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    Clinical Trial Results:
    A Phase II, Multicenter, Randomized Study To Compare The Efficacy Of Venetoclax Plus Fulvestrant Versus Fulvestrant In Women With Estrogen Receptor-Positive, HER2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy

    Summary
    EudraCT number
    		 2017-005118-74
    Trial protocol
    		 GB   DE  
    Global end of trial date
    06 May 2021

    Results information
    Results version number
    		 v4(current)
    This version publication date
    11 Oct 2022
    First version publication date
    05 Aug 2021
    Other versions
    		 v1 , v2 , v3
    Version creation reason
    • Correction of full data set
    Changes in adverse event section

    Trial information

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    Trial identification
    Sponsor protocol code
    WO40181
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03584009
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    06 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate and compare the efficacy of Venetoclax in combination with Fulvestrant versus Fulvestrant in Women with Estrogen Receptor-Positive, HER2-Negative locally advanced or Metastatic Breast Cancer
    Protection of trial subjects
    All study subjects were required to sign an Informed Consent Form
    Background therapy
    		 Subjects must not have received more than two prior lines of hormonal therapy in the locally advanced or metastatic setting. In addition, at least one line of treatment must be a CDK4/6i AND subjects must have experienced disease recurrence or progression during or after CDK4/6i therapy, which must have been administered for a minimum of 8 weeks prior to progression.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Sep 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    103
    EEA total number of subjects
    14
    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)
    72
    From 65 to 84 years
    30
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 38 centers in 5 countries.

    Pre-assignment
    Screening details
    		 A total of 103 subjects were randomized in this study. Of these, 101 subjects received at least one dose of any study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Venetoclax + Fulvestrant
    Arm description
    		 Subjects were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Venetoclax was administered orally QD at a dose of 800mg.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant was administered IM at a dose of 500mg (on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Arm title
    		 Fulvestrant
    Arm description
    		 Subjects were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant was administered IM at a dose of 500mg (on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Number of subjects in period 1
    		Venetoclax + Fulvestrant Fulvestrant
    Started
    51
    52
    Completed
    0
    0
    Not completed
    51
    52
         Physician decision
    1
    1
         Death
    25
    18
         Withdrawal by Subject
    3
    2
         Study Terminated by Sponsor
    22
    30
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Venetoclax + Fulvestrant
    Reporting group description
    		 Subjects were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Subjects were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Reporting group values
    		 Venetoclax + Fulvestrant Fulvestrant Total
    Number of subjects
    		 51 52 103
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.4 ± 10.6 58.8 ± 11.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 51 52 103
        Male
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 3 4
        Not Hispanic or Latino
    		 47 46 93
        Not Reported
    		 3 3 6
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 3 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 2 5
        White
    		 40 46 86
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Venetoclax + Fulvestrant
    Reporting group description
    		 Subjects were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Subjects were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Subject analysis set title
    Fulvestrant in Presence of Venetoclax
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Primary: Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) lasting >= 24 weeks, as determined by the Investigator according to RECIST v1.1

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    End point title
    		 Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) lasting >= 24 weeks, as determined by the Investigator according to RECIST v1.1
    End point description
    Clinical Benefit was defined as CR, PR, or SD lasting more than equal to 24 weeks from randomisation in participants with measurable disease at baseline, as determined by the investigator according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. Per RECIST v1.1 for target lesions assessed by CT or MRI: CR, Disappearance of all target lesions; PR, PR >= 30% decrease in the sum of diameters of target lesions (TL) taking as reference the baseline sum of diameters; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Disease Progression (PD), PD>= 20% increase in the sum of diameters of TL taking as reference the smallest sum on study (Nadir). In addition to the relative increase of 20% sum must have demonstrate an absolute increase of at least 5mm.
    End point type
    Primary
    End point timeframe
    Randomization through till 6 months after the last subject is enrolled into the study (up to approximately 23 months)
    End point values
    		 Venetoclax + Fulvestrant Fulvestrant
    Number of subjects analysed
    51
    51
    Units: Percentage of Subjects
        number (confidence interval 95%)
    11.8 (4.44 to 23.87)
    13.7 (5.70 to 26.26)
    Statistical analysis title
    		 (Venetoclax + Fulvestrant) vs Fulvestrant
    Comparison groups
    Venetoclax + Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7286 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.86
         upper limit
    		 12.94
    Notes
    [1] - P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Randomization through till 6 months after the last subject is enrolled into the study (up to approximately 23 months)
    End point values
    		 Venetoclax + Fulvestrant Fulvestrant
    Number of subjects analysed
    51
    52
    Units: Months
        median (confidence interval 95%)
    2.69 (1.94 to 3.71)
    1.94 (1.84 to 3.55)
    Statistical analysis title
    		 (Venetoclax + Fulvestrant) vs Fulvestrant
    Comparison groups
    Venetoclax + Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7853 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.45
    Notes
    [2] - P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).

    Secondary: Objective Response (OR)

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    End point title
    		 Objective Response (OR)
    End point description
    OR was defined as CR or PR, in subjects with measurable disease at baseline as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Randomization through till 6 months after the last subject is enrolled into the study (up to approximately 23 months)
    End point values
    		 Venetoclax + Fulvestrant Fulvestrant
    Number of subjects analysed
    51
    51
    Units: Percentage of Subjects
        number (confidence interval 95%)
    3.9 (0.48 to 13.46)
    5.9 (1.23 to 16.24)
    Statistical analysis title
    		 (Venetoclax + Fulvestrant) vs Fulvestrant
    Comparison groups
    Venetoclax + Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5978 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.29
         upper limit
    		 8.37
    Notes
    [3] - P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first. Here, 9999 = Insufficient number of subjects meant that Median, Lower Limit and Upper Limit values could not be estimated.
    End point type
    Secondary
    End point timeframe
    Time from first occurrence of a documented objective response to the first documented disease progression or death from any cause, whichever occurs first, until 6 months after the last subject is enrolled in the study (up to approximately 23 months)
    End point values
    		 Venetoclax + Fulvestrant Fulvestrant
    Number of subjects analysed
    2
    3
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    3.61 (1.94 to 9999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. ITT population included all randomized subjects whether or not they were assigned to the arm where the study treatment was administered. Here, 9999 signifies median and upper limit of confidence interval (CI) were not estimable due to fewer number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Randomization to death from any cause, through till the end of the study (Up to approximately 32 months)
    End point values
    		 Venetoclax + Fulvestrant Fulvestrant
    Number of subjects analysed
    51
    52
    Units: Months
        median (confidence interval 95%)
    19.71 (13.73 to 9999)
    9999 (20.93 to 9999)
    Statistical analysis title
    		 Venetoclax + Fulvestrant vs Fulvestrant
    Comparison groups
    Venetoclax + Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0403 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 3.43
    Notes
    [4] - P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).

    Secondary: Percentage of Subjects with Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study were also considered as AEs. Safety-evaluable population which included all subjects who received any amount of any component of the investigational or non-investigational study treatments.
    End point type
    Secondary
    End point timeframe
    Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months
    End point values
    		 Venetoclax + Fulvestrant Fulvestrant
    Number of subjects analysed
    50
    51
    Units: Percentage of Subjects
        number (not applicable)
    94.0
    76.5
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Venetoclax (in Presence of Fulvestrant)

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    End point title
    		 Plasma Concentrations of Venetoclax (in Presence of Fulvestrant) [5]
    End point description
    Pharmacokinetic (PK) evaluable population included all subjects who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. “n” = number analyzed is the number of subjects with data available for analyses at the given time-point. 9999 indicates not reportable for Geometric Coefficient of Variation for that timepoint where more than one-third values are lower than reportable.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 4 hours (hrs) post-dose; Cycle 2 Day 1: pre-dose (within 1 hr) and 2, 4, 6, 8 hrs post-dose; any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)
    Notes
    [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: No statistical analyses was planned for this end point.
    End point values
    		 Venetoclax + Fulvestrant
    Number of subjects analysed
    47
    Units: Micrograms per Millilitres (μg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1: 4 hrs post-dose (n=47)
    1.78 ± 61.8
        Cycle 2 Day 1: pre-dose (n=40)
    1.04 ± 85.4
        Cycle 2 Day 1: 2 hrs post-dose (n=39)
    1.45 ± 74.1
        Cycle 2 Day 1: 4 hrs post-dose (n=40)
    2.51 ± 57.2
        Cycle 2 Day 1: 6 hrs post-dose (n=35)
    3.32 ± 56.4
        Cycle 2 Day 1: 8 hrs post-dose (n=28)
    3.55 ± 57.8
        Treatment discontinuation visit (n=21)
    0.0112 ± 9999
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Fulvestrant (in Presence of Venetoclax)

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    End point title
    		 Plasma Concentrations of Fulvestrant (in Presence of Venetoclax)
    End point description
    PK evaluable population included all subjects who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. “n” = number analyzed is the number of subjects with data available for analyses at the given time-point.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1 and Cycle 6 Day 1: pre-dose (within 1 hr); any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)
    End point values
    		 Fulvestrant in Presence of Venetoclax
    Number of subjects analysed
    42
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1: pre-dose (n=42)
    0.0129 ± 37.1
        Cycle 6 Day 1: pre-dose (n=7)
    0.0145 ± 31.8
        Treatment discontinuation visit (n=28)
    0.00985 ± 29.1
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Fulvestrant (in Absence of Venetoclax)

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    End point title
    		 Plasma Concentrations of Fulvestrant (in Absence of Venetoclax) [6]
    End point description
    PK evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. “n” = number analyzed is the number of subjects with data available for analyses at the given time-point. 9999 indicates that the data for Geometric Coefficient of Variation was not estimable due to lower number of participants at given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1: pre-dose (within 1 hr); any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)
    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: No statistical analyses was planned for this end point.
    End point values
    		 Fulvestrant
    Number of subjects analysed
    5 [7]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1: pre-dose (n=5)
    0.0103 ± 29.4
        Treatment discontinuation visit (n=1)
    0.0139 ± 9999
    Notes
    [7] - Number of subject analysed are the subjects who were evaluated for the endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months.
    Adverse event reporting additional description
    1 additional death in Venetoclax+Fulvestrant compared to in Subject Disposition section,relates to participant who had withdrawn consent and later died.Their death reported in public records(reported as post-study reporting death). All-cause mortality=ITT population(Venetoclax+Fulvestrant=51,Fulvestrant=52); serious and other AEs=safety population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    FULVESTRANT
    Reporting group description
    		 Subjects were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Reporting group title
    VENETOCLAX + FULVESTRANT
    Reporting group description
    		 Subjects were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

    Serious adverse events
    		 FULVESTRANT VENETOCLAX + FULVESTRANT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 50 (8.00%)
         number of deaths (all causes)
    18
    26
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 FULVESTRANT VENETOCLAX + FULVESTRANT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 51 (66.67%)
    45 / 50 (90.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    9 / 51 (17.65%)
    1 / 50 (2.00%)
         occurrences all number
    9
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
         occurrences all number
    2
    6
    Fatigue
         subjects affected / exposed
    9 / 51 (17.65%)
    18 / 50 (36.00%)
         occurrences all number
    9
    20
    Injection site reaction
         subjects affected / exposed
    15 / 51 (29.41%)
    11 / 50 (22.00%)
         occurrences all number
    21
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 51 (7.84%)
    8 / 50 (16.00%)
         occurrences all number
    4
    9
    Dyspnoea
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 50 (10.00%)
         occurrences all number
    3
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 51 (7.84%)
    8 / 50 (16.00%)
         occurrences all number
    4
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 50 (4.00%)
         occurrences all number
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 50 (4.00%)
         occurrences all number
    4
    2
    Weight decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Injury, poisoning and procedural complications
    Injection related reaction
         subjects affected / exposed
    5 / 51 (9.80%)
    4 / 50 (8.00%)
         occurrences all number
    5
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 50 (10.00%)
         occurrences all number
    2
    5
    Headache
         subjects affected / exposed
    8 / 51 (15.69%)
    7 / 50 (14.00%)
         occurrences all number
    8
    8
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Anaemia
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    Lymphopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    7 / 50 (14.00%)
         occurrences all number
    0
    7
    Neutropenia
         subjects affected / exposed
    0 / 51 (0.00%)
    8 / 50 (16.00%)
         occurrences all number
    0
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Abdominal distension
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 50 (10.00%)
         occurrences all number
    1
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
         occurrences all number
    1
    4
    Diarrhoea
         subjects affected / exposed
    5 / 51 (9.80%)
    28 / 50 (56.00%)
         occurrences all number
    6
    39
    Constipation
         subjects affected / exposed
    2 / 51 (3.92%)
    8 / 50 (16.00%)
         occurrences all number
    2
    8
    Vomiting
         subjects affected / exposed
    1 / 51 (1.96%)
    15 / 50 (30.00%)
         occurrences all number
    1
    23
    Nausea
         subjects affected / exposed
    9 / 51 (17.65%)
    32 / 50 (64.00%)
         occurrences all number
    10
    40
    Dry mouth
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
         occurrences all number
    1
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 51 (11.76%)
    5 / 50 (10.00%)
         occurrences all number
    10
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    8 / 51 (15.69%)
    1 / 50 (2.00%)
         occurrences all number
    9
    2
    Pain in extremity
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Back pain
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 50 (6.00%)
         occurrences all number
    6
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 51 (3.92%)
    9 / 50 (18.00%)
         occurrences all number
    2
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2018
    Primarily to provide clarifications and to ensure consistency across sections.
    16 Oct 2020
    1. The protocol was amended to update study rationale and benefit-risk assessment, based on the results of the primary analysis, it was no longer considered appropriate for subjects in this study to receive venetoclax. As of 8 October 2020, all active subjects in the venetoclax plus fulvestrant arm of the study were requested to discontinue the venetoclax treatment immediately and were given the option to continue fulvestrant treatment alone. 2. Study design, study treatment, and treatment interruption were updated to reflect the immediate discontinuation of venetoclax treatment. 3. The frequency of survival follow-up was increased from approximately every 6 months to approximately every 3 months or more frequently after treatment discontinuation, to enhance safety data collection. 4. Update was made in use of contraception to indicate that contraception should be used for up to 2 years after the last dose of study drug or based on local prescribing information for fulvestrant. 5. Adverse events of special interest for the study were modified to remove hepatitis B reactivation. 6. Statistical considerations for primary and secondary efficacy endpoints were amended to specify the calculation of the 95% CI for CBR estimate, and 95% CI for the Cox proportional hazards model for PFS, following reporting conventions.

    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.
    Study terminated due to Sponsor’s decision with no safety concerns. Primary/secondary efficacy endpoints- updated to report 95% CI for Clinical Benefit estimate and 95% CI for Cox proportional hazards model for PFS, following reporting conventions.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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