab 
will be compared statistically. 
The statistical model used for the analyses will be an ANOVA model on the logarithmic scale 
and will be based on the PKS. The treatment enzalutamide alone in steady state (PK 
parameters collected at Day -1/Day 1 in the phase Ib expansion cohort) will be regarded as 
reference treatment. The treatment enzalutamide + xentuzumab in steady state (PK 
parameters collected at cycle 2 Day -1/Day 1 in phase Ib expansion cohort) will be referred to 
as test treatment in this context.
The effect ‘subject’ will be considered as random, whereas the effect ‘treatment’ will be 
considered as fixed for the main analysis. For the sensitivity analysis the effects ‘subject’ and 
‘treatment’ will be both considered as fixed. The model is described by the following 
equation:
ykm
= μ + τk + sm + εkm,
where
ykm
= logarithm of response (AUCτ,ss or Cmax,ss) in subject m receiving treatment k,
μ
= the overall mean, 
τk
= the k-th treatment effect, k = 1, 2,
sm
= the effect associated with the m-th subject, m=1,…n,
εkm
= the random error associated with the m-th subject receiving treatment k.
The PK parameters AUCτ,ss and Cmax,ss will be log-transformed (natural logarithm) prior to 
fitting the ANOVA model. The difference between the expected means for the log-
transformed PK parameters will be estimated by the difference in the corresponding LS
Means (point estimate) and 2-sided 90% confidence intervals based on the t-distribution will 
be computed. These quantities will then be back-transformed to the original scale to give the 
point estimator (geometric mean) and interval estimates for the intra-subject ratio of the 
geometric means for treatments test and reference.


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7.9.7
Exposure- and biomarker-efficacy analyses
A Kaplan-Meier analysis (including median, 95% confidence interval, Q1 and Q3 statistics) 
plus corresponding plot will be conducted for PFS by exposure and selected biomarkers over 
time (Total and Free IGF’s group).
For exposure, the categorized pre-dose concentration at steady-state (>21 days after start of 
treatment) Cpre,ss, closest to the efficacy assessment from noncompartmental analysis (see 
Section 7.6), will be the group determining factor.
For selected biomarkers over time, this analysis will be performed using pre-dose 
measurements at steady-state accordingly, if feasible.
Cox proportional hazard analysis will additionally be conducted for exposure-efficacy 
relationship. The validity of the underlying assumptions will be checked.
7.9.8
Immune response (ADA)
The presence of ADAs will be tested at the beginning of each treatment cycle (until cycle 
12), at EOT and at the first FU visit. This analysis is done for patients in phase Ib and for 
patients in the xentuzumab arm in phase II. 
The number and percentage of patients with positive and negative results will be presented.
If considered reasonable, the correlation between ADA (positive / negative) and PK and/or 
PD endpoints may be performed.
If considered reasonable, the correlation between ADA (positive / negative) and disease 
control (yes / no), and between ADA (positive / negative) and occurrence of acute/non-acute 
specific adverse events (yes / no) will be studied using a contingency table, along with 95% 
confidence interval and a Fisher’s exact test.


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8
REFERENCES
1
001-MCS-40-415_RD-02: "Trial Statistical Analysis Plan - Template", 
current version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON.
3
001-MCS-36-472: "Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics", current version, 
and related reference documents; IDEA for CON.
4
001-MCG-156: "Handling and summarisation of adverse event data for 
clinical trial reports and integrated summaries", current version; IDEA for 
CON.
5
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH
Guideline Topic E9, Note For Guidance on Statistical Principles for
Clinical Trials, current version.
6
001-MCG-157: "Display and Analysis of Laboratory Data", current 
version, IDEA for CON.
7
001-MCS-50-413: “Handling of Protocol Violations in Clinical Trials and 
Projects”, current version; IDEA for CON.
8
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", 
current version; IDEA for CON.
9
Sauerbrei W, Royston P, Zapien K. Detecting an interaction between 
treatment and a continuous covariate: A comparison of two approaches. 
Comp. Statistics & Data Analysis 51: 4054 – 4063.
10
Jiang W, Freidlin B, Simon R. Biomarker-Adaptive Threshold Design: A 
Procedure for Evaluating Treatment With Possible Biomarker-Defined 
Subset Effect. J Natl Cancer Inst 2007, 99: 1036 – 43.
P09-12413
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation U.S. Departement of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), 
Center for Biologics Evaluation and Research (CBER), 2009.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, 
Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, 
Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation 
criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45: 228-247
R10-1504
Littell RC, Milliken GA, Stroup WW, Wolfinger RD, Schabenberger O. 
SAS for Mixed Models. 2nd ed. Cary: SAS Institute (2006)
R10-2920
Ring A. Statistical models for heart rate correction of the QT interval. Stat 
Med 29, 786–796 (2010) 


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R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
Website: evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (2010)
R12-2036
Strasser H, Weber C(1999) On the Asymptotic Theory of Permutation 
Statistics.
Report Series SFB "Adaptive Information Systems and Modelling in 
Economics and Management Science", 27. SFB Adaptive Information 
Systems and Modelling in Economics and Management
Science, WU Vienna University of Economics and Business, Vienna.
R13-1642
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, 
Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, 
Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, 
Hussain M
Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of 
the Prostate Cancer Clinical Trials Working Group.
J Clin Oncol 26 (7), 1148 - 1159 (2008)
R14-0865
Saad F, Pantel K. The current role of circulating tumor cells in the 
diagnosis and management of bone metastases in advanced prostate 
cancer. Future Oncol 8(3), 321-331(2012)
R14-1341
Foster JC, Taylor JMG, Ruberg SJ
Subgroup identification from randomized clinical trial data. Statistics in 
Medicine. 2012 30:2867-2880
R15-1067
Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga 
A, Quarmby V, Richards S, Schneider CK, Subramanyam M, Swanson S, 
Vethelyi D, Yim S. 
Assessment and reporting of the clinical immunogenicity of therapeutic 
proteins and peptides-harmonized terminology and tactical 
recommendations. AAPS J 16 (4), 658 - 673 (2014)
R16-0801
Scher HI, Heller G, Molina A, Attard G, Danila DC, Jia X, Peng W, 
Sandhu SK, Olmos D, Riisnaes R, McCormack R, Burzykowski T, Kheoh 
T, Fleisher M, Buyse M, Bono JS de.
Circulating tumor cell biomarker panel as an individual-level surrogate 
for survival in metastatic castration-resistant prostate cancer. J Clin Oncol 
33 (12), 1348 - 1355 (2015)
R17-0553
Garnett C, Needleman K, Liu J, Brundage R, Wang Y
Operational characteristics of linear concentration-QT models for 
assessing QTc interval in the thorough QT and phase I clinical studies.
Clin Pharmacol Ther 100 (2), 170 - 178 (2016)
c09122174-
01
Biomarker Statistical Analysis Plan, Final Version, 01 Mar 2016.


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10 HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP:
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
11-JUN-16
None
This is the final TSAP.
Revised
28-SEP-17
All
The whole TSAP has been adapted 
including the following:
The analysis of the phase II part has 
been added (it was not fully available 
in the first version).
The analysis of other assessments such 
as PK, immunogenicity, biomarkers or 
ECG analysis has been added (it was 
not fully available in the first version).
Protocol amendments have been 
implemented, as well as updates in 
company standards and 
updates/clarifications in project 
standards


 
 
 
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