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    Clinical Trial Results:
    A Phase 2, Single-Arm, Open-Label, Multicenter Study of the Clinical Activity and Safety of Enzalutamide in Subjects With Advanced, Androgen Receptor-Positive, Triple-Negative Breast Cancer.

    Summary
    EudraCT number
    2013-000698-57
    Trial protocol
    GB   BE   IT   IE   ES  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Aug 2018
    First version publication date
    11 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MDV3100-11
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01889238
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Alias identifier: MDV3100-11
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer, Inc., Pfizer ClinicalTrials.gov Call Center, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_inquiries@pfizer.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
    Interim
    Date of interim/final analysis
    28 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To determine the clinical benefit rate, defined as the proportion of evaluable subjects with androgen receptor positive (AR+) triple negative breast cancer (TNBC) with a best response of complete response (CR), partial response (PR), or stable disease greater than or equal (≥) 16 weeks
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jun 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 74
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    118
    EEA total number of subjects
    35
    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)
    74
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted at 34 centres in 7 countries. Data reported based on primary analysis date (01 March 2015).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Enzalutamide
    Arm description
    Subjects received enzalutamide 160 milligram (mg) (as four 40 mg soft gelatin capsules), orally once daily until disease progression (DP), intolerable adverse events (AEs) (including any seizures), noncompliance with protocol requirements, initiation of a new antitumor treatment, or subjectt or physician decision to discontinue treatment (up to a maximum of 87 Weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was administered as four 40-mg soft gelatin capsules by mouth once daily.

    Number of subjects in period 1
    Enzalutamide
    Started
    118
    Completed
    109
    Not completed
    9
         Treatment ongoing
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    Subjects received enzalutamide 160 milligram (mg) (as four 40 mg soft gelatin capsules), orally once daily until disease progression (DP), intolerable adverse events (AEs) (including any seizures), noncompliance with protocol requirements, initiation of a new antitumor treatment, or subjectt or physician decision to discontinue treatment (up to a maximum of 87 Weeks).

    Reporting group values
    Enzalutamide Total
    Number of subjects
    118 118
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    74 74
        From 65-84 years
    44 44
        85 years and over
    0 0
    Age Continuous
    Age Continuous is provided for treated subjects only
    Units: years
        arithmetic mean (standard deviation)
    58.3 ± 12.95 -
    Sex: Female, Male
    Units: Subjects
        Female
    118 118
        Male
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    Subjects received enzalutamide 160 milligram (mg) (as four 40 mg soft gelatin capsules), orally once daily until disease progression (DP), intolerable adverse events (AEs) (including any seizures), noncompliance with protocol requirements, initiation of a new antitumor treatment, or subjectt or physician decision to discontinue treatment (up to a maximum of 87 Weeks).

    Primary: Percentage of Subjects With Clinical Benefit (CB) at Week 16: Evaluable Population

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    End point title
    Percentage of Subjects With Clinical Benefit (CB) at Week 16: Evaluable Population [1]
    End point description
    CB at Week 16:best response of complete response (CR), partial response(PR),stable disease(SD) for>=16 weeks on radiologic imaging per Investigator using RECIST 1.1. Estimate of percentage, its exact 2-sided 85% confidence interval were calculated by Blaker method. CR: disappearance of all target, non-target lesions, normalization of tumor marker level, all lymph nodes decreased to non-pathological in size <10mm short axis. PR: >=30% decrease in sum of longest diameter (LD) of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using smallest sum diameters during study as a reference. Evaluable population: enrolled subjects with centrally assessed AR + breast cancer (total nuclear AR expression in >= 10% of tumor cells), had at least 1 dose of study drug with >=1 available post baseline tumor assessment per RECIST 1.1.
    End point type
    Primary
    End point timeframe
    Week 16
    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: Only descriptive data was planned to be analyzed for the endpoint
    End point values
    Enzalutamide
    Number of subjects analysed
    78
    Units: percentage of subjects
        number (confidence interval 85%)
    33.3 (25.53 to 41.63)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Clinical Benefit (CB) at Week 16: Intent-to-Treat (ITT) Population

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    End point title
    Percentage of Subjects With Clinical Benefit (CB) at Week 16: Intent-to-Treat (ITT) Population [2]
    End point description
    Clinical benefit at Week 16 defined as percentage of subjects with a best response of CR, PR, or SD for >= 16 weeks on radiologic imaging based on Investigator assessment using RECIST 1.1. An estimate of % and its exact 2-sided 85% CI were calculated using Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size<10 mm short axis. PR: >=30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using smallest sum diameters during study as a reference. ITT population included all enrolled participants who had centrally assessed AR+ breast cancer and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 16
    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: Only descriptive data was planned to be analyzed for the endpoint
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: percentage of subjects
        number (confidence interval 85%)
    24.6 (18.98 to 30.88)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Benefit at Week 24: Evaluable Population

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    End point title
    Percentage of Subjects With Clinical Benefit at Week 24: Evaluable Population
    End point description
    Percentage of subjects with a clinical benefit at Week 24 defined as percentage of subjects with a best response of CR, PR, or SD for >= 24 weeks on radiologic imaging based on investigator assessment using RECIST 1.1. An estimate of the percentage and its exact 2-sided 85% CI were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size <10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference. Evaluable population set was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Enzalutamide
    Number of subjects analysed
    78
    Units: percentage of subjects
        number (confidence interval 85%)
    28.2 (21.04 to 36.48)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Benefit at Week 24: ITT Population

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    End point title
    Percentage of Subjects With Clinical Benefit at Week 24: ITT Population
    End point description
    Clinical benefit at Week 24 defined as percentage of subjects with a best response of CR, PR, or SD for >= 24 weeks on radiologic imaging based on investigator assessment using RECIST 1.1. An estimate of the percentage and its exact 2-sided 85% CI were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size <10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference. ITT population set was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: percentage of subjects
        number (confidence interval 85%)
    20.3 (15.16 to 26.21)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Objective Response: Evaluable Population

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    End point title
    Percentage of Subjects With Best Objective Response: Evaluable Population
    End point description
    Percentage of subjects with best objective response defined as percentage of subjects with a best response of CR and PR based on investigator assessment of target, non-target and new lesions using RECIST 1.1. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in <10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. Analysis was performed on subjects from Evaluable population who had measurable disease.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression or death due to any cause (up to 87 Weeks)
    End point values
    Enzalutamide
    Number of subjects analysed
    59
    Units: percentage of subjects
        number (confidence interval 85%)
    8.5 (3.05 to 12.02)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Objective Response: ITT Population

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    End point title
    Percentage of Subjects With Best Objective Response: ITT Population
    End point description
    Percentage of subjects with best objective response defined as percentage of subjects with a best response of CR and PR based on investigator assessment of target, non-target and new lesions using RECIST 1.1. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in <10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. Analysis was performed on subjects from ITT population who had measurable disease.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression or death due to any cause (up to 87 Weeks)
    End point values
    Enzalutamide
    Number of subjects analysed
    97
    Units: percentage of subjects
        number (confidence interval 85%)
    6.2 (2.80 to 8.95)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS): Evaluable Population

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    End point title
    Progression-Free Survival (PFS): Evaluable Population
    End point description
    PFS was defined as the time (in weeks) from the date of first dose of study drug to the date of documented disease progression or death due to any cause whichever occurs first as determined by the investigator using RECIST 1.1. As per RECIST 1.1, progression was defined as: >=20 percent increase in sum of LD of target lesions taking as a reference the smallest sum of the LD recorded since the treatment started, or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions. Evaluable population included all enrolled subjects who had centrally assessed AR + breast cancer (total nuclear AR expression in >= 10% of tumor cells), had at least 1 dose of study drug and had at least 1 available post baseline tumor assessment evaluable as per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression or death due to any cause (up to 87 Weeks)
    End point values
    Enzalutamide
    Number of subjects analysed
    78
    Units: weeks
        median (confidence interval 85%)
    14.3 (8.3 to 16.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival: ITT Population

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    End point title
    Progression-Free Survival: ITT Population
    End point description
    PFS was defined as the time (in weeks) from the date of first dose of study drug to the date of documented disease progression or death due to any cause whichever occurs first as determined by the investigator using RECIST 1.1. As per RECIST 1.1, progression was defined as: >=20 percent increase in sum of LD of target lesions taking as a reference the smallest sum of the LD recorded since the treatment started, or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions. ITT population included all enrolled subjects who had centrally assessed AR+ breast cancer and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression or death due to any cause (up to 87 Weeks)
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: weeks
        median (confidence interval 85%)
    12.6 (8.1 to 15.1)
    No statistical analyses for this end point

    Other pre-specified: Trough Plasma Concentration of Enzalutamide and its Metabolite

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    End point title
    Trough Plasma Concentration of Enzalutamide and its Metabolite
    End point description
    M2 was the metabolite of enzalutamide. The lower limit of of quantitation (LLQ) was 0.0200 micrograms per milliliter (mcg/ml) for enzalutamide and M2. Pharmacokinetics (PK) analysis population included all subjects who received 1 dose or partial dose of study drug, and who had at least 1 enzalutamide or M2 plasma concentration assessment. Here, "99999" signifies that none of the subjects ts had data above LLQ and as per the predefined protocol, values below the limit of quatitation (BLQ) were set to missing and hence not reported.
    End point type
    Other pre-specified
    End point timeframe
    Predose on Day 1 (Baseline), Week 9 and Week 17
    End point values
    Enzalutamide
    Number of subjects analysed
    115
    Units: mcg/ml
    geometric mean (geometric coefficient of variation)
        Enzalutamide Day 1
    99999 ± 99999
        M2 Day 1
    99999 ± 99999
        Enzalutamide Week 9
    12.59 ± 33.46
        M2 Week 9
    13.48 ± 35.64
        Enzalutamide Week 17
    12.79 ± 37.33
        M2 Week 17
    13.88 ± 25.47
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AEs was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent are events between first dose of study drug and up to 87 weeks that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs. Safety population included all subjects who received 1 dose or partial dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 87 weeks
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: subjects
        Adverse Events
    109
        Serious Adverse Events
    29
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Study Drug Discontinuation due to Adverse Events

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    End point title
    Number of Subjects With Study Drug Discontinuation due to Adverse Events
    End point description
    Safety population included all subjects who received 1 dose or partial dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 87 weeks
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: subjects
    8
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs

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    End point title
    Number of Subjects With Clinically Significant Change From Baseline in Vital Signs
    End point description
    Criteria: Systolic blood pressure (SBP):absolute SBP<90 millimeters of mercury (mmHg) and decrease from baseline (DFB)>30mmHg, absolute SBP>180mmHg and increase from baseline (IFB)>40 mmHg, final visit or 2 consecutive visits SBP>=20 mmHg change from baseline (CFB), most extreme post-baseline SBP>=140mmHg, most extreme post-baseline SBP>=180mmHg, most extreme SBP>=140mmHg and>=20 mmHg CFB, most extreme SBP>=180mmHg and>=20mmHg CFB; diastolic blood pressure (DBP): absolute DBP>105mmHg and IFB>30mmHg, absolute DBP<50mmHg and DFB>20mmHg, final visit or 2 consecutive visits DBP>=15mmHg CFB, most extreme post-baseline DBP>=90mmHg, most extreme post-baseline DBP>=105mmHg, most extreme DBP>=90mmHg and>=15mmHg CFB, most extreme DBP>=105mmHg and>=15mmHg CFB; heart rate<50beats per minute (BPM) and DFB>20BPM or heart rate>120BPM and IFB>30BPM. Only those categories, in which at least 1 subject had data were reported. Safety population set was used in the analysis.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 87 weeks
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: subjects
        SBP: absolute SBP <90 mmHg and DFB>30 mmHg
    1
        SBP: FV or 2 CV SBP>=20 mmHg CFB
    9
        SBP: Most extreme post baseline SBP >=140 mmHg
    36
        SBP: Most extreme post baseline SBP >=180 mmHg
    1
        SBP:Most extreme SBP>=140 mmHg and>=20 mmHg CFB
    11
        DBP: FV or 2 CV DBP>=15 mmHg CFB
    10
        DBP: Most extreme post baseline result >=90 mmHg
    22
        DBP: Most extreme post baseline result >=105 mmHg
    4
        DBP:Most extreme DBP>=105 mmHg and>=15 mmHg CFB
    2
        DBP:Most extreme DBP>=90 mmHg and>=15 mmHg CFB
    12
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Grade 3 or Higher Adverse Events

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    End point title
    Number of Subjects With Grade 3 or Higher Adverse Events
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. As per the NCI CTCAE, version 4.0, Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening and Grade 5= death. Only the subjects with treatment-emergent AEs of Grade 3 (severe) or higher grade were reported in this endpoint. Safety population included all subjects who received 1 dose or partial dose of study drug
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 87 weeks
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: subjects
    36
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Change From Baseline in Laboratory Parameters Grades by 2 or More Grades

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    End point title
    Number of Participants With Change From Baseline in Laboratory Parameters Grades by 2 or More Grades
    End point description
    Laboratory tests included hematology parameters (low lymphocytes, WBC, neutrophils, hemoglobin and platelets) and chemistry parameters (mean albumin, Blood urea nitrogen [BUN], calcium, Lactate dehydrogenase [LDH], alanine aminotransferase, Aspartate aminotransferase , bilirubin, Alkaline phosphatase, creatinine and glucose). Number of participants with change from baseline in laboratory parameters Grades by 2 or More Grades as per National Cancer Institute Common Terminology Criteria (NCI CTC) (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) were reported. Safety population included all participants who receive 1 dose or partial dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 87 weeks
    End point values
    Enzalutamide
    Number of subjects analysed
    118
    Units: subjects
        Hemoglobin
    1
        Leukocytes
    4
        Lymphocytes
    12
        Neutrophils
    2
        Platelets
    1
        Alanine aminotransferase
    1
        Albumin
    4
        Alkaline phosphatase
    3
        Bilirubin
    2
        Calcium
    2
        Glucose
    5
        Phosphate
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 87 weeks
    Adverse event reporting additional description
    Same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject or one subject may have experienced both a serious and non-serious event during the study. AEs and SAEs were collected for safety population.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    Subjects received enzalutamide 160 mg (as four 40 mg soft gelatin capsules), orally once daily until disease progression, intolerable AEs (including any seizures), noncompliance with protocol requirements, initiation of a new antitumor treatment, or subject or physician decision to discontinue treatment (up to a maximum of 87 Weeks).

    Serious adverse events
    Enzalutamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 118 (24.58%)
         number of deaths (all causes)
    12
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    3 / 118 (2.54%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Metastatic pain
         subjects affected / exposed
    3 / 118 (2.54%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pericardial effusion malignant
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Myocardial infarction
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    3 / 118 (2.54%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Pleuritic pain
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    3 / 118 (2.54%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pain
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Enzalutamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 118 (84.75%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    12 / 118 (10.17%)
         occurrences all number
    13
    Investigations
    Weight decrease
         subjects affected / exposed
    8 / 118 (6.78%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    13 / 118 (11.02%)
         occurrences all number
    15
    Cough
         subjects affected / exposed
    7 / 118 (5.93%)
         occurrences all number
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 118 (14.41%)
         occurrences all number
    17
    Neuropathy peripheral
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    6
    Dizziness
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    49 / 118 (41.53%)
         occurrences all number
    64
    Pain
         subjects affected / exposed
    9 / 118 (7.63%)
         occurrences all number
    9
    Asthenia
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 118 (14.41%)
         occurrences all number
    17
    Anxiety
         subjects affected / exposed
    7 / 118 (5.93%)
         occurrences all number
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    40 / 118 (33.90%)
         occurrences all number
    51
    Diarrhoea
         subjects affected / exposed
    18 / 118 (15.25%)
         occurrences all number
    22
    Constipation
         subjects affected / exposed
    18 / 118 (15.25%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    11 / 118 (9.32%)
         occurrences all number
    14
    Abdominal pain
         subjects affected / exposed
    7 / 118 (5.93%)
         occurrences all number
    7
    Reproductive system and breast disorders
    Breast Pain
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 118 (14.41%)
         occurrences all number
    23
    Arthralgia
         subjects affected / exposed
    17 / 118 (14.41%)
         occurrences all number
    19
    Pain in extremity
         subjects affected / exposed
    9 / 118 (7.63%)
         occurrences all number
    16
    Muscle spasms
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    7
    Musculoskeletal pain
         subjects affected / exposed
    10 / 118 (8.47%)
         occurrences all number
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    22 / 118 (18.64%)
         occurrences all number
    23
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    6
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 118 (5.08%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Oct 2013
    1- Modified to require head imaging using magnetic resonance imaging (MRI) with contrast to rule out central nervous system (CNS) metastatic disease; head computed tomography (CT) with contrast could be considered after discussion with the medical monitor. Instructions for head imaging were provided for subjects enrolled before this amendment. 2- Increased the sample size from 80 to 95 subjects to ensure an adequate number of evaluable subjects for the primary and secondary efficacy endpoint analyses. 3- Modified exclusion criterion 10 to remove the option of using a creatinine clearance estimation by Cockcroft Gault. Renal function was to be assessed using a single parameter (serum creatinine) to enable analysis by common terminology criteria for adverse events (CTCAE) severity grading. 4- Clarified that modalities other than radiographic methods (such as physical examination) could be used for disease status assessments per RECIST 1.1; positron emission tomography (PET) imaging was not to be used. 5- Clarified that the primary efficacy endpoint of clinical benefit rate at 16 weeks was to be based on investigator determination of response using RECIST 1.1. 6- Provided guidance for late doses and updated the directions for dose modification. 7- Added instructions for reporting pregnancies. 8- Removed requirements for reporting certain adverse events as serious.

    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.
    As per change in planned analysis, AR low population (all enrolled subjects who had AR nuclear staining > 0%, < 10% assessed centrally) was not analyzed for efficacy and duration of response, time to response were not analyzed for any population
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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