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    Clinical Trial Results:
    A Phase 1b Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors

    Summary
    EudraCT number
    		 2015-005488-18
    Trial protocol
    		 ES   BE   FR  
    Global end of trial date
    26 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2018
    First version publication date
    20 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8628-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02698176
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-8628-006, IND Number: 123,715
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    26 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study determined the recommended phase 2 dose (RP2D) of MK-8628 (formerly known as OTX015) for further studies in participants with advanced nuclear protein in testis (NUT) midline carcinoma (NMC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), or castration-resistant prostate cancer (CRPC). This was a 2 part study: Part A was a dose-escalation study and established the RP2D by evaluating dose limiting toxicity (DLT), safety, discontinuation, and early efficacy. Part B was to enroll participants with NMC only and evaluate safety and efficacy. The sponsor decided to terminate the program after the dose levels tested in Part A due to limited efficacy signals and not due to safety-related concerns. No participants entered or were treated in Part B of the study.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2016
    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
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    13
    EEA total number of subjects
    7
    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)
    2
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a Phase I, multi-center, open-label, dose-escalating study in participants with advanced or metastatic NSCLC, TNBC, CRPC, or NMC for which standard therapy either does not exist, has proven ineffective, intolerable, or unacceptable.

    Pre-assignment
    Screening details
    		 Participants with CRPC, NMC, and TNBC were enrolled in the study; no participants with NSCLC were enrolled. All participants had a Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≤1 and 76.9% of participants had 2 or more prior lines of therapy. No participants were enrolled in Part B of the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MK-8628 20 mg CRPC Cohort-Part A
    Arm description
    		 Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8628
    Investigational medicinal product code
    Other name
    OTX015
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered PO, BID, in a fasted state, for 21 consecutive days per cycle and administered in consecutive cycles for up to 24 months

    Arm title
    		 MK-8628 20 mg NMC Cohort-Part A
    Arm description
    		 Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8628
    Investigational medicinal product code
    Other name
    OTX015
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered PO, BID, in a fasted state, for 21 consecutive days per cycle and administered in consecutive cycles for up to 24 months

    Arm title
    		 MK-8628 20 mg TNBC Cohort-Part A
    Arm description
    		 Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8628
    Investigational medicinal product code
    Other name
    OTX015
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered PO, BID, in a fasted state, for 21 consecutive days per cycle and administered in consecutive cycles for up to 24 months

    Number of subjects in period 1
    		MK-8628 20 mg CRPC Cohort-Part A MK-8628 20 mg NMC Cohort-Part A MK-8628 20 mg TNBC Cohort-Part A
    Started
    9
    3
    1
    Completed
    0
    0
    0
    Not completed
    9
    3
    1
         Clinical progression
    3
    -
    -
         Adverse event, non-fatal
    2
    -
    -
         Progressive disease
    4
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-8628 20 mg CRPC Cohort-Part A
    Reporting group description
    		 Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.

    Reporting group title
    MK-8628 20 mg NMC Cohort-Part A
    Reporting group description
    		 Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.

    Reporting group title
    MK-8628 20 mg TNBC Cohort-Part A
    Reporting group description
    		 Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.

    Reporting group values
    		 MK-8628 20 mg CRPC Cohort-Part A MK-8628 20 mg NMC Cohort-Part A MK-8628 20 mg TNBC Cohort-Part A Total
    Number of subjects
    		 9 3 1 13
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 2 0 2
        From 65-84 years
    		 9 1 1 11
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 71.2 (67 to 81) 42.7 (30 to 67) 66.0 (66 to 66) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 1 1 2
        Male
    		 9 2 0 11

    End points

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    End points reporting groups
    Reporting group title
    MK-8628 20 mg CRPC Cohort-Part A
    Reporting group description
    		 Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.

    Reporting group title
    MK-8628 20 mg NMC Cohort-Part A
    Reporting group description
    		 Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.

    Reporting group title
    MK-8628 20 mg TNBC Cohort-Part A
    Reporting group description
    		 Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.

    Subject analysis set title
    MK-8628 20 mg CRPC Cohort-Part A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in the CRPC cohort in Part A of the study received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months. No participants were enrolled in Part B of the study.

    Subject analysis set title
    MK-8628 20 mg NMC Cohort-Part A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in the NMC cohort in Part A of the study received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months. No participants were enrolled in Part B of the study.

    Subject analysis set title
    MK-8628 20 mg TNBC Cohort-Part A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in the TNBC cohort in Part A of the study received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months. No participants were enrolled in Part B of the study.

    Subject analysis set title
    MK-8628 20 mg-PK Cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Total number of participants from all 3 cohorts (CRPC+NMC+TNBC) in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state and had data available for the Pharmacokinetic (PK) parameter being analyzed.

    Subject analysis set title
    MK-8628 20 mg CRPC Cohort-Part A: DLT Cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in CRPC Cohort in Part A of the study that received at least 85% of the planned MK-8628 20 mg dose (18 days) PO, BID, in a fasted state or experienced a DLT during the first 21-day cycle.

    Subject analysis set title
    MK-8628 20 mg NMC Cohort-Part A: DLT Cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in NMC Cohort in Part A of the study that received at least 85% of the planned MK-8628 20 mg dose (18 days) PO, BID, in a fasted state or experienced a DLT during the first 21-day cycle.

    Subject analysis set title
    MK-8628 20 mg TNBC Cohort-Part A: DLT Cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in TNBC Cohort in Part A of the study that received at least 85% of the planned MK-8628 20 mg dose (18 days) PO, BID, in a fasted state or experienced a DLT during the first 21-day cycle.

    Subject analysis set title
    MK-8628 20 mg CRPC Cohort-Part A: Safety Cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in CRPC Cohort in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state. No participants were enrolled in Part B of the study.

    Subject analysis set title
    MK-8628 20 mg NMC Cohort-Part A: Safety Cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in NMC Cohort in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state. No participants were enrolled in Part B of the study.

    Subject analysis set title
    MK-8628 20 mg TNBC Cohort-Part A: Safety Cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in TNBC Cohort in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state. No participants were enrolled in Part B of the study.

    Primary: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1

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    End point title
    		 Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1
    End point description
    A DLT was any of the following deemed drug related (DR) by investigator: Grade (G)4 hematologic toxicity lasting ≥7 days except thrombocytopenia; G4 thrombocytopenia; G3 thrombocytopenia with bleeding; G3 or 4 febrile neutropenia. G4 non-hematologic (NH) toxicity (not laboratory); G3 NH toxicity (not laboratory), nausea, vomiting, or diarrhea lasting >3 days despite supportive care; G3 or 4 NH laboratory abnormality requiring medical intervention, hospitalization, or persisting >1 week; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X Upper Limit of Normal(ULN); ALT or AST >5XULN for >2 weeks; ALT or AST >3XULN and total bilirubin >2XULN or international normalization ratio >1.5; ALT or AST >3XULN with fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%); DR adverse event leading to discontinuation or >20% missed planned doses in Cycle 1; DR toxicity causing >2 week delay in starting Cycle 2; or G5 toxicity.
    End point type
    Primary
    End point timeframe
    From time of first dose up to the end of the first cycle (up to 21 days)
    End point values
    		 MK-8628 20 mg CRPC Cohort-Part A: DLT Cohort MK-8628 20 mg NMC Cohort-Part A: DLT Cohort MK-8628 20 mg TNBC Cohort-Part A: DLT Cohort
    Number of subjects analysed
    8
    3
    1
    Units: Participants
    2
    1
    0
    Statistical analysis title
    		 Estimation of DLT Rate
    Statistical analysis description
    A point estimate and a 2-sided 80% Bayesian credible interval for DLT rate was estimated for the total number of participants from all 3 cohorts (CRPC+NMC+TNBC) that were evaluable for DLT analysis based on a non-informative prior distribution of Beta (1,1).
    Comparison groups
    MK-8628 20 mg CRPC Cohort-Part A: DLT Cohort v MK-8628 20 mg NMC Cohort-Part A: DLT Cohort v MK-8628 20 mg TNBC Cohort-Part A: DLT Cohort
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 DLT Rate and Bayesian credible interval
    Point estimate
    0.25
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.121
         upper limit
    		 0.418

    Secondary: Number of Participants Who Experienced at Least One Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced at Least One Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who experienced at least one AE is presented.
    End point type
    Secondary
    End point timeframe
    From time of first dose until the end of the 30-day follow-up (up to 25 months)
    End point values
    		 MK-8628 20 mg CRPC Cohort-Part A: Safety Cohort MK-8628 20 mg NMC Cohort-Part A: Safety Cohort MK-8628 20 mg TNBC Cohort-Part A: Safety Cohort
    Number of subjects analysed
    9
    3
    1
    Units: Participants
    9
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE
    End point description
    The number of participants who discontinued study treatment due to an AE is presented.
    End point type
    Secondary
    End point timeframe
    From time of first dose until the end of treatment (up to 24 months)
    End point values
    		 MK-8628 20 mg CRPC Cohort-Part A: Safety Cohort MK-8628 20 mg NMC Cohort-Part A: Safety Cohort MK-8628 20 mg TNBC Cohort-Part A: Safety Cohort
    Number of subjects analysed
    9
    3
    1
    Units: Participants
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the number of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1) and lack of progression according to the guidelines for prostate cancer endpoints developed by Prostate Cancer Clinical Trials Working Group (PCWG) 2 as assessed by investigator radiologic review. The number of participants who achieved a CR or PR is presented.
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)
    End point values
    		 MK-8628 20 mg CRPC Cohort-Part A MK-8628 20 mg NMC Cohort-Part A MK-8628 20 mg TNBC Cohort-Part A
    Number of subjects analysed
    9
    3
    1
    Units: Participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    For participants who demonstrated CR or PR, DOR was defined as the time from first documented evidence of CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 and PCWG2 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression per RECIST 1.1. Per PCWG2, progressive disease was defined as a confirmed increase of at least two new lesions on a bone scan. DOR assessments were assessed by investigator radiologic review. The DOR for all participants who experienced a CR or PR is presented. Since no participants experienced a CR or PR, DOR could not be calculated.
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)
    End point values
    		 MK-8628 20 mg CRPC Cohort-Part A MK-8628 20 mg NMC Cohort-Part A MK-8628 20 mg TNBC Cohort-Part A
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [1] - No participants had a response of CR or PR.
    [2] - No participants had a response of CR or PR.
    [3] - No participants had a response of CR or PR.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR was defined as the number of subjects with CR, PR, or stable disease (SD) as assessed by investigator radiologic review according to RECIST version 1.1 and PCWG2. CR: defined as disappearance of all target and all non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm per RECIST 1.1. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions per RECIST 1.1. SD: defined as, neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study per RECIST 1.1 and lack of a confirmed increase of at least two new lesions on a bone scan per PCWG2. The number of participants who experienced DCR is presented.
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)
    End point values
    		 MK-8628 20 mg CRPC Cohort-Part A MK-8628 20 mg NMC Cohort-Part A MK-8628 20 mg TNBC Cohort-Part A
    Number of subjects analysed
    9 [4]
    3
    1
    Units: Participants
    6
    0
    0
    Notes
    [4] - Best Response was Stable Disease
    No statistical analyses for this end point

    Secondary: Observed Maximum Concentration (Cmax) of MK-8628

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    End point title
    		 Observed Maximum Concentration (Cmax) of MK-8628
    End point description
    Blood samples were obtained at specified time points for the pharmacokinetic (PK) analysis of Cmax of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Cmax of MK-8628 after oral administration is presented.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    355 ( 157 )
    No statistical analyses for this end point

    Secondary: Observed Minimum Concentration (Cmin) of MK-8628

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    End point title
    		 Observed Minimum Concentration (Cmin) of MK-8628
    End point description
    Blood samples were obtained at specified time points for the PK analysis of Cmin of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Cmin of MK-8628 after oral administration is presented.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    111 ( 45.9 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Concentration (Tmax) of MK-8628

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    End point title
    		 Time to Maximum Concentration (Tmax) of MK-8628
    End point description
    Blood samples were obtained at specified time points for the PK analysis of Tmax of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Tmax of MK-8628 after oral administration is presented.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    13
    Units: hours
        median (full range (min-max))
    2.25 (1.00 to 3.25)
    No statistical analyses for this end point

    Secondary: Apparent Terminal Half-Life (t1/2) of MK-8628

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    End point title
    		 Apparent Terminal Half-Life (t1/2) of MK-8628
    End point description
    Blood samples were obtained at specified time points for the PK analysis of t1/2 of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The t1/2 of MK-8628 after oral administration is presented. Due to limited PK sampling for t1/2, caution must be exercised when interpreting the results of t1/2, CL/F, and AUC 0-∞ values.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    8
    Units: hours
        arithmetic mean (standard deviation)
    6.17 ( 1.17 )
    No statistical analyses for this end point

    Secondary: Apparent Total Body Clearance (CL/F) of MK-8628

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    End point title
    		 Apparent Total Body Clearance (CL/F) of MK-8628
    End point description
    Blood samples were obtained at specified time points for the PK analysis of CL/F of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The CL/F of MK-8628 after oral administration is presented. Due to limited PK sampling for t1/2, caution must be exercised when interpreting the results of t1/2, CL/F, and AUC 0-∞ values.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    8
    Units: Liters/hour
        arithmetic mean (standard deviation)
    6.44 ( 2.23 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628

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    End point title
    		 Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628
    End point description
    Blood samples were obtained at specified time points for the PK analysis of Vz/F of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Vz/F of MK-8628 after oral administration is presented.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    8
    Units: Liters
        arithmetic mean (standard deviation)
    55.0 ( 15.3 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)

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    End point title
    		 Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)
    End point description
    Blood samples were obtained at specified time points for the PK analysis of AUC 0-∞ of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The AUC 0-∞ of MK-8628 after oral administration is presented. Due to limited PK sampling for t1/2, caution must be exercised when interpreting the results of t1/2, CL/F, and AUC 0-∞ values.
    End point type
    Secondary
    End point timeframe
    Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
    End point values
    		 MK-8628 20 mg-PK Cohort
    Number of subjects analysed
    8
    Units: hours•ng/mL
        arithmetic mean (standard deviation)
    3520 ( 1410 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of first dose until the end of the 30-day follow-up (up to 25 months)
    Adverse event reporting additional description
    The safety population consisted of all participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    MK-8628 20 mg CRPC Cohort-Part A: Safety Cohort
    Reporting group description
    		 Participants in CRPC Cohort in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state.

    Reporting group title
    MK-8628 20 mg NMC Cohort-Part A: Safety Cohort
    Reporting group description
    		 Participants in NMC Cohort in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state.

    Reporting group title
    MK-8628 20 mg TNBC Cohort-Part A: Safety Cohort
    Reporting group description
    		 Participants in TNBC Cohort in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state.

    Serious adverse events
    		 MK-8628 20 mg CRPC Cohort-Part A: Safety Cohort MK-8628 20 mg NMC Cohort-Part A: Safety Cohort MK-8628 20 mg TNBC Cohort-Part A: Safety Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MK-8628 20 mg CRPC Cohort-Part A: Safety Cohort MK-8628 20 mg NMC Cohort-Part A: Safety Cohort MK-8628 20 mg TNBC Cohort-Part A: Safety Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    3 / 3 (100.00%)
    1 / 1 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Leukocytosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    0
    Dyspepsia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    6 / 9 (66.67%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    0
    Odynophagia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Bone pain
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    Dehydration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2016
    Amendment 01: Primary reason for amendment was to incorporate revisions to the eligibility criteria to update the requirement for contraception.

    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.
    This study was terminated 16-Dec-2016 because limited efficacy was detected. The study was not terminated due to safety reasons.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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