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    Clinical Trial Results:
    A Phase 1b/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-5829 as a Single Agent and In Combination with Enzalutamide in Subjects with Metastatic Castrate-Resistant Prostate Cancer

    Summary
    EudraCT number
    		 2015-003741-26
    Trial protocol
    		 BE  
    Global end of trial date
    03 Sep 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    20 Dec 2020
    First version publication date
    19 Sep 2020
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    A few updates were made to the primary endpoints.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-350-1604
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02607228
    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
    03 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1b Dose Escalation: To characterize safety & tolerability of alobresib alone and in combination with enzalutamide in participants with metastatic castrate-resistant prostate cancer (mCRPC); determine the maximum tolerated dose (MTD) of alobresib alone and in combination with enzalutamide. Phase 2 Dose Expansion: Group 1: Evaluate the efficacy of alobresib alone in participants with mCRPC who have progressed while receiving enzalutamide (may have also received abiraterone); Group 2: Evaluate the efficacy of alobresib combined with enzalutamide in participants with mCRPC who have progressed while receiving treatment with abiraterone; Group 3: Evaluate the efficacy of alobresib combined with enzalutamide in participants with mCRPC who had prostate-specific antigen, but not radiographic progression, while receiving treatment with enzalutamide.
    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
    08 Dec 2015
    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: 31
    Worldwide total number of subjects
    31
    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)
    11
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at 4 study sites in the United States. The first participant was screened on 08 December 2015. The last study visit occurred on 03 September 2019. Phase 2 Dose Expansion of the study was not conducted. Results are reported for only Dose Escalation Monotherapy and Combination Therapy.

    Pre-assignment
    Screening details
    		 43 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
    		 Monotherapy: Alobresib 2 mg
    Arm description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 2 mg tablets administered orally once daily to determine the maximum tolerated dose (MTD).
    Arm type
    		 Experimental

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

    Arm title
    		 Monotherapy: Alobresib 3 mg
    Arm description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 3 mg tablets administered orally once daily to determine the MTD.
    Arm type
    		 Experimental

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

    Arm title
    		 Monotherapy: Alobresib 4 mg
    Arm description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 4 mg tablets administered orally once daily to determine the MTD.
    Arm type
    		 Experimental

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

    Arm title
    		 Monotherapy: Alobresib 6 mg
    Arm description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 6 mg tablets administered orally once daily to determine the MTD.
    Arm type
    		 Experimental

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

    Arm title
    		 Monotherapy: Alobresib 9 mg
    Arm description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 9 mg tablets administered orally once daily to determine the MTD.
    Arm type
    		 Experimental

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

    Arm title
    		 Combination Therapy: Alobresib 3 mg + Enzalutamide
    Arm description
    		 Participants who had progressed on abiraterone, received alobresib 3 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    XTANDI®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg administered once daily.

    Arm title
    		 Combination Therapy: Alobresib 6 mg + Enzalutamide
    Arm description
    		 Participants who had progressed on abiraterone, received alobresib 6 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    XTANDI®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg administered once daily.

    Number of subjects in period 1
    		Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Started
    5
    4
    3
    6
    5
    6
    2
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    5
    4
    3
    6
    5
    6
    2
         Withdrew Consent
    -
    1
    -
    -
    -
    1
    -
         Adverse Event
    1
    -
    1
    -
    1
    1
    1
         Progressive Disease
    4
    3
    1
    5
    4
    3
    1
         Investigator's Discretion
    -
    -
    1
    -
    -
    1
    -
         Study Terminated by Sponsor
    -
    -
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Monotherapy: Alobresib 2 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 2 mg tablets administered orally once daily to determine the maximum tolerated dose (MTD).

    Reporting group title
    Monotherapy: Alobresib 3 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 3 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 4 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 4 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 6 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 6 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 9 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 9 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Combination Therapy: Alobresib 3 mg + Enzalutamide
    Reporting group description
    		 Participants who had progressed on abiraterone, received alobresib 3 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.

    Reporting group title
    Combination Therapy: Alobresib 6 mg + Enzalutamide
    Reporting group description
    		 Participants who had progressed on abiraterone, received alobresib 6 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.

    Reporting group values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide Total
    Number of subjects
    		 5 4 3 6 5 6 2 31
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.2 ( 9.28 ) 67.3 ( 10.69 ) 67.7 ( 5.69 ) 66.8 ( 9.39 ) 69.2 ( 6.61 ) 62.5 ( 10.23 ) 67.0 ( 0.00 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0 0 0
        Male
    		 5 4 3 6 5 6 2 31
    Race
    Units: Subjects
        Black or African American
    		 1 0 1 0 0 1 0 3
        White
    		 4 4 2 6 4 5 2 27
        Other
    		 0 0 0 0 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 1 1 0 2
        Not Hispanic or Latino
    		 5 4 3 6 3 5 2 28
        Unknown or Not Reported
    		 0 0 0 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Monotherapy: Alobresib 2 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 2 mg tablets administered orally once daily to determine the maximum tolerated dose (MTD).

    Reporting group title
    Monotherapy: Alobresib 3 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 3 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 4 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 4 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 6 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 6 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 9 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 9 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Combination Therapy: Alobresib 3 mg + Enzalutamide
    Reporting group description
    		 Participants who had progressed on abiraterone, received alobresib 3 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.

    Reporting group title
    Combination Therapy: Alobresib 6 mg + Enzalutamide
    Reporting group description
    		 Participants who had progressed on abiraterone, received alobresib 6 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.

    Primary: Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs)

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    End point title
    		 Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) [1]
    End point description
    A DLT was a toxicity, considered possibly related to alobresib, and which occurred during the DLT assessment window (Days 1 through 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count (ANC) < 500/mm^3), Grade ≥ 3 neutropenia (ANC< 1000/mm^3) with fever (a single temperature > 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour (h)), Grade ≥ 3 thrombocytopenia, Grade ≥ 2 bleeding (eg, gastrointestinal, respiratory, epistaxis, purpura), Grade ≥ 3 non hematologic toxicity, except- Grade 3 nausea or emesis with maximum duration of 48 h on adequate medical therapy and Grade 3 diarrhea which persists for < 72 h in the absence of maximal medical therapy, Grade ≥ 2 non hematologic treatment emergent adverse event (TEAE) that in the opinion of the investigator was of potential clinical significance such that further dose escalation would expose participants to unacceptable risk, treatment interruption ≥ 7 days due to unresolved toxicity. The DLT Analysis Set.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 28
    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
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: participants
        number (not applicable)
    0
    0
    0
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Phase 1b Dose Expansion: Non-progression Rate at Week 24 According to Prostate Cancer Working Group (PCWG2) Criteria

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    End point title
    		 Phase 1b Dose Expansion: Non-progression Rate at Week 24 According to Prostate Cancer Working Group (PCWG2) Criteria [2]
    End point description
    The non-progression rate at Week 24 was defined as the proportion of participants who did not progress by Week 24.
    End point type
    Primary
    End point timeframe
    Week 24
    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: No statistical comparison was planned or performed.
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    Units: proportion of participants
        number (not applicable)
    Notes
    [3] - The Phase 2 Dose Expansion of the study was not conducted.
    [4] - The Phase 2 Dose Expansion of the study was not conducted.
    [5] - The Phase 2 Dose Expansion of the study was not conducted.
    [6] - The Phase 2 Dose Expansion of the study was not conducted.
    [7] - The Phase 2 Dose Expansion of the study was not conducted.
    [8] - The Phase 2 Dose Expansion of the study was not conducted.
    [9] - The Phase 2 Dose Expansion of the study was not conducted.
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib

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    End point title
    		 Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib
    End point description
    Cmax is the maximum observed concentration of drug in plasma. The PK Analysis Set included participants who took at least 1 dose of study drug and have at least 1 non-missing postdose concentration value. Participants with available data were analyzed. Here, 99999 = Samples were not collected at this timepoint. 9999 = Standard Deviation (SD) was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Days 1 and 15
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=5,4,3,6,4,6,2)
    99999 ( 99999 )
    9999 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    111.07 ( 37.957 )
    199.00 ( 9.899 )
        Cycle 1 Day 8 (n=5,4,3,6,4,6,2)
    263.00 ( 141.875 )
    263.75 ( 132.011 )
    367.33 ( 49.359 )
    293.33 ( 123.362 )
    526.00 ( 280.391 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1 Day 15 (n=5,4,3,6,5,6,2)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    84.4 ( 48.58 )
    173.5 ( 28.99 )
        Cycle 2 Day 1 (n=5,2,3,2,1,6,2)
    99999 ( 99999 )
    220.50 ( 95.459 )
    99999 ( 99999 )
    203.50 ( 143.543 )
    641.00 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib

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    End point title
    		 Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib
    End point description
    Ctau is the observed concentration of drug in plasma at the end of dosing. Participants in the PK Analysis Set with available data were analyzed. Here, 99999 = Samples were not collected at this timepoint. 9999 = SD was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 15
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 8 (n=5,4,3,6,2,6,2)
    180.00 ( 77.679 )
    156.78 ( 100.307 )
    141.67 ( 22.811 )
    70.93 ( 32.905 )
    157.20 ( 126.996 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1 Day 15 (n=5,4,3,6,5,5,2)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    8.8 ( 7.77 )
    3.9 ( 3.21 )
        Cycle 2 Day 1 (n=5,2,3,1,1,6,2)
    99999 ( 99999 )
    127.60 ( 59.963 )
    99999 ( 99999 )
    33.80 ( 9999 )
    268.00 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib

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    End point title
    		 Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib
    End point description
    AUClast is the concentration of drug over time zero to last concentration (area under the plasma concentration versus time curve). Participants in the PK Analysis Set with available data were analyzed. Here, 99999 = Samples were not collected at this timepoint. 9999 = SD was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Days 1 and 15
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=5,4,3,6,5,6,2)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    1026.99 ( 359.220 )
    1741.42 ( 737.521 )
        Cycle 1 Day 8 (n=5,4,3,6,4,6,2)
    4207.55 ( 2319.854 )
    3742.30 ( 2106.308 )
    4646.08 ( 890.441 )
    3105.70 ( 1008.730 )
    4494.79 ( 4124.948 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1 Day 15 (n=5,4,3,6,5,6,2)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    652.7 ( 395.52 )
    701.3 ( 353.25 )
        Cycle 2 Day 1 (n=5,2,3,2,1,6,2)
    99999 ( 99999 )
    3264.79 ( 2024.141 )
    99999 ( 99999 )
    1709.71 ( 264.402 )
    10264.74 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib

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    End point title
    		 Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib
    End point description
    AUCtau is defined as the 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. Here, 99999 = Samples were not collected at this timepoint. 9999 = SD was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 15
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 8 (n=5,4,3,6,5,6,2)
    4264.51 ( 2384.628 )
    3758.92 ( 2076.013 )
    4655.48 ( 949.099 )
    3128.58 ( 998.059 )
    7217.02 ( 4559.957 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1 Day 15 (n=5,4,3,6,5,4,2)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    765.3 ( 373.39 )
    701.3 ( 353.25 )
        Cycle 2 Day 1 (n=5,2,3,1,1,6,2)
    99999 ( 99999 )
    3243.01 ( 2110.324 )
    99999 ( 99999 )
    1522.75 ( 9999 )
    10264.74 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib

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    End point title
    		 Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib
    End point description
    Tmax is the time observed for the Cmax of alobresib. Participants in the PK Analysis Set with available data were analyzed. Here, 99999 = Samples were not collected at this timepoint.
    End point type
    Secondary
    End point timeframe
    Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Days 1 and 15
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: hour
    median (full range (min-max))
        Cycle 1 Day 1 (n=5,4,3,6,5,6,2)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    1.07 (0.50 to 2.92)
    0.46 (0.42 to 0.50)
        Cycle 1 Day 8 (n=5,4,3,6,4,6,2)
    0.50 (0.48 to 23.85)
    0.66 (0.50 to 1.05)
    0.58 (0.50 to 2.00)
    1.42 (0.50 to 3.97)
    0.72 (0.50 to 2.08)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Cycle 1 Day 15 (n=5,4,3,6,5,6,2)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0.5 (0.5 to 7.9)
    0.5 (0.5 to 0.5)
        Cycle 2 Day 1 (n=5,2,3,2,1,6,2)
    99999 (99999 to 99999)
    1.76 (0.50 to 3.02)
    99999 (99999 to 99999)
    4.93 (3.87 to 6.00)
    4.08 (4.08 to 4.08)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12

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    End point title
    		 Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12
    End point description
    PSA response was defined as percentage of participants with ≥ 30% decline in PSA from baseline by 12 weeks. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    33.3
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the interval from first dose date of study drug to the earlier of the first documentation of definitive disease progression (assessed per PCWG2) or death from any cause. PCWG2 criteria for progression was determined as 'Decline from baseline' when record start of therapy to first prostate-specific antigen (PSA) increase that is ≥ 25% and ≥ 2 ng/mL above the nadir and confirmed by a second value 3 or more weeks later; 'No decline from baseline' when PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks. Participants in the Full Analysis Set with available data were analyzed. Here, 999999 = Upper and lower limit of 95% confidence interval are not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    4
    3
    2
    6
    4
    5
    1
    Units: months
        median (confidence interval 95%)
    2.61 (1.58 to 8.61)
    2.10 (1.97 to 2.60)
    4.17 (2.79 to 5.55)
    2.78 (2.69 to 11.07)
    2.69 (0.53 to 14.00)
    3.25 (1.15 to 21.59)
    5.98 (.999999 to 999999)
    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 is defined as the interval from first dose date of study drug to death from any cause. Participants in the Full Analysis Set were analyzed. Here, 999999 = Data were not evaluable because participants discontinued the study without death.
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Number of subjects analysed
    5
    4
    3
    6
    5
    6
    2
    Units: years
        median (full range (min-max))
    999999 (999999 to 999999)
    999999 (3.12 to 999999)
    999999 (999999 to 999999)
    999999 (999999 to 999999)
    999999 (999999 to 999999)
    999999 (1.15 to 999999)
    999999 (999999 to 999999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events: From first dose through last dose of the study drug (maximum: 131 weeks) plus 30 days; All-Cause Mortality: First dose date up to approximately 4 years
    Adverse event reporting additional description
    The Safety Analysis Set included all participants who received >= 1 dose of study treatment with treatment group designated according to actual treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Monotherapy: Alobresib 2 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 2 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 3 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 3 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 4 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 4 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 6 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 6 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Monotherapy: Alobresib 9 mg
    Reporting group description
    		 Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 9 mg tablets administered orally once daily to determine the MTD.

    Reporting group title
    Combination Therapy: Alobresib 3 mg + Enzalutamide
    Reporting group description
    		 Participants who had progressed on abiraterone, received alobresib 3 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.

    Reporting group title
    Combination Therapy: Alobresib 6 mg + Enzalutamide
    Reporting group description
    		 Participants who had progressed on abiraterone, received alobresib 6 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily.

    Serious adverse events
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    1 / 2 (50.00%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Monotherapy: Alobresib 2 mg Monotherapy: Alobresib 3 mg Monotherapy: Alobresib 4 mg Monotherapy: Alobresib 6 mg Monotherapy: Alobresib 9 mg Combination Therapy: Alobresib 3 mg + Enzalutamide Combination Therapy: Alobresib 6 mg + Enzalutamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    3 / 4 (75.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    5 / 6 (83.33%)
    2 / 2 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    3 / 3 (100.00%)
    3 / 6 (50.00%)
    4 / 5 (80.00%)
    2 / 6 (33.33%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    3
    3
    5
    2
    1
    Pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    1
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Catheter site extravasation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Device related thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Early satiety
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    9
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    2
    7
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Iliotibial band syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Joint injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Upper limb fracture
    Additional description: 1
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Wound haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hemiparesis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    1
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
         occurrences all number
    1
    1
    1
    3
    3
    1
    1
    Nausea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    3 / 5 (60.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    1
    3
    0
    0
    Constipation
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    1
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Eructation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pain of skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Renal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Urinary tract disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    2
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pathological fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Kidney infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    4 / 5 (80.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    5
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Sep 2015
    Amendment 1 included the following major changes: • Updated study design including objective and endpoints, number of participants, the introduction of a Study Day 1 visit to allow for an enzalutamide lead in for participants in the Phase 1b combination therapy and Phase 2 groups. • Modified the starting dose to a dose that was deemed safe and tolerable in Study GS-US-350-1599. • Added a risk:benefit assessment section • Updated planned number of study centers and regions. • Introduced new formulations of alobresib available for use. • Clarified the SRT members that would assess dose level reviews. • Included a study schema for additional clarification of study design. • Updated reasons for discontinuing treatment or discontinuation from the study. • Added minor clarifications to the study procedures table.
    30 Jun 2016
    Amendment 2 included the following major changes: • Updated the background, risk/benefit, study design, objectives, endpoints and number of participants to allow a third group of participants in the Phase 2 portion of this study (participants who were currently on enzalutamide and showing the early signs of progressive disease). • Updated the change in Gilead medical oversight of the study. • Modified the study design to allow enrollment in the Phase 1b combination therapy dose escalation cohorts prior to determination of the MTD in the monotherapy cohorts. • Updated inclusion/exclusion criteria for participants participating in Group 3. • Updated PK/PD collections for Group 3 participants. • Updated the statistical analysis sections and the study schema based on the new study design. • Updated current clinical experience with alobresib. • Removed the 0.2 mg formulation of alobresib and updated the minimum dose reduction level allowed. • Clarified food effect sub study procedures. • Included additional laboratory analytes for safety monitoring.

    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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