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Clinical Trial Results:
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

Summary
EudraCT number	2013-004011-41
Trial protocol	NL ES
Global end of trial date	01 Jun 2023

Results information
Results version number	v1(current)
This version publication date	14 Jun 2024
First version publication date	14 Jun 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1280.8

ISRCTN number

US NCT number

NCT02204072

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 Aug 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Oct 2019

Global end of trial reached?

Yes

Global end of trial date

01 Jun 2023

Was the trial ended prematurely?

Main objective of the trial

Phase Ib dose escalation: Determine the safety and tolerability of xentuzumab in combination with enzalutamide following progression on docetaxel-based chemotherapy and abiraterone. Phase Ib expansion cohort: Evaluate the anti-tumour activity of xentuzumab and enzalutamide in patients naive to taxane-based chemotherapy and abiraterone. Phase II: Evaluate the anti-tumour activity of xentuzumab in combination with enzalutamide versus enzalutamide alone following progression on docetaxel-based chemotherapy and abiraterone.

Protection of trial subjects

All patients were informed that they were free to withdraw their consent at any time during the study without penalty or prejudice. The patients were informed that their personal trial related data would be considered confidential and used by BI in accordance with the local data protection laws. The level of disclosure was explained to the patients. The patients were also informed that their medical records could be examined by Clinical Quality Assurance auditors appointed by BI, by members of the appropriate IEC/IRB, and by inspectors from regulatory authorities. Confidentiality of patient data was ensured by the use of depersonalised patient identification codes (patient numbers).

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Nov 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 70

Country: Number of subjects enrolled

Spain: 38

Country: Number of subjects enrolled

United States: 8

Country: Number of subjects enrolled

Hong Kong: 2

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Singapore: 9

Country: Number of subjects enrolled

Korea, Republic of: 6

Country: Number of subjects enrolled

Taiwan: 17

Worldwide total number of subjects

154

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

117

85 years and over

Subject disposition

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Recruitment details

A multicentre, open-label, randomised study to determine the safety, tolerability and anti-tumour activity of xentuzumab (BI 836845) in combination with enzalutamide in patients with advanced prostate cancer that has spread. The trial consists of 3 parts: Phase 1b dose escalation part, Phase 1b expansion part, Phase 2 two arm, parallel design.

Screening details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. Population was based on the treated set.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Open-label study.

Are arms mutually exclusive

Yes

Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide

Arm description

750 milligram (mg) xentuzumab (10mg/milliliter (mL)) was supplied in 20mL vials and diluted in physiological sodium chloride solution (0.9%)) as liquid formulation was administered as weekly 1-hour intravenous (i.v.) infusion on Days 1, 8, 15 and 22 together with four liquid-filled soft gelatin capsules of 40mg (total: 160mg) enzalutamide administered orally once daily during each 28-day cycle of treatment until disease progression or occurrence of undue toxicities. Infusion duration of xentuzumab could be extended to more than 1 hour in case of infusion reaction or adverse events. Phase Ib escalation part.

Arm type

Experimental

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

Other name

Xtandi®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Xentuzumab

Investigational medicinal product code

Other name

BI 836845

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide

Arm description

1000 milligram (mg) xentuzumab (10mg/mL was supplied in 20mL vials and diluted in physiological sodium chloride solution (0.9%)) as liquid formulation was administered as weekly 1-hour intravenous (i.v.) infusion on Days 1, 8, 15 and 22 together with four liquid-filled soft gelatin capsules of 40mg (total: 160mg) enzalutamide administered orally once daily during each 28-day cycle of treatment until disease progression or occurrence of undue toxicities. Infusion duration of xentuzumab could be extended to more than 1 hour in case of infusion reaction or adverse events. Phase Ib escalation part.

Arm type

Experimental

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

Other name

Xtandi®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Xentuzumab

Investigational medicinal product code

Other name

BI 836845

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide

Arm description

Arm type

Experimental

Investigational medicinal product name

Xentuzumab

Investigational medicinal product code

Other name

BI 836845

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

Other name

Xtandi®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide

Arm description

Arm type

Experimental

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

Other name

Xtandi®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Xentuzumab

Investigational medicinal product code

Other name

BI 836845

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase II: 160 mg Enzalutamide

Arm description

Four liquid-filled soft gelatin capsules of 40mg (total: 160mg) enzalutamide administered orally once daily during each 28-day cycle of treatment until disease progression or occurrence of undue toxicities. Phase II part.

Arm type

Experimental

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

Other name

Xtandi®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Started	3	7	24	43	43
Treated	3	7	24	43	43
Discon. Xen. due to progressive disease	2	4	21	24	0
Discon. Xen. due to adverse event	0	3	0	7	0
Discon. Xen due to withdrawal by subject	1	0	2	9	0
Discon. Xen. due to other reason	0	0	1	1 ^[2]	0
Completed	0	0	0	2	0
Not completed	3	7	24	41	43
Discon. Enz. due to progressive disease	2	4	19	26	31
Dison. Enz. due to other reason	-	-	2	-	-
Discon. Enz. due to adverse events	-	3	1	6	6
Discon. Enz. due to withdrawal by subject	1	-	2	9	6

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Worldwide 154 patients were enrolled into the trial, whereof 120 patients actually started the trial.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 43 subjects were treated in this arm, whereof 41 discontinued all treatment medication and 2 subjects were on treatment at the time of the final analysis.

Baseline characteristics

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Reporting group title

Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase II: 160 mg Enzalutamide

Reporting group description

Reporting group values	Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide	Total
Number of subjects	3	7	24	43	43	120
Age categorical
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	1	1	2	11	10	25
From 65-84 years	2	6	21	31	33	93
85 years and over	0	0	1	1	0	2
Age Continuous
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: years
arithmetic mean (standard deviation)	68.67 ( 11.85 )	70.71 ( 7.09 )	73.38 ( 7.81 )	68.58 ( 8.80 )	69.91 ( 7.92 )	-
Sex: Female, Male
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
Female	0	0	0	0	0	0
Male	3	7	24	43	43	120
Ethnicity (NIH/OMB)
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
Hispanic or Latino	0	0	4	5	12	21
Not Hispanic or Latino	3	7	20	37	31	98
Unknown or Not Reported	0	0	0	1	0	1
Race (NIH/OMB)
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	15	10	25
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	1	0	0	1
White	3	7	23	27	33	93
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	1	0	1
Phase Ib expansion part: Prostate Surface Antigen (PSA) at baseline
Treated Set (TS): All patients who were documented to have received and taken at least one dose of study medication during treatment cycles (from Day 1). Only phase Ib expansion. 99999 = Not applicable.
Units: Microgram / Liter
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)	99999 (99999 to 99999)	35.95 (14.13 to 73.39)	99999 (99999 to 99999)	99999 (99999 to 99999)	-

Subject analysis set title

Xentuzumab + Enzalutamide

Subject analysis set type

Full analysis

Subject analysis set description

This arm comprises all dose groups from Phase Ib escalation phase (750 mg Xentuzumab + 160 mg Enzalutamide and 1000 mg Xentuzumab + 160 mg Enzalutamide)

Subject analysis sets values	Xentuzumab + Enzalutamide
Number of subjects	9
Age categorical
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: years
arithmetic mean (standard deviation)	( )
Sex: Female, Male
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
Female
Male
Ethnicity (NIH/OMB)
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported
Race (NIH/OMB)
Treated Set: All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles.
Units: Subjects
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
Phase Ib expansion part: Prostate Surface Antigen (PSA) at baseline
Treated Set (TS): All patients who were documented to have received and taken at least one dose of study medication during treatment cycles (from Day 1). Only phase Ib expansion. 99999 = Not applicable.
Units: Microgram / Liter
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)

End points

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Reporting group title

Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase II: 160 mg Enzalutamide

Reporting group description

Subject analysis set title

Xentuzumab + Enzalutamide

Subject analysis set type

Full analysis

Subject analysis set description

This arm comprises all dose groups from Phase Ib escalation phase (750 mg Xentuzumab + 160 mg Enzalutamide and 1000 mg Xentuzumab + 160 mg Enzalutamide)

Primary: Phase Ib expansion part: Prostate Specific Antigen (PSA) response

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End point title

Phase Ib expansion part: Prostate Specific Antigen (PSA) response ^[1] ^[2]

End point description

The primary endpoint of the Phase Ib expansion part was PSA response. PSA response was defined as a decline in PSA value >50% compared to baseline which was confirmed by the next available value occurring at least 3 weeks later. The confirmatory value had to be at least 50% lower than the baseline, but could be higher than the first PSA value taken into account for response. However the confirmatory value was not allowed to be 50% higher than this first PSA value. If it was ≥ 50% higher than the first PSA value, the next available sample was to be taken to determine if response had been achieved. The date of response was the date that the first 50% (or greater) decline was observed. Number of subjects with response is reported. Treated Set (TS): All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Phase Ib expansion part.

End point type

Primary

End point timeframe

At Cycle 1 Day 1 before study treatment and from Cycle 3 Day 1 and Day 1 of every cycle thereafter until the end of treatment, up to 35 months.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint was analyzed descriptively.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase Ib expansion part only.

End point values	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
Number of subjects analysed	24
Units: Subjects
Yes, Confirmed	1
Yes, Unconfirmed	1
No	21
Missing	1

No statistical analyses for this end point

Primary: Phase Ib escalation part: Number of patients with dose limiting toxicities (DLTs)

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End point title

Phase Ib escalation part: Number of patients with dose limiting toxicities (DLTs) ^[3] ^[4]

End point description

Number of patients with DLTs were used to determine the maximum tolerated dose (MTD) in the Phase Ib escalation part. The MTD in this study was defined as the highest protocol dose level of xentuzumab in combination with enzalutamide, at which no more than 1 out of 6 patients in a cohort experienced a DLT during the MTD evaluation period. MTD-set: The MTD set defined the set of patients in the Phase Ib escalation part who were fully evaluable for determination of the MTD in the first treatment course. 1 patient in the 1000 mg Xentuzumab + 160 mg Enzalutamide arm was not evaluable for the MTD determination due to missed doses. Phase Ib escalation part.

End point type

Primary

End point timeframe

From first administration of xentuzumab up to start of Cycle 2, up to 28 days.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint is assessed for Phase Ib escalation part only.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase Ib escalation part only.

End point values	Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide
Number of subjects analysed	3	6
Units: Subjects	0	0

No statistical analyses for this end point

Primary: Phase 1b esclation part: Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course

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End point title

Phase 1b esclation part: Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course ^[5]

End point description

Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. The MTD in this study was defined as the highest protocol dose level of xentuzumab in combination with enzalutamide, at which no more than 1 out of 6 patients in a cohort experienced a DLT during the MTD evaluation period. MTD-set: The MTD set defined the set of patients in the Phase Ib escalation part who were fully evaluable for determination of the MTD in the first treatment course. 1 patient in the 1000 mg Xentuzumab + 160 mg Enzalutamide arm was not evaluable for the MTD determination due to missed doses. Phase Ib escalation part.

End point type

Primary

End point timeframe

From first administration of xentuzumab up to start of Cycle 2, up to 28 days.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint was analyzed descriptively.

End point values	Xentuzumab + Enzalutamide
Number of subjects analysed	9
Units: Milligram	1000

No statistical analyses for this end point

Primary: Phase II part: Progression Free Survival (PFS) based on investigator assessment

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End point title

Phase II part: Progression Free Survival (PFS) based on investigator assessment ^[6]

End point description

PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: PFS [days] = date of outcome - date of randomisation + 1. For patients with 'censored' as an outcome for PFS: PFS (censored) [days] = date of outcome - date of randomisation + 1. Randomised Set (RS): All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

End point type

Primary

End point timeframe

From randomisation until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1269 days.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	43	43
Units: Months
median (confidence interval 95%)	7.4 (3.5 to 8.7)	6.2 (3.5 to 11.1)

Statistical analysis

Comparison groups

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9549

Method

Two-sided log-rank test.

Parameter type

Hazard ratio (HR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.7

Secondary: Phase Ib expansion part: Progression free survival (PFS) based on investigator assessment

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End point title

Phase Ib expansion part: Progression free survival (PFS) based on investigator assessment ^[7]

End point description

PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: PFS [days] = date of outcome - date of first treatment administration + 1. For patients with 'censored' as an outcome for PFS: PFS (censored) [days] = date of outcome - date of first treatment administration + 1. Treated Set (TS): All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Phase Ib expansion part.

End point type

Secondary

End point timeframe

From first treatment administration of any study medication until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1114 days.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase Ib expansion part only.

End point values	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
Number of subjects analysed	24
Units: Months
median (confidence interval 95%)	8.2 (3.5 to 14.6)

No statistical analyses for this end point

Secondary: Phase II part: Overall survival (OS)

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End point title

Phase II part: Overall survival (OS) ^[8]

End point description

Overall survival (OS) defined as the time from randomisation to death from any cause. Median survival time in months is reported. Overall survival at cut-off date for final analysis (24-Oct-2019) is reported. Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

End point type

Secondary

End point timeframe

From randomisation until radiological tumor progression or death from any cause (until cut-off date for final analysis), whichever occurred earlier, up to 1269 days.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	43	43
Units: Months
median (confidence interval 95%)	13.6 (8.7 to 19.4)	13.6 (8.7 to 21.3)

Statistical Analysis

Comparison groups

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5534

Method

Two-sided log-rank test.

Parameter type

Hazard ratio (HR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.9

Secondary: Phase Ib expansion part: Changes in circulating tumour cells (CTC) response – CTC reduction from >=5 to <5 cells per 7.5 mL blood for at least one post-baseline time point

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End point title

Phase Ib expansion part: Changes in circulating tumour cells (CTC) response – CTC reduction from >=5 to <5 cells per 7.5 mL blood for at least one post-baseline time point ^[9]

End point description

Changes in circulating tumour cells (CTC) response – CTC reduction from >=5 to <5 cells per 7.5 mL blood for at least one post-baseline time point. Number of subjects with CTC Response (yes/no) is reported. Treated Set (TS): All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Only subjects with baseline CTC value >= 5 cells per 7.5mL were included in the analysis. Phase Ib expansion part.

End point type

Secondary

End point timeframe

Prior to study drug administration at Day 1 Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1 Cycle 5, Day 1 Cycle 7 and every 12 weeks thereafter, up to end of treatment. Up to 35 months.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase Ib expansion part only.

End point values	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
Number of subjects analysed	9
Units: Subjects
Yes	1
No	8

No statistical analyses for this end point

Secondary: Phase II part: Radiological Progression Free Survivial (PFS), based on central review

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End point title

Phase II part: Radiological Progression Free Survivial (PFS), based on central review ^[10]

End point description

PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 criteria) or soft tissue or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: PFS [days] = date of outcome - date of first treatment administration + 1. For patients with 'censored' as an outcome for PFS: PFS (censored) [days] = date of outcome - date of first treatment administration + 1. Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

End point type

Secondary

End point timeframe

From randomisation until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1269 days.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	43	43
Units: Months
median (confidence interval 95%)	3.6 (3.5 to 8.1)	7.1 (3.6 to 8.2)

Statistical Analysis

Comparison groups

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5425

Method

Two-sided log-rank test.

Parameter type

Hazard ratio (HR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

2.06

Secondary: Phase II part: Maximum decline in Prostate Specific Antigen (PSA)

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End point title

Phase II part: Maximum decline in Prostate Specific Antigen (PSA) ^[11]

End point description

Maximum decline in (PSA) compared to baseline. 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. Randomised Set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

End point type

Secondary

End point timeframe

At screening, at Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	40	37
Units: Microgram / Liter
arithmetic mean (standard deviation)	-102.20 ( 580.59 )	-94.13 ( 1020.31 )

No statistical analyses for this end point

Secondary: Phase II part: Time to Prostate Specific Antigen (PSA) progression

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End point title

Phase II part: Time to Prostate Specific Antigen (PSA) progression ^[12]

End point description

For the definition of time to PSA progression, the following rules are used: - 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 or more from baseline, is documented (which is confirmed by the next available value occurring at least 3 weeks later). - 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 or more from baseline, is documented. However, only values after 12 weeks of therapy are considered. 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) [days] = date of censoring - date of randomisation + 1. Randomised Set.

End point type

Secondary

End point timeframe

At screening, at Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	43	43
Units: Months
median (confidence interval 95%)	4.6 (2.8 to 5.7)	3.7 (2.8 to 4.6)

Statistical Analysis

Comparison groups

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1514

Method

Two-sided log-rank test.

Parameter type

Hazard ratio (HR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

1.18

Secondary: Phase II part: Percentage change in Prostate Specific Antigen (PSA) at Week 12

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End point title

Phase II part: Percentage change in Prostate Specific Antigen (PSA) at Week 12 ^[13]

End point description

Percentage change in PSA from baseline to 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). Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only subjects with non-missing values were included in the analysis. Phase II part.

End point type

Secondary

End point timeframe

At baseline and at Week 12.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	31	30
Units: Percentage change
arithmetic mean (standard deviation)	10.13 ( 83.25 )	49.72 ( 109.91 )

No statistical analyses for this end point

Secondary: Phase II part: Prostate Specific Antigen (PSA) response

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End point title

Phase II part: Prostate Specific Antigen (PSA) response ^[14]

End point description

PSA response – defined as a decline in PSA value >50% (which is confirmed by a second value 3 to 4 weeks apart). PSA response was defined as a decline in PSA value >50% compared to baseline which was confirmed by the next available value occurring at least 3 weeks later. The confirmatory value had to be at least 50% lower than the baseline, but could be higher than the first PSA value taken into account for response. However the confirmatory value was not allowed to be 50% higher than this first PSA value. If it was ≥ 50% higher than the first PSA value, the next available sample was to be taken to determine if response had been achieved. Number of participants with response is reported. Randomised Set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

End point type

Secondary

End point timeframe

At Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	43	43
Units: Subjects
Yes - confirmed	7	8
Yes - unconfirmed	2	0
No	31	29
Missing	3	6

No statistical analyses for this end point

Secondary: Phase II part: Circulating tumour cells (CTC) reduction defined as CTC decline from ≥5 to <5 cells per 7.5 mL blood for at least one post-baseline time-point

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End point title

Phase II part: Circulating tumour cells (CTC) reduction defined as CTC decline from ≥5 to <5 cells per 7.5 mL blood for at least one post-baseline time-point ^[15]

End point description

CTC reduction is defined as CTC decline from ≥5 to <5 cells per 7.5 mL blood for at least one post-baseline time-point. Patients with a CTC value < 5 cells per 7.5mL blood at baseline, or with missing baseline values were not taken into consideration for this endpoint. Baseline value is the value collected before a patient starts treatment with trial medication. Number of participants per category is reported. Randomised Set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only patients with baseline CTC value >=5 cells per 7.5mL were included in the analysis. Phase II part.

End point type

Secondary

End point timeframe

Prior to study drug administration at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 and then every 12 weeks thereafter, until end of treatment. Up to 40.1 months.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	25	19
Units: Subjects
Yes	4	2
No	19	15
Missing on treatment	2	2

Statistical Analysis

Comparison groups

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6186

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.579

Confidence interval

level

95%

sides

2-sided

lower limit

0.269

upper limit

12.515

Secondary: Phase II part: Circulating tumour cells (CTC) status at Week 12

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End point title

Phase II part: Circulating tumour cells (CTC) status at Week 12 ^[16]

End point description

CTC status (≥5 or <5 cells per 7.5mL blood) at Week 12. Number of participants per category is reported. Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

End point type

Secondary

End point timeframe

At Week 12.

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	43	43
Units: Subjects
≥5 cells per 7.5ml blood	26	20
<5 cells per 7.5ml blood	11	16
Missing on treatment	6	7

Statistical Analysis

Comparison groups

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.192

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.891

Confidence interval

level

95%

sides

2-sided

lower limit

0.727

upper limit

5.059

Secondary: Phase II part: Maximum decline (%) in circulating tumour cells (CTC) counts

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End point title

Phase II part: Maximum decline (%) in circulating tumour cells (CTC) counts ^[17]

End point description

Maximum decline in CTC counts (in number of cells) compared with baseline that occurred at any point after treatment start , defined as the difference between the minimum post-baseline CTC value and the baseline CTC value. Patients with missing baseline value are considered missing for this criterion. Baseline value is the value collected before a patient starts treatment with trial medication. Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only subjects with baseline CTC value were included in the analysis. Phase II part.

End point type

Secondary

End point timeframe

Prior to study drug administration at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 and then every 12 weeks thereafter, until end of treatment. Up to 40.1 months.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is assessed for Phase II part only.

End point values	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide
Number of subjects analysed	32	28
Units: Percentage
arithmetic mean (standard deviation)	41.96 ( 289.085 )	21.33 ( 201.353 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

[All cause mortality]: Up to 430 days for Phase 1b escalation, 1107 days for Phase 1b expansion and up to 1322 days for Phase II part. [Serious/other AE]: Up to 370 days for Phase 1b escalation, 1107 days for Phase 1b expansion, 1262 days for Phase II.

Adverse event reporting additional description

Treated Set (TS): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). All-cause mortality includes all death throughout the whole study period, also including death reports after the cut-off date of the final analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase II: 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Reporting group title

Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide

Reporting group description

Serious adverse events	Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	17 / 43 (39.53%)	19 / 43 (44.19%)	5 / 7 (71.43%)	8 / 24 (33.33%)
number of deaths (all causes)	1	31	34	2	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Condition aggravated
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	2 / 43 (4.65%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Investigations
Electrocardiogram T wave inversion
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Acetabulum fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Spinal cord compression
subjects affected / exposed	1 / 3 (33.33%)	4 / 43 (9.30%)	0 / 43 (0.00%)	2 / 7 (28.57%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cauda equina syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	2 / 43 (4.65%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	2 / 43 (4.65%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	2 / 43 (4.65%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide	Phase II: 160 mg Enzalutamide	Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide	Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	43 / 43 (100.00%)	43 / 43 (100.00%)	7 / 7 (100.00%)	24 / 24 (100.00%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	1 / 43 (2.33%)	1 / 7 (14.29%)	2 / 24 (8.33%)
occurrences all number	0	2	1	1	2
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	4 / 43 (9.30%)	3 / 43 (6.98%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	4	5	0	13
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	7 / 43 (16.28%)	3 / 43 (6.98%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	7	3	0	1
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	4 / 43 (9.30%)	2 / 43 (4.65%)	1 / 7 (14.29%)	3 / 24 (12.50%)
occurrences all number	0	4	2	1	3
Pain
subjects affected / exposed	0 / 3 (0.00%)	6 / 43 (13.95%)	3 / 43 (6.98%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	7	4	1	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	1 / 43 (2.33%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	6	1	0	3
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	21 / 43 (48.84%)	29 / 43 (67.44%)	5 / 7 (71.43%)	9 / 24 (37.50%)
occurrences all number	13	40	50	22	15
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	11 / 43 (25.58%)	7 / 43 (16.28%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	22	13	0	7
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	5 / 43 (11.63%)	4 / 43 (9.30%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	5	4	0	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	2	1	0	2
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	2	1	1	0
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	1	1	0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	1 / 3 (33.33%)	2 / 43 (4.65%)	3 / 43 (6.98%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	3	3	4	0	0
Perineal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 3 (33.33%)	2 / 43 (4.65%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	2	1	0	0
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	4 / 43 (9.30%)	4 / 43 (9.30%)	1 / 7 (14.29%)	2 / 24 (8.33%)
occurrences all number	1	4	4	1	2
Cough
subjects affected / exposed	1 / 3 (33.33%)	5 / 43 (11.63%)	7 / 43 (16.28%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences all number	1	7	8	1	1
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	1	1	0
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	4 / 43 (9.30%)	0 / 43 (0.00%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences all number	0	4	0	2	1
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	7 / 43 (16.28%)	6 / 43 (13.95%)	3 / 7 (42.86%)	2 / 24 (8.33%)
occurrences all number	0	8	6	3	2
Nightmare
subjects affected / exposed	1 / 3 (33.33%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	1	0	0	1	0
Distractibility
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	3 / 43 (6.98%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	2	6	0	8
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	3	0	0	0
Electrocardiogram T wave inversion
subjects affected / exposed	1 / 3 (33.33%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	4 / 43 (9.30%)	2 / 43 (4.65%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	6	4	0	0
Weight decreased
subjects affected / exposed	2 / 3 (66.67%)	5 / 43 (11.63%)	16 / 43 (37.21%)	2 / 7 (28.57%)	4 / 24 (16.67%)
occurrences all number	2	6	20	2	5
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	4 / 43 (9.30%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	6	4	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	3	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	2 / 43 (4.65%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	3	2	1	0
Blood calcium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	1	0	0	5
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	2 / 43 (4.65%)	1 / 7 (14.29%)	3 / 24 (12.50%)
occurrences all number	0	0	2	1	4
Fall
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	3 / 43 (6.98%)	1 / 7 (14.29%)	3 / 24 (12.50%)
occurrences all number	0	3	4	5	6
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	0	1	0	5
Humerus fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	1	0	2
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	3 / 43 (6.98%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	2	3	0	1
Dizziness
subjects affected / exposed	1 / 3 (33.33%)	4 / 43 (9.30%)	5 / 43 (11.63%)	0 / 7 (0.00%)	5 / 24 (20.83%)
occurrences all number	1	4	5	0	6
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	3 / 43 (6.98%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	3	3	0	2
Headache
subjects affected / exposed	0 / 3 (0.00%)	4 / 43 (9.30%)	3 / 43 (6.98%)	1 / 7 (14.29%)	6 / 24 (25.00%)
occurrences all number	0	6	5	1	7
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	4 / 43 (9.30%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences all number	0	2	4	2	1
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	3	0	0	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	4 / 43 (9.30%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	6	2	1	0
Somnolence
subjects affected / exposed	1 / 3 (33.33%)	0 / 43 (0.00%)	0 / 43 (0.00%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	1	0	0	0	2
Taste disorder
subjects affected / exposed	1 / 3 (33.33%)	3 / 43 (6.98%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	1	3	1	1	0
Restless legs syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences all number	0	2	0	1	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	1	5	0
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	1 / 7 (14.29%)	2 / 24 (8.33%)
occurrences all number	0	1	0	1	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 3 (33.33%)	19 / 43 (44.19%)	15 / 43 (34.88%)	2 / 7 (28.57%)	4 / 24 (16.67%)
occurrences all number	1	52	57	7	5
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	3 / 43 (6.98%)	1 / 7 (14.29%)	3 / 24 (12.50%)
occurrences all number	0	1	6	4	4
Lymphadenopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	2	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	2 / 43 (4.65%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	1	3	0	3
Constipation
subjects affected / exposed	1 / 3 (33.33%)	14 / 43 (32.56%)	11 / 43 (25.58%)	5 / 7 (71.43%)	5 / 24 (20.83%)
occurrences all number	2	16	12	8	5
Abdominal discomfort
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	1	0	0	1
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	3 / 7 (42.86%)	0 / 24 (0.00%)
occurrences all number	0	0	1	3	0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	9 / 43 (20.93%)	9 / 43 (20.93%)	2 / 7 (28.57%)	3 / 24 (12.50%)
occurrences all number	0	14	15	2	5
Nausea
subjects affected / exposed	2 / 3 (66.67%)	12 / 43 (27.91%)	11 / 43 (25.58%)	4 / 7 (57.14%)	8 / 24 (33.33%)
occurrences all number	2	21	13	6	11
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	10 / 43 (23.26%)	10 / 43 (23.26%)	2 / 7 (28.57%)	3 / 24 (12.50%)
occurrences all number	1	14	16	4	3
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	0 / 43 (0.00%)	3 / 43 (6.98%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences all number	5	0	3	0	1
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	1	1	1	0
Anal incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	2	0
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	2	0	1	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	1	0	1	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Gingival pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	1	1	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	1 / 3 (33.33%)	5 / 43 (11.63%)	2 / 43 (4.65%)	1 / 7 (14.29%)	2 / 24 (8.33%)
occurrences all number	2	5	2	2	2
Pruritus
subjects affected / exposed	1 / 3 (33.33%)	2 / 43 (4.65%)	8 / 43 (18.60%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	2	2	10	0	3
Rash
subjects affected / exposed	0 / 3 (0.00%)	6 / 43 (13.95%)	6 / 43 (13.95%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences all number	0	7	11	1	3
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	1 / 24 (4.17%)
occurrences all number	0	0	0	3	1
Erythema
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	1	0	0	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 3 (33.33%)	3 / 43 (6.98%)	3 / 43 (6.98%)	0 / 7 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	3	3	0	1
Urinary retention
subjects affected / exposed	1 / 3 (33.33%)	2 / 43 (4.65%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	2	2	0	0
Pollakiuria
subjects affected / exposed	1 / 3 (33.33%)	3 / 43 (6.98%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	3	3	1	0	0
Haematuria
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	6 / 43 (13.95%)	1 / 7 (14.29%)	2 / 24 (8.33%)
occurrences all number	3	1	10	3	4
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	1	1	0	2
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	3 / 43 (6.98%)	2 / 7 (28.57%)	2 / 24 (8.33%)
occurrences all number	0	2	3	2	3
Myalgia
subjects affected / exposed	1 / 3 (33.33%)	2 / 43 (4.65%)	5 / 43 (11.63%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	3	2	6	1	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	3 / 43 (6.98%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	1	4	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	4 / 43 (9.30%)	1 / 7 (14.29%)	3 / 24 (12.50%)
occurrences all number	0	3	6	2	4
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	5 / 43 (11.63%)	2 / 43 (4.65%)	2 / 7 (28.57%)	3 / 24 (12.50%)
occurrences all number	0	6	3	2	3
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	4 / 43 (9.30%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	3	4	0	4
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	2 / 43 (4.65%)	0 / 7 (0.00%)	4 / 24 (16.67%)
occurrences all number	0	1	2	0	6
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	6 / 43 (13.95%)	2 / 43 (4.65%)	1 / 7 (14.29%)	2 / 24 (8.33%)
occurrences all number	0	9	4	1	2
Back pain
subjects affected / exposed	1 / 3 (33.33%)	17 / 43 (39.53%)	13 / 43 (30.23%)	3 / 7 (42.86%)	12 / 24 (50.00%)
occurrences all number	1	27	24	6	21
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	10 / 43 (23.26%)	7 / 43 (16.28%)	2 / 7 (28.57%)	6 / 24 (25.00%)
occurrences all number	0	15	8	2	7
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	19 / 43 (44.19%)	13 / 43 (30.23%)	4 / 7 (57.14%)	14 / 24 (58.33%)
occurrences all number	0	32	22	5	17
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	2 / 7 (28.57%)	1 / 24 (4.17%)
occurrences all number	0	0	0	2	1
Sacral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	1 / 43 (2.33%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	2	1	0
Infections and infestations
Viral infection
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	2	0	0	0
Urinary tract infection
subjects affected / exposed	2 / 3 (66.67%)	5 / 43 (11.63%)	3 / 43 (6.98%)	1 / 7 (14.29%)	4 / 24 (16.67%)
occurrences all number	3	7	5	2	5
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 43 (2.33%)	6 / 43 (13.95%)	0 / 7 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	1	7	0	3
Oral candidiasis
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	2 / 43 (4.65%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	2	1	2	0	0
Nasopharyngitis
subjects affected / exposed	1 / 3 (33.33%)	5 / 43 (11.63%)	4 / 43 (9.30%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	1	5	6	0	2
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	3 / 43 (6.98%)	3 / 43 (6.98%)	2 / 7 (28.57%)	1 / 24 (4.17%)
occurrences all number	0	4	3	2	1
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Infected skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 43 (0.00%)	0 / 43 (0.00%)	1 / 7 (14.29%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0
Metabolism and nutrition disorders
Hypophosphataemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	0 / 43 (0.00%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	2	0	0	0
Hyponatraemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 43 (2.33%)	1 / 43 (2.33%)	0 / 7 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	3	8	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	3 / 43 (6.98%)	0 / 7 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	3	16	0	2
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 43 (4.65%)	3 / 43 (6.98%)	0 / 7 (0.00%)	4 / 24 (16.67%)
occurrences all number	0	3	3	0	7
Decreased appetite
subjects affected / exposed	3 / 3 (100.00%)	26 / 43 (60.47%)	26 / 43 (60.47%)	3 / 7 (42.86%)	9 / 24 (37.50%)
occurrences all number	6	35	43	5	11

More information

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Were there any global substantial amendments to the protocol? Yes

11 Sep 2014

Amendment 1: At the request of the Medicines and Healthcare products Regulatory Agency (MHRA), the option of de-escalation of the enzalutamide dose in Phase 1b was removed. Furthermore, the use of contraception for patients and their partners during the study was clarified and expanded. This amendment was issued before the first patient was recruited for the trial. The amendment was implemented after approval of the Institutional review board (IRB)/ (Independent ethics committee) IEC/ Competent Authorities.

20 Mar 2015

Amendment 2 (Part 1): This amendment was issued before commencing the Phase Ib expansion part and the Phase II part of the trial. It was implemented after approval of the IRB/IEC/Competent Authorities. To bring the Phase Ib expansion part in line with US practice, patients entering the expansion cohort were no longer allowed to have received prior taxane therapy. Furthermore, several inclusion/exclusion criteria were updated. Reasons were the change of the patient population in the expansion cohort, updating according to the current enzalutamide Summary of product characteristics (SmPC), and site feedback. Bone scans were made mandatory at screening, and should then be followed up every 12 weeks if clinically indicated. In the previous version of the protocol bone scans were only required at screening if clinically indicated. The requirement for an additional Computed tomography (CT) scan 6 weeks later to confirm progression was removed if progression was seen at the first tumour assessment. This update was in line with RECIST 1.1 requirements.

20 Mar 2015

Amendment 2 (Part 2): The requirements for fresh tissue biopsies changed. From this point onwards, they were only mandatory at baseline and Cycle 1 Day 15 and then optional at End of treatment (EOT) for the Phase Ib expansion cohort and optional at all time points in Phase II. This was changed to allow more flexibility for patients. An additional blood sample was added at Cycle 4 Day 1 to collect circulating DNA. The handling of restricted medications was updated in line with the current enzalutamide SmPC. Originally, the Clinical Trial Protocol (CTP) contained an exhaustive list of CYP inducers/inhibitors and substrates and investigators needed to get approval from Boehringer Ingelheim (BI) to keep patient on one of these medications. The CTP was updated to refer investigators to the enzalutamide SmPC to make a decision on whether a patient should stay on any medications involving the CYP pathway. After elective surgery, patients were now allowed to restart treatment within 3 d as there had not been concern with wound healing following treatment with xentuzumab. The quality of life questionnaire Functional Assessment of Cancer Therapy-Prostate (FACT-P) was added to the Phase II part of the trial at several time points as it was considered important to collect this data to compare quality of life between the two treatment arms.

09 Apr 2015

Amendment 3: Exclusion criterion no. 22 was re-written by Amendment 2 (formerly exclusion criterion no. 1) as the original wording in the CTP was considered unclear. In error the new language was worded as an inclusion criterion rather than an exclusion criterion. This was corrected by Amendment 3. This amendment was issued before commencing the Phase Ib expansion part and the Phase II part of the trial. The amendment was implemented after approval of the IRB/IEC/Competent Authorities.

15 Sep 2015

Amendment 4 (Part 1): This amendment was issued before commencing the Phase Ib expansion part and the Phase II part of the trial. It was implemented after approval of the IRB/IEC/Competent Authorities. The primary endpoint of the Phase II part was changed from Progression-free survival (PFS) assessed by central imaging to PFS assessed by investigator. The change was based on data available from the Phase Ib dose escalation part of the trial as well as feedback on the discrepancy seen between central imaging and investigator assessment in other prostate cancer trials. This raised concern that the planned number of 90 PFS events might not be met. As this was a Phase II trial, PFS assessed by central imaging was not required as a primary endpoint. PFS assessed by central imaging was made a secondary endpoint. The frequency of the imaging assessments, both CT/Magnetic resonance imaging (MRI) and bone scans was changed from being at baseline and thereafter every 12 weeks to baseline and then every 8 weeks until Week 24 (Week 8, Week 16, Week 24) and then every 12 weeks thereafter. This change was implemented based on data showing the PFS for this type of patient is around 3-5 months and therefore it was important to be able to capture any early progressions. Circulating tumour cells (CTC), Prostate-specific antigen (PSA) and FACT-P assessments were amended in line with the imaging assessments so that efficacy assessments were performed at the same time points.

15 Sep 2015

Amendment 4 (Part 2): Inclusion criterion no. 6 was changed to only allow patients with Eastern Cooperative Oncology Group (ECOG) 0 and 1 in the trial and no longer allow patients with ECOG 2. The rationale for this change was that patients should be fit enough to manage weekly infusions and be able to stay on treatment for long enough to potentially receive benefit. To avoid unnecessary Serious adverse event (SAE) reporting, it was added that an adverse event (AE) did not meet the SAE criteria for hospitalization if the patient was treated in the emergency room but was not admitted for an overnight stay, if they were hospitalized for diagnostic reasons without AE, or if the hospitalization was due to pre-planned treatments or procedures, social circumstances, or administrative reasons. For the same reason, an exemption was added so that disease progression unrelated to treatments no longer needed to be reported. These changes were implemented according to updated company standards. The section on the primary analysis was updated to allow analysis to be performed in the case that 90 radiological progression events are not reached. If it became foreseeable that 90 PFS events would not be reached, analysis for PFS was to be performed around 23 months after the first patient had been randomised in the Phase II part. The scheduling of the pharmacogenomic sample was changed and an additional sample was added at Cycle 3 Day 1. For this protocol version, a note to file was issued to document an error in an appendix table showing the time points of Pharmacokinetics (PK) and biomarker sample collection. The correct information was available in the flow chart and the main part of the clinical trial report (CTR) as well as in the laboratory manual and PK/ Pharmacodynamics (PD) worksheets that were distributed to the investigational sites.

19 Nov 2015

Amendment 5: Based on feedback from the FDA, two changes were implemented: Firstly, the number of patients in the Phase Ib expansion part was changed from at least 21 to 25 to ensure that 21 evaluable patients would be available for analysis. And secondly, an exclusion criterion was added for the Phase Ib expansion part to exclude patients who were in immediate need of chemotherapy (e.g. for visceral disease, or intractable pain). The amendment was implemented after approval of the IRB/IEC/Competent Authorities.

31 May 2016

Amendment 6: Due to new statistical estimations, a project level decision, and new project standards, the number of patients in the Phase II part was changed from 120 to 80 with the number of targeted PFS events decreased from 90 to 60 events. Furthermore, in- and exclusion criteria were updated to address changes in PSA and international normalised ratio (INR) value requirements. Luteinizing hormone releasing hormone (LHRH) antagonists were added as an accepted concomitant treatment during the trial. The amendment was implemented after approval of the IRB/IEC/Competent Authorities.

06 Feb 2018

Amendment 7: This amendment involved logistical or administrative aspects only. It was implemented without IRB/IEC/Competent Authority approval.

15 Jul 2019

Amendment 8: Amendment 8 was issued when all data required to achieve the trial objectives had been collected. The amount of procedures and data collected was reduced: procedures were limited to those necessary to continue with trial treatment; data collection was limited to those data necessary to ensure patient safety and to support safety reporting to authorities. However, CTP version 9 (based on Amendment 8) was rejected by a health authority because, as patients were on experimental therapy, the safety laboratory tests should be clearly defined in the CTP rather than being per standard of care. CTP Version 9 was therefore not implemented by any sites with ongoing patients.

13 Sep 2019

Amendment 9: Instead the CTP was updated to Version 10 (based on Amendment 9) to include safety lab testing on Day 1 of every cycle, at EOT, and at the follow-up visit for all patients ongoing on trial treatment.

11 Aug 2020

Amendment 10: CTP updated to provide additional guidance in response to the COVID-19 pandemic to ensure patient's safety by decreasing patient visits to site if needed by permitting direct shipment of enzalutamide from site to patient, local safety lab analyses and remote patient visits.

06 Jun 2022

Amendment 11: CTP updated to include the rationale for discontinuation of the clinical development program with xentuzumab in Castration-resistant prostate cancer (CRPC), including how the trial would proceed towards termination.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase Ib expansion part: Prostate Specific Antigen (PSA) response

Primary: Phase Ib expansion part: Prostate Specific Antigen (PSA) response

Primary: Phase Ib escalation part: Number of patients with dose limiting toxicities (DLTs)

Primary: Phase Ib escalation part: Number of patients with dose limiting toxicities (DLTs)

Primary: Phase 1b esclation part: Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course

Primary: Phase 1b esclation part: Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course

Primary: Phase II part: Progression Free Survival (PFS) based on investigator assessment

Primary: Phase II part: Progression Free Survival (PFS) based on investigator assessment

Secondary: Phase Ib expansion part: Progression free survival (PFS) based on investigator assessment

Secondary: Phase Ib expansion part: Progression free survival (PFS) based on investigator assessment

Secondary: Phase II part: Overall survival (OS)

Secondary: Phase II part: Overall survival (OS)

Secondary: Phase Ib expansion part: Changes in circulating tumour cells (CTC) response – CTC reduction from >=5 to <5 cells per 7.5 mL blood for at least one post-baseline time point

Secondary: Phase Ib expansion part: Changes in circulating tumour cells (CTC) response – CTC reduction from >=5 to <5 cells per 7.5 mL blood for at least one post-baseline time point

Secondary: Phase II part: Radiological Progression Free Survivial (PFS), based on central review

Secondary: Phase II part: Radiological Progression Free Survivial (PFS), based on central review

Secondary: Phase II part: Maximum decline in Prostate Specific Antigen (PSA)

Secondary: Phase II part: Maximum decline in Prostate Specific Antigen (PSA)

Secondary: Phase II part: Time to Prostate Specific Antigen (PSA) progression

Secondary: Phase II part: Time to Prostate Specific Antigen (PSA) progression

Secondary: Phase II part: Percentage change in Prostate Specific Antigen (PSA) at Week 12

Secondary: Phase II part: Percentage change in Prostate Specific Antigen (PSA) at Week 12

Secondary: Phase II part: Prostate Specific Antigen (PSA) response

Secondary: Phase II part: Prostate Specific Antigen (PSA) response

Secondary: Phase II part: Circulating tumour cells (CTC) reduction defined as CTC decline from ≥5 to <5 cells per 7.5 mL blood for at least one post-baseline time-point

Secondary: Phase II part: Circulating tumour cells (CTC) reduction defined as CTC decline from ≥5 to <5 cells per 7.5 mL blood for at least one post-baseline time-point

Secondary: Phase II part: Circulating tumour cells (CTC) status at Week 12

Secondary: Phase II part: Circulating tumour cells (CTC) status at Week 12

Secondary: Phase II part: Maximum decline (%) in circulating tumour cells (CTC) counts

Secondary: Phase II part: Maximum decline (%) in circulating tumour cells (CTC) counts

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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