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    Clinical Trial Results:
    A Phase 1b/2 Study of GS-5829 in Combination with Fulvestrant or Exemestane in Subjects with Advanced Estrogen Receptor Positive, HER2 Negative Breast Cancer

    Summary
    EudraCT number
    		 2016-002365-63
    Trial protocol
    		 ES   BE   GB   FR  
    Global end of trial date
    19 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jul 2019
    First version publication date
    31 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-350-1937
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02983604
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    19 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of the Phase 1b Dose Escalation part of this study were to characterize the safety and tolerability of GS-5829 in combination with exemestane or fulvestrant and to determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose of GS-5829 in combination with fulvestrant in women with advanced estrogen receptor positive, HER2-negative (ER+/HER2-) breast cancer. The primary objective of the Randomized Phase 2 Dose Expansion portion of this study was to evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant alone in women with advanced ER+/HER2- breast cancer.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    0
    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)
    14
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States. The first participant was screened on 10 January 2017. The last study visit occurred on 19 July 2018.

    Pre-assignment
    Screening details
    		 17 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GS-5829 4 mg + Exemestane
    Arm description
    		 GS-5829 4 mg tablets once daily + exemestane 25 mg tablet once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-5829
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg once daily

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasin®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg once daily

    Arm title
    		 GS-5829 4 mg + Fulvestrant
    Arm description
    		 GS-5829 4 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-5829
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg once daily

    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 every 28 days (± 3 days)

    Arm title
    		 GS-5829 6 mg + Fulvestrant
    Arm description
    		 GS-5829 6 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-5829
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6 mg once daily

    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 every 28 days (± 3 days)

    Arm title
    		 GS-5829 9 mg + Fulvestrant
    Arm description
    		 GS-5829 9 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-5829
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    9 mg once daily

    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 every 28 days (± 3 days)

    Number of subjects in period 1 [1]
    		GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Started
    4
    3
    3
    3
    Completed
    4
    3
    3
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant who was enrolled but not treated is not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GS-5829 4 mg + Exemestane
    Reporting group description
    		 GS-5829 4 mg tablets once daily + exemestane 25 mg tablet once daily

    Reporting group title
    GS-5829 4 mg + Fulvestrant
    Reporting group description
    		 GS-5829 4 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)

    Reporting group title
    GS-5829 6 mg + Fulvestrant
    Reporting group description
    		 GS-5829 6 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)

    Reporting group title
    GS-5829 9 mg + Fulvestrant
    Reporting group description
    		 GS-5829 9 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)

    Reporting group values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant Total
    Number of subjects
    		 4 3 3 3 13
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.3 ± 4.50 61.3 ± 7.51 63.0 ± 9.54 65.0 ± 12.29 -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 3 3 13
        Male
    		 0 0 0 0 0
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 4 3 3 3 13
    Race
    Units: Subjects
        White
    		 3 3 3 3 12
        Other
    		 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    GS-5829 4 mg + Exemestane
    Reporting group description
    		 GS-5829 4 mg tablets once daily + exemestane 25 mg tablet once daily

    Reporting group title
    GS-5829 4 mg + Fulvestrant
    Reporting group description
    		 GS-5829 4 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)

    Reporting group title
    GS-5829 6 mg + Fulvestrant
    Reporting group description
    		 GS-5829 6 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)

    Reporting group title
    GS-5829 9 mg + Fulvestrant
    Reporting group description
    		 GS-5829 9 mg tablets once daily + fulvestrant 500 mg administered intramuscularly on Days 1, 15, and 29, and then every 28 days (or in accordance with locally approved labeling)

    Primary: Phase 1b Dose Escalation: Number of Participants Experiencing Dose Limiting Toxicities (DLTs) Through Day 28 at Each Dose Level of GS-5829

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    End point title
    		 Phase 1b Dose Escalation: Number of Participants Experiencing Dose Limiting Toxicities (DLTs) Through Day 28 at Each Dose Level of GS-5829 [1]
    End point description
    A DLT was a toxicity defined as: ● Grade ≥ 4 neutropenia, ● Grade ≥ 3 neutropenia with fever, ● Grade ≥ 3 thrombocytopenia, ● Grade ≥ 2 bleeding, ● Grade ≥ 3 or higher non-hematologic toxicity, except: 1) Grade 3 nausea or emesis with maximum duration of 48 hrs on adequate medical therapy, 2) Grade 3 diarrhea which persists for < 72 hrs in the absence of adequate medical therapy, ● Grade ≥ 2 non-hematologic TEAE that in the opinion of the investigator is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk, ● Treatment interruption of ≥ 7 days due to unresolved toxicity, or ● Grade 3 or Grade 4 elevation in aspartate transaminase or alanine transaminase associated with a Grade 2 elevation in bilirubin that is at least possibly related to study drug. DLT Analysis Set included participants who completed all treatment & safety procedures through Day 28, inclusive, or experienced a DLT prior to Day 28, exclusive.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    3
    3
    3
    3
    Units: participants
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Randomized Phase 2 Dose Expansion: Progression-Free Survival

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    End point title
    		 Randomized Phase 2 Dose Expansion: Progression-Free Survival [2]
    End point description
    Progression-Free Survival (PFS) was defined as the interval from date of randomization to the earlier of the first documented confirmed disease progression or death from any cause. As the study was terminated prior to the Phase 2 portion of the study, no participants were enrolled in the Phase 2 portion of the study and data was not collected for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to 2 years
    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: As the study was terminated prior to the Phase 2 portion of the study, no participants were enrolled in the Phase 2 portion of the study and data was not collected for this endpoint.
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: Not applicable
    Notes
    [3] - No participants were enrolled in the Phase 2 portion of the study.
    [4] - No participants were enrolled in the Phase 2 portion of the study.
    [5] - No participants were enrolled in the Phase 2 portion of the study.
    [6] - No participants were enrolled in the Phase 2 portion of the study.
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: Pharmacokinetic (PK) Parameter: Cmax of GS-5829

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    End point title
    		 Phase 1b Dose Escalation: Pharmacokinetic (PK) Parameter: Cmax of GS-5829
    End point description
    Cmax is defined as the maximum observed concentration of drug. The PK Analysis Set included all enrolled participants who received at least 1 dose of study drug and have at least 1 nonmissing postdose concentration value reported by the PK laboratory, excluding participants who received concomitant medications prohibited in this study. Only participants with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1 and 15
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    4
    3
    3
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (N = 4, 3, 3, 2)
    318.25 ± 107.844
    247.00 ± 3.464
    244.00 ± 9.000
    518.00 ± 60.811
        Day 15 (N = 3, 3, 3, 2)
    389.666 ± 105.6424
    370.333 ± 52.5483
    375.666 ± 67.0919
    634.000 ± 46.6690
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: PK Parameter: AUCtau of GS-5829

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    End point title
    		 Phase 1b Dose Escalation: PK Parameter: AUCtau of GS-5829
    End point description
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). Participants in the PK Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Day 15
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    3
    3
    3
    2
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    4989.809 ± 1655.8737
    5218.820 ± 1326.2407
    3937.709 ± 667.4396
    7638.847 ± 938.3444
    No statistical analyses for this end point

    Secondary: Randomized Phase 2 Dose Expansion: Overall Safety Profile as Assessed by the Percentage of Participants Experiencing Any Adverse Events (AEs), Grade 3 or 4 AEs, Treatment-Related AEs, or Abnormalities in Laboratory Tests or Electrocardiograms

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    End point title
    		 Randomized Phase 2 Dose Expansion: Overall Safety Profile as Assessed by the Percentage of Participants Experiencing Any Adverse Events (AEs), Grade 3 or 4 AEs, Treatment-Related AEs, or Abnormalities in Laboratory Tests or Electrocardiograms
    End point description
    As the study was terminated prior to the Phase 2 portion of the study, no participants were enrolled in the Phase 2 portion of the study and data was not collected for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 years
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: Not applicable
    Notes
    [7] - No participants were enrolled in the Phase 2 portion of the study.
    [8] - No participants were enrolled in the Phase 2 portion of the study.
    [9] - No participants were enrolled in the Phase 2 portion of the study.
    [10] - No participants were enrolled in the Phase 2 portion of the study.
    No statistical analyses for this end point

    Secondary: Randomized Phase 2 Dose Expansion: Overall Response Rate

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    End point title
    		 Randomized Phase 2 Dose Expansion: Overall Response Rate
    End point description
    Overall response rate (ORR) was defined as the proportion of participants who achieve complete response (CR) or partial response (PR), based on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 study progression criteria. As the study was terminated prior to the Phase 2 portion of the study, no participants were enrolled in the Phase 2 portion of the study and data was not collected for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 years
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    Units: Not applicable
    Notes
    [11] - No participants were enrolled in the Phase 2 portion of the study.
    [12] - No participants were enrolled in the Phase 2 portion of the study.
    [13] - No participants were enrolled in the Phase 2 portion of the study.
    [14] - No participants were enrolled in the Phase 2 portion of the study.
    No statistical analyses for this end point

    Secondary: Randomized Phase 2 Dose Expansion: Clinical Benefit Rate

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    End point title
    		 Randomized Phase 2 Dose Expansion: Clinical Benefit Rate
    End point description
    Clinical benefit rate (CBR) was defined as the proportion of participants who achieve CR, PR, or stable disease that lasts for > 24 weeks based on RECIST v. 1.1 study progression criteria. As the study was terminated prior to the Phase 2 portion of the study, no participants were enrolled in the Phase 2 portion of the study and data was not collected for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 years
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: Not applicable
    Notes
    [15] - No participants were enrolled in the Phase 2 portion of the study.
    [16] - No participants were enrolled in the Phase 2 portion of the study.
    [17] - No participants were enrolled in the Phase 2 portion of the study.
    [18] - No participants were enrolled in the Phase 2 portion of the study.
    No statistical analyses for this end point

    Secondary: Randomized Phase 2 Dose Expansion: Overall Survival

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    End point title
    		 Randomized Phase 2 Dose Expansion: Overall Survival
    End point description
    Overall survival was defined as the interval from date of randomization to date of death from any cause. As the study was terminated prior to the Phase 2 portion of the study, no participants were enrolled in the Phase 2 portion of the study and data was not collected for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 years
    End point values
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    Units: Not applicable
    Notes
    [19] - No participants were enrolled in the Phase 2 portion of the study.
    [20] - No participants were enrolled in the Phase 2 portion of the study.
    [21] - No participants were enrolled in the Phase 2 portion of the study.
    [22] - No participants were enrolled in the Phase 2 portion of the study.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date to last dose date (average: 14.5 weeks; maximum: 53 weeks) plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set included all participants who were enrolled and received at least 1 dose of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    GS-5829 4 mg + Exemestane
    Reporting group description
    		 GS-5829 4 mg tablets once daily + exemestane 25 mg tablet once daily

    Reporting group title
    GS-5829 4 mg + Fulvestrant
    Reporting group description
    		 GS-5829 4 mg tablets once daily + fulvestrant 500 mg administered intramuscularly every 28 days (± 3 days)

    Reporting group title
    GS-5829 6 mg + Fulvestrant
    Reporting group description
    		 GS-5829 6 mg tablets once daily + fulvestrant 500 mg administered intramuscularly every 28 days (± 3 days)

    Reporting group title
    GS-5829 9 mg + Fulvestrant
    Reporting group description
    		 GS-5829 9 mg tablets once daily + fulvestrant 500 mg administered intramuscularly every 28 days (± 3 days)

    Serious adverse events
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GS-5829 4 mg + Exemestane GS-5829 4 mg + Fulvestrant GS-5829 6 mg + Fulvestrant GS-5829 9 mg + Fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    1
    1
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Injection site bruising
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Breast haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    0
    0
    3
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
         occurrences all number
    4
    1
    1
    3
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
         occurrences all number
    1
    2
    2
    3
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    1
    Dry mouth
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal tenderness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Alopecia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Arthralgia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2016
    ● Updated inclusion/exclusion criteria ● Clarified contraception methods ● Clarified prior therapies ● Updated clinical experience with GS-5829 ● Updated statistical modeling of probability of DLT occurrence rate based on emerging safety data from Studies GS-US-350-1604 and GS-US-350-1599 ● Clarified pregnancy testing timing
    05 May 2017
    ● Updated study design: 1) Phase 1b Dose Escalation: Group A (GS-5829 + exemestane) no longer enrolled past the 4-mg safety assessment, 2) Phase 2 Dose Expansion: Removal of Group 1 (GS-5829+ exemestane and exemestane alone) ● Added stratification to the Phase 2 Dose Expansion. Participants were to be stratified by prior CDK4/6 inhibitor plus AI status (naive vs. progressed). The target number of participants in each of the 2 strata was approximately 60 (40 subjects for GS-5829 + fulvestrant and 20 participants for fulvestrant alone). ● Reduced the Phase 1b target number of participants from 60 to 30 ● Revised the inclusion/exclusion criteria for clarity and due to changing study design ● Defined study drug initiation as Cycle 1 Day 1 throughout the inclusion/exclusion criteria

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jul 2018
    Enrollment in Group A (GS-5829 + exemestane) was stopped following safety assessments of the 4-mg GS-5829 dose. Enrollment in Group B (GS-5829 + fulvestrant) was stopped following safety assessments of the 9-mg GS-5829 dose. The study was terminated prior to the initiation of the Phase 2 portion of the study.
    -

    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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    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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