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    Clinical Trial Results:
    A Phase 2, Randomized, Open-Label, Two-arm Study to Assess the Efficacy and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine) in Combination With Fulvestrant in Postmenopausal Women with ER+, HER2- Metastatic Breast Cancer Who Have Progressed on an Aromatase Inhibitor

    Summary
    EudraCT number
    		 2014-003220-52
    Trial protocol
    		 BE   ES   DE   FR   IT  
    Global end of trial date
    21 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Dec 2018
    First version publication date
    06 Dec 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-486-BRSTM-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02374099
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Ileana Elias, Celgene Corporation, 01 647-968-4300, ilelias@celgene.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
    02 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of CC-486 in combination with fulvestrant relative to fulvestrant monotherapy, by estimation of the hazard ratio of progression free survival (PFS).
    Protection of trial subjects
    The study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2015
    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
    France: 15
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 21
    Worldwide total number of subjects
    97
    EEA total number of subjects
    80
    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)
    54
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 35 sites in Spain, Germany, Belgium, Italy and the United States.

    Pre-assignment
    Screening details
    		 The study enrolled adult, postmenopausal women, with metastatic breast cancer who progressed on an aromatase inhibitor. Participants were randomly assigned in a 1:1 ratio to one of two treatment arms to CC-486 tablets and fulvestrant or fulvestrant alone.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CC-486 and Fulvestrant
    Arm description
    		 Participants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-486
    Investigational medicinal product code
    Other name
    Oral Azacitidine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg of CC-486 tablets by mouth daily (QD) on days 1-21 of each 28 day-cycle

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Faslodex
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg fulvestrant administered by intramuscular (IM) injection on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles.

    Arm title
    		 Fulvestrant
    Arm description
    		 Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Faslodex
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg fulvestrant administered by intramuscular (IM) injection on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles.

    Number of subjects in period 1
    		CC-486 and Fulvestrant Fulvestrant
    Started
    48
    49
    Participants Treated
    46
    48
    Completed
    0
    0
    Not completed
    48
    49
         Consent withdrawn by subject
    5
    1
         Randomized, but not treated
    2
    1
         Adverse event, non-fatal
    1
    -
         Progressive Disease
    35
    40
         Miscellaneous
    2
    3
         Study Terminated by Sponsor
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CC-486 and Fulvestrant
    Reporting group description
    		 Participants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.

    Reporting group values
    		 CC-486 and Fulvestrant Fulvestrant Total
    Number of subjects
    		 48 49 97
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 29 25 54
        From 65-84 years
    		 19 24 43
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ( 10.99 ) 62.9 ( 10.03 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 48 49 97
    Race
    Units: Subjects
        White
    		 34 39 73
        Asian
    		 0 1 1
        American Indian/Alaska Native
    		 1 0 1
        Not Collected or Reported
    		 13 9 22
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    ECOG performance status is used by doctors and researchers to assess how a subject's disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
    Units: Subjects
        0 = Fully Active
    		 36 21 57
        1 = Restrictive but ambulatory
    		 12 28 40
        2 = = Ambulatory but unable to work
    		 0 0 0
        3 = Limited Self Care
    		 0 0 0
    Time from Primary Diagnosis of Breast Cancer to Study Randomization
    Units: months
        arithmetic mean (standard deviation)
    		 119.05 ( 70.322 ) 95.57 ( 76.434 ) -
    Duration of Prior Hormonal Anti-Cancer Therapy
    Units: Months
        arithmetic mean (standard deviation)
    		 31.39 ( 14.830 ) 35.84 ( 27.409 ) -

    End points

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    End points reporting groups
    Reporting group title
    CC-486 and Fulvestrant
    Reporting group description
    		 Participants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.

    Primary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

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    End point title
    		 Kaplan-Meier Estimate of Progression Free Survival (PFS)
    End point description
    Progression-free survival was defined as the duration from the date of randomization to the date of disease progression based on investigator’s assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or death (from any cause), whichever occurred first. Per RECIST 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target or non-target lesions from nadir or appearance of a new lesion. The Intent-to-treat (ITT) population included all randomized participants regardless of whether the participant received any investigational product (IP) or had any efficacy assessments collected.
    End point type
    Primary
    End point timeframe
    From the date of randomization of study drug to the date of the cut off date of 13 December 2016; follow-up for PFS was 21 months
    End point values
    		 CC-486 and Fulvestrant Fulvestrant
    Number of subjects analysed
    48
    49
    Units: months
        median (confidence interval 95%)
    5.49 (2.07 to 8.25)
    5.46 (3.58 to 7.36)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    CC-486 and Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.599
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.42
    Notes
    [1] - Hazard ratio and associated two-sided 95% confidence intervals (CI) were estimated by the Cox proportional hazard models.

    Secondary: Percentage of Participants who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment

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    End point title
    		 Percentage of Participants who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment
    End point description
    Overall response rate was defined as the percentage of participants who achieved a confirmed complete response or partial response based on RECIST Version 1.1 criteria. RECIST criteria v 1.1 defined a CR as the disappearance of all target lesions and a PR with at least a 30% decrease in the sum of diameters of target lesions from baseline. The two-sided 95% exact binomial CI each arm was estimated by the Clopper-Pearson method. The Intent-to-treat population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 8 weeks, for the first 24 weeks, then every 12 weeks until DP; from date of randomization of study drug to the data cut-off date of 13 December 2016; follow-up for overall response was 21 months.
    End point values
    		 CC-486 and Fulvestrant Fulvestrant
    Number of subjects analysed
    48
    49
    Units: percentage of participants
        number (confidence interval 95%)
    8.3 (2.32 to 19.98)
    2.0 (0.05 to 10.85)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    CC-486 and Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.1479
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Response Rates
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.47
         upper limit
    		 15.06
    Notes
    [2] - The two-sided 95% confidence interval for the difference in ORR was estimated by the Wilson method.

    Secondary: Percentage of Participants who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment

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    End point title
    		 Percentage of Participants who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment
    End point description
    Percentage of participants with CR or PR or SD was defined per RECIST criteria v 1.1 as a CR that includes a disappearance of all target lesions, a PR was defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline and SD as neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. The two-sided 95% exact binomial CI each arm was estimated by the Clopper-Pearson method. The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 8 weeks, for the first 24 weeks, then every 12 weeks until DP; from date of randomization of study drug to data cut-off date of 13 December 2016; follow-up for clinical benefit response was 21 months.
    End point values
    		 CC-486 and Fulvestrant Fulvestrant
    Number of subjects analysed
    48
    49
    Units: Percentage of Participants
        number (confidence interval 95%)
    31.3 (18.66 to 46.25)
    30.6 (18.25 to 45.42)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    CC-486 and Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1732
    Method
    		 Fisher exact
    Parameter type
    		 Difference in clinical benefit rate
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.76
         upper limit
    		 19.04
    Notes
    [3] - The two-sided 95% confidence interval for the difference in clinical benefit rate was estimated by the Wilson method.

    Secondary: Kaplan Meier Estimate of Overall Survival

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    End point title
    		 Kaplan Meier Estimate of Overall Survival
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death (from any cause). All participants who were lost to follow up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact. The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected. 99999 indicates overall survival was not estimable due to the data not being mature at the time of the data cut off date. The median OS was not reached.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug to the data cut off date of 13 December 2016; participants were followed for overall survival for 21 months
    End point values
    		 CC-486 and Fulvestrant Fulvestrant
    Number of subjects analysed
    48
    49
    Units: months
        median (confidence interval 95%)
    99999 (13.7 to 99999)
    99999 (10.7 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    CC-486 and Fulvestrant v Fulvestrant
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.2725
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 1.53
    Notes
    [4] - Hazard Ratio and associated two-sided 95% CI were estimated by the Cox proportional hazard model.

    Secondary: Kaplan Meier Estimate of Duration of Response

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    End point title
    		 Kaplan Meier Estimate of Duration of Response
    End point description
    Duration of response was defined as the time from the first tumor assessment when the confirmed CR/PR criterion was first met to the date of disease progression, based on investigator’s assessment following RECIST Version 1.1 criteria. Only participants who had a confirmed CR or PR response are included in the analysis. 99999 indicates the median duration of response was not estimable due to the data not being mature at the time of the data cut off date.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug to the data cut off of 13 December 2016; follow-up for duration of response was 21 months.
    End point values
    		 CC-486 and Fulvestrant Fulvestrant
    Number of subjects analysed
    48
    49
    Units: months
        median (confidence interval 95%)
    99999 (6.61 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as any AEs that begin or worsen with an onset date on or after the date of the first dose of IP through 28 days after the last dose. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on the participant's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity as follows: Grade 1 = Mild – transient or mild discomfort; no medical intervention required; Grade 2 = Moderate – mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death. The safety population includes all randomized participants who received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Randomization to 28 days after the last dose of IP; those AEs known at any time thereafter being related to IP; up to the last subject last visit of 21 November 2017; TEAE follow-up occurred up to 155 weeks and 2 days
    End point values
    		 CC-486 and Fulvestrant Fulvestrant
    Number of subjects analysed
    46
    48
    Units: participants
        TEAE
    46
    48
        Grade 3 or 4 TEAE
    32
    15
        Grade 5 TEAE (Death)
    2
    1
        Serious TEAE
    10
    7
        TEAE Leading to Stopping Any Study Drug
    14
    1
        TEAE Leading to Dose Reduction Any Study Drug
    19
    0
        TEAE Leading to Interruption Any Study Drug
    22
    3
        Treatment-Related TEAE
    46
    30
        Treatment-Related TEAE Grade 3 or 4 TEAE
    29
    2
        Treatment-Related TEAE Grade 5
    0
    0
        Treatment-Related Serious TEAE
    4
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization to 28 days after the last dose of IP; those AEs known at any time thereafter being related to IP; up to final cut off date of the last subject last visit of 21 November 2017.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    CC-486 and Fulvestrant
    Reporting group description
    		 Participants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.

    Serious adverse events
    		 CC-486 and Fulvestrant Fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 46 (21.74%)
    7 / 48 (14.58%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cervical myelopathy
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CC-486 and Fulvestrant Fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 46 (97.83%)
    44 / 48 (91.67%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 48 (10.42%)
         occurrences all number
    1
    10
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Weight decreased
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 48 (0.00%)
         occurrences all number
    7
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 46 (8.70%)
    5 / 48 (10.42%)
         occurrences all number
    4
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 48 (8.33%)
         occurrences all number
    3
    6
    Headache
         subjects affected / exposed
    5 / 46 (10.87%)
    5 / 48 (10.42%)
         occurrences all number
    7
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 48 (6.25%)
         occurrences all number
    1
    4
    Neutropenia
         subjects affected / exposed
    10 / 46 (21.74%)
    0 / 48 (0.00%)
         occurrences all number
    22
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 46 (34.78%)
    10 / 48 (20.83%)
         occurrences all number
    28
    13
    Fatigue
         subjects affected / exposed
    13 / 46 (28.26%)
    12 / 48 (25.00%)
         occurrences all number
    18
    16
    Injection site pain
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 48 (10.42%)
         occurrences all number
    1
    5
    Oedema peripheral
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 48 (6.25%)
         occurrences all number
    1
    5
    Pyrexia
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 48 (4.17%)
         occurrences all number
    5
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 46 (13.04%)
    2 / 48 (4.17%)
         occurrences all number
    6
    2
    Abdominal pain upper
         subjects affected / exposed
    6 / 46 (13.04%)
    1 / 48 (2.08%)
         occurrences all number
    7
    1
    Constipation
         subjects affected / exposed
    19 / 46 (41.30%)
    10 / 48 (20.83%)
         occurrences all number
    26
    10
    Diarrhoea
         subjects affected / exposed
    20 / 46 (43.48%)
    6 / 48 (12.50%)
         occurrences all number
    53
    11
    Nausea
         subjects affected / exposed
    35 / 46 (76.09%)
    14 / 48 (29.17%)
         occurrences all number
    73
    16
    Vomiting
         subjects affected / exposed
    33 / 46 (71.74%)
    5 / 48 (10.42%)
         occurrences all number
    56
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 46 (10.87%)
    4 / 48 (8.33%)
         occurrences all number
    5
    6
    Dyspnoea
         subjects affected / exposed
    3 / 46 (6.52%)
    7 / 48 (14.58%)
         occurrences all number
    4
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 48 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Insomnia
         subjects affected / exposed
    2 / 46 (4.35%)
    4 / 48 (8.33%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 46 (13.04%)
    9 / 48 (18.75%)
         occurrences all number
    9
    11
    Back pain
         subjects affected / exposed
    3 / 46 (6.52%)
    7 / 48 (14.58%)
         occurrences all number
    3
    8
    Bone pain
         subjects affected / exposed
    5 / 46 (10.87%)
    6 / 48 (12.50%)
         occurrences all number
    7
    7
    Muscle spasms
         subjects affected / exposed
    4 / 46 (8.70%)
    1 / 48 (2.08%)
         occurrences all number
    4
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 48 (6.25%)
         occurrences all number
    1
    5
    Musculoskeletal pain
         subjects affected / exposed
    2 / 46 (4.35%)
    7 / 48 (14.58%)
         occurrences all number
    3
    11
    Myalgia
         subjects affected / exposed
    1 / 46 (2.17%)
    4 / 48 (8.33%)
         occurrences all number
    1
    4
    Pain in extremity
         subjects affected / exposed
    3 / 46 (6.52%)
    6 / 48 (12.50%)
         occurrences all number
    4
    6
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 48 (8.33%)
         occurrences all number
    3
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 46 (6.52%)
    3 / 48 (6.25%)
         occurrences all number
    3
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 46 (28.26%)
    8 / 48 (16.67%)
         occurrences all number
    18
    9
    Hyperuricaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 48 (6.25%)
         occurrences all number
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2014
    Provided additional dose modification criteria for renal dysfunction related toxicities as requested and agreed to with the FDA and in order to be consistent with other CC-486 clinical study protocols.

    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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    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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