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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

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    Trial identification
    Sponsor protocol code
    1280.8
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02204072
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    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?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    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
    42
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    34
    From 65 to 84 years
    117
    85 years and over
    3

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    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
    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.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    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.

    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
    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.

    Arm title
    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
    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.

    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
    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.

    Arm title
    Phase Ib expansion: 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 expansion part.
    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
    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.

    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
    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.

    Arm title
    Phase II: 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 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
    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

    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
    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.

    Arm title
    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
    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.

    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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    Baseline characteristics reporting groups
    Reporting group title
    Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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 expansion part.

    Reporting group title
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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 II part.

    Reporting group title
    Phase II: 160 mg Enzalutamide
    Reporting group 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.

    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 sets

    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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    End points reporting groups
    Reporting group title
    Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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 expansion part.

    Reporting group title
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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 II part.

    Reporting group title
    Phase II: 160 mg Enzalutamide
    Reporting group 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.

    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 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 [1]
    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
    [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.
    End point values
    Xentuzumab + Enzalutamide
    Number of subjects analysed
    9
    Units: Milligram
    1000
    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) [2] [3]
    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
    [2] - 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.
    [3] - 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 Ib expansion part: Prostate Specific Antigen (PSA) response

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    End point title
    Phase Ib expansion part: Prostate Specific Antigen (PSA) response [4] [5]
    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
    [4] - 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.
    [5] - 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 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 title
    Statistical analysis
    Comparison groups
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide
    Number of subjects included in analysis
    86
    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: 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 [8]
    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
    [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%)
    3.6 (3.5 to 8.1)
    7.1 (3.6 to 8.2)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide
    Number of subjects included in analysis
    86
    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 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: Overall survival (OS)

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    End point title
    Phase II part: Overall survival (OS) [10]
    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
    [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%)
    13.6 (8.7 to 19.4)
    13.6 (8.7 to 21.3)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide
    Number of subjects included in analysis
    86
    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 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 [11]
    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
    [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
    43
    43
    Units: Months
        median (confidence interval 95%)
    4.6 (2.8 to 5.7)
    3.7 (2.8 to 4.6)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide
    Number of subjects included in analysis
    86
    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: Maximum decline in Prostate Specific Antigen (PSA)

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    End point title
    Phase II part: Maximum decline in Prostate Specific Antigen (PSA) [12]
    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
    [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
    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: 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 title
    Statistical Analysis
    Comparison groups
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide
    Number of subjects included in analysis
    44
    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: 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 [16]
    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
    [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
    32
    28
    Units: Percentage
        arithmetic mean (standard deviation)
    41.96 ( 289.085 )
    21.33 ( 201.353 )
    No statistical analyses for this end point

    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 [17]
    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
    [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
    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 title
    Statistical Analysis
    Comparison groups
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide v Phase II: 160 mg Enzalutamide
    Number of subjects included in analysis
    86
    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

    Adverse events

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    Adverse events information
    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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Phase Ib escalation: 750 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase II: 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase II: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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 II part.

    Reporting group title
    Phase Ib escalation: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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.

    Reporting group title
    Phase Ib expansion: 1000 mg Xentuzumab + 160 mg Enzalutamide
    Reporting group 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 expansion part.

    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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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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