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    Clinical Trial Results:
    0A phase I dose finding study of oral LTT462 in adult patients with advanced solid tumors harboring MAPK pathway alterations

    Summary
    EudraCT number
    		 2015-003614-24
    Trial protocol
    		 DE   NL   IT  
    Global end of trial date
    21 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2019
    First version publication date
    06 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLTT462X2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02711345
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    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
    21 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To characterize safety and tolerability of LTT462 and identify a recommended dose and regimen for future studies in adult and adolescent patients with advanced solid tumors harboring MAPK pathway alterations.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 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
    Japan: 7
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    65
    EEA total number of subjects
    24
    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)
    1
    Adults (18-64 years)
    44
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 65 subjects were enrolled into 10 treatment groups in the escalation part.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LTT462 45 mg QD
    Arm description
    		 Subjects received LTT462 45 milligram (mg) once daily (QD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 100 mg QD
    Arm description
    		 Subjects received 100 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 150 mg QD
    Arm description
    		 Subjects received 150 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 200 mg QD
    Arm description
    		 Subjects received 200 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 300 mg QD
    Arm description
    		 Subjects received 300 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 400 mg QD
    Arm description
    		 Subjects received 400 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 450 mg QD
    Arm description
    		 Subjects received 450 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 600 mg QD
    Arm description
    		 Subjects received 600 mg LTT462 QD as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 QD as oral capsules.

    Arm title
    		 LTT462 150 mg BID
    Arm description
    		 Subjects received 150 mg LTT462 twice daily (BID) as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 BID as oral capsules.

    Arm title
    		 LTT462 200 mg BID
    Arm description
    		 Subjects received 200 mg LTT462 BID as oral capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LTT462
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LTT462 BID as oral capsules.

    Number of subjects in period 1
    		LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Started
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Entered post-treatment follow-up
    0
    0
    1
    1
    1
    2
    3
    0
    1
    1
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
         Physician decision
    -
    -
    1
    -
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
    1
    2
    1
    -
    -
    2
         Death
    1
    -
    -
    -
    -
    -
    -
    1
    -
    -
         Progressive disease
    1
    3
    5
    3
    7
    2
    8
    4
    5
    6
         Subject/guardian decision
    -
    -
    -
    -
    -
    2
    3
    1
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LTT462 45 mg QD
    Reporting group description
    		 Subjects received LTT462 45 milligram (mg) once daily (QD)

    Reporting group title
    LTT462 100 mg QD
    Reporting group description
    		 Subjects received 100 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 150 mg QD
    Reporting group description
    		 Subjects received 150 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 200 mg QD
    Reporting group description
    		 Subjects received 200 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 300 mg QD
    Reporting group description
    		 Subjects received 300 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 400 mg QD
    Reporting group description
    		 Subjects received 400 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 450 mg QD
    Reporting group description
    		 Subjects received 450 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 600 mg QD
    Reporting group description
    		 Subjects received 600 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 150 mg BID
    Reporting group description
    		 Subjects received 150 mg LTT462 twice daily (BID) as oral capsules.

    Reporting group title
    LTT462 200 mg BID
    Reporting group description
    		 Subjects received 200 mg LTT462 BID as oral capsules.

    Reporting group values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID Total
    Number of subjects
    		 2 3 6 4 8 6 12 6 6 12 65
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 0 0 0 0 1 0 0 0 0 0 1
        Adults (18-64 years)
    		 1 2 5 3 5 5 7 5 5 6 44
        From 65-84 years
    		 1 1 1 1 2 1 5 1 1 6 20
    Gender categorical
    Units: Subjects
        Female
    		 1 3 4 2 6 4 5 4 4 7 40
        Male
    		 1 0 2 2 2 2 7 2 2 5 25
    Subject analysis sets

    Subject analysis set title
    All LTT462 QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received 45 to 600 mg LTT462 QD as oral capsules

    Subject analysis set title
    All LTT462 BID
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received 150 and 200 mg LTT462 BID as oral capsules.

    Subject analysis sets values
    		 All LTT462 QD All LTT462 BID
    Number of subjects
    47
    18
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    1
    0
        Adults (18-64 years)
    33
    11
        From 65-84 years
    13
    7
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    29
    11
        Male
    18
    7

    End points

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    End points reporting groups
    Reporting group title
    LTT462 45 mg QD
    Reporting group description
    		 Subjects received LTT462 45 milligram (mg) once daily (QD)

    Reporting group title
    LTT462 100 mg QD
    Reporting group description
    		 Subjects received 100 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 150 mg QD
    Reporting group description
    		 Subjects received 150 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 200 mg QD
    Reporting group description
    		 Subjects received 200 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 300 mg QD
    Reporting group description
    		 Subjects received 300 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 400 mg QD
    Reporting group description
    		 Subjects received 400 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 450 mg QD
    Reporting group description
    		 Subjects received 450 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 600 mg QD
    Reporting group description
    		 Subjects received 600 mg LTT462 QD as oral capsules.

    Reporting group title
    LTT462 150 mg BID
    Reporting group description
    		 Subjects received 150 mg LTT462 twice daily (BID) as oral capsules.

    Reporting group title
    LTT462 200 mg BID
    Reporting group description
    		 Subjects received 200 mg LTT462 BID as oral capsules.

    Subject analysis set title
    All LTT462 QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received 45 to 600 mg LTT462 QD as oral capsules

    Subject analysis set title
    All LTT462 BID
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received 150 and 200 mg LTT462 BID as oral capsules.

    Primary: Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An adverse events is defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occur after subject’s signed informed consent has been obtained. Analysis was performed in safety set population defined as all subjects who had received at least one dose of LTT462.
    End point type
    Primary
    End point timeframe
    Up to 2.8 years
    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: The statistical analyses was not planned for this outcome measure.
    End point values
    		 All LTT462 QD All LTT462 BID
    Number of subjects analysed
    47
    18
    Units: Percentage of subjects
    number (not applicable)
        AEs
    100
    100
        SAEs
    48.9
    44.4
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Dose Limiting Toxicities (DLTs)

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    End point title
    		 Percentage of Subjects With Dose Limiting Toxicities (DLTs) [2]
    End point description
    Percentage of subjects with dose limiting toxicity were reported. The dose determining set included all subjects from the safety set enrolled in the escalation part of the study who, during the first 28 days of dosing, had received at least 75 percent of the planned daily doses of LTT462 and had had sufficient safety evaluations, or had experienced a DLT.
    End point type
    Primary
    End point timeframe
    Up to 2.8 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analyses was not planned for this outcome measure.
    End point values
    		 All LTT462 QD All LTT462 BID
    Number of subjects analysed
    36
    13
    Units: Percentage of subjects
        number (not applicable)
    19.4
    30.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least One Dose Reduction

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    End point title
    		 Percentage of Subjects With at Least One Dose Reduction [3]
    End point description
    Percentage of subjects with at least one dose reduction were reported. The safety set included all subjects who had received at least one dose of LTT462.
    End point type
    Primary
    End point timeframe
    Up to 2.8 years
    Notes
    [3] - 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: The statistical analyses was not planned for this outcome measure.
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Units: Percentage of subjects
        number (not applicable)
    0
    0
    16.7
    0
    0
    0
    16.7
    33.3
    16.7
    33.3
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least One Dose Interruptions

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    End point title
    		 Percentage of Subjects With at Least One Dose Interruptions [4]
    End point description
    Percentage of subjects with at least dose interruptions were reported. The safety set included all subjects who had received at least one dose of LTT462.
    End point type
    Primary
    End point timeframe
    Up to 2.8 years
    Notes
    [4] - 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: The statistical analyses was not planned for this outcome measure.
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Units: Percentage of subjects
        number (not applicable)
    100
    100
    100
    100
    100
    100
    100
    100
    100
    100
    No statistical analyses for this end point

    Primary: Dose Intensity Received by Subjects

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    End point title
    		 Dose Intensity Received by Subjects [5]
    End point description
    Dose intensity of LTT462 received by treatment group was reported. The safety set included all subjects who had received at least one dose of LTT462.
    End point type
    Primary
    End point timeframe
    Up to 2.8 years
    Notes
    [5] - 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: The statistical analyses was not planned for this outcome measure.
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Units: milligram per day (mg/day)
        arithmetic mean (standard deviation)
    65.3 ( 28.74 )
    98.1 ( 3.21 )
    133.9 ( 21.84 )
    200 ( 0 )
    272.7 ( 30.9 )
    326.7 ( 81.54 )
    409.2 ( 64.88 )
    468.2 ( 171.48 )
    131.6 ( 22.08 )
    178.0 ( 35.32 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Response Rate (ORR)

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    End point title
    		 Percentage of Subjects With Overall Response Rate (ORR)
    End point description
    Percentage of subjects with ORR were reported. The full analysis set included all Subjects who had received at least one dose of LTT462.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Units: Percentage of Subjects
        number (confidence interval 95%)
    0 (0 to 84.2)
    0 (0 to 70.8)
    0 (0 to 45.9)
    0 (0 to 60.2)
    0 (0 to 36.9)
    0 (0 to 45.9)
    0 (0 to 26.5)
    0 (0 to 45.9)
    0 (0 to 45.9)
    0 (0 to 26.5)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Control Rate (DCR)

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    End point title
    		 Percentage of Subjects With Disease Control Rate (DCR)
    End point description
    Percentage of subjects with DCR were reported. The full analysis set included all Subjects who had received at least one dose of LTT462.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Units: Percentage of subjects
        number (confidence interval 95%)
    50 (1.3 to 98.7)
    0 (0 to 70.8)
    0 (0 to 45.9)
    0 (0 to 60.2)
    37.5 (8.5 to 75.5)
    16.7 (0.4 to 64.1)
    8.3 (0.2 to 38.5)
    16.7 (0.4 to 64.1)
    16.7 (0.4 to 64.1)
    0 (0 to 26.5)
    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
    Percentage of subjects with DOR were reported. The study was stopped due to limited clinical activity at the end of the dose escalation phase. The dose expansion part was not opened.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    Units: Months
        number (not applicable)
    Notes
    [6] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [7] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [8] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [9] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [10] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [11] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [12] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [13] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [14] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    [15] - The study was stopped due to limited clinical activity at the end of the dose escalation phase.
    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
    Median time for progression free survival was reported. The full analysis set included all Subjects who had received at least one dose of LTT462.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
    End point values
    		 All LTT462 QD All LTT462 BID
    Number of subjects analysed
    47
    18
    Units: Months
        median (confidence interval 95%)
    1.7 (1.3 to 1.8)
    1.6 (1.2 to 1.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - Only for Dose Expansion Phase

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    End point title
    		 Overall Survival (OS) - Only for Dose Expansion Phase
    End point description
    Median time for overall survival, only for dose expansion phase was reported. Overall survival was not evaluated because the study ended before enrolling into the dose-expansion part.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    Units: Months
        number (not applicable)
    Notes
    [16] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [17] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [18] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [19] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [20] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [21] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [22] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [23] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [24] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    [25] - Overall survival was not evaluated because the study ended before enrolling into the dose-expansion
    No statistical analyses for this end point

    Secondary: Maximum (Peak) Observed Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Cmax) After Single Dose Administration of LTT462

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    End point title
    		 Maximum (Peak) Observed Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Cmax) After Single Dose Administration of LTT462
    End point description
    Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration expressed in mass x volume-1. Pharmacokinetic (PK) analysis set (PAS) included of all Subjects who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn’t vomit within 4 hours post-dose, had at least 1 primary PK parameter. Here ‘n’ number analyzed signifies number of Subjects who were evaluable at each time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    11
    4
    6
    12
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1 (n=2,3,6,4,7,6,10,3,5,12)
    61.3 ( 55.9 )
    134 ( 38.8 )
    218 ( 230.9 )
    494 ( 126.8 )
    717 ( 127.4 )
    1580 ( 60.8 )
    1420 ( 83.5 )
    1280 ( 47.7 )
    598 ( 83 )
    575 ( 73.8 )
        Day 15 (n=2,3,5,3,6,4,8,2,5,6)
    139 ( 29.9 )
    938 ( 82.5 )
    707 ( 69 )
    972 ( 92.4 )
    1330 ( 131.9 )
    2370 ( 83.3 )
    3470 ( 49.7 )
    1030 ( 248.8 )
    1390 ( 58.5 )
    1510 ( 108 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LTT462

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    End point title
    		 Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LTT462
    End point description
    AUClast is the area under the curve from time zero to the last measurable concentration sampling time calculated by mass * time *volume^-1. PAS included of all Subjects who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn’t vomit within 4 hours postdose, had at least 1 primary PK parameter. Here ‘N’ number of Subjects analyzed signifies number of Subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    2
    6
    4
    7
    6
    10
    3
    5
    12
    Units: hour*nanogram per milliliter (h*ng/mL)
        geometric mean (geometric coefficient of variation)
    851 ( 106 )
    2260 ( 30 )
    3880 ( 133.6 )
    10400 ( 95.4 )
    12800 ( 157.4 )
    23300 ( 55.5 )
    23800 ( 115.3 )
    11800 ( 64.2 )
    9240 ( 78.3 )
    7630 ( 98.8 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum (Peak) Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Tmax) After Single Dose Administration of LTT462

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    End point title
    		 Time to Reach Maximum (Peak) Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Tmax) After Single Dose Administration of LTT462
    End point description
    Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration. PAS included of all Subjects who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn’t vomit within 4 hours post-dose, had at least 1 primary PK parameter. Here ‘n’ number analyzed signifies number of Subjects who were evaluable at each time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    11
    4
    6
    12
    Units: Hours
    median (full range (min-max))
        Day 1 (n=2,3,6,4,7,6,10,3,5,12)
    2.45 (0.967 to 3.93)
    1.98 (0.867 to 24)
    3.49 (2 to 24.3)
    5.48 (3 to 46.4)
    3.08 (2.08 to 48.8)
    3.04 (1.12 to 4)
    3.98 (2.42 to 7.77)
    3.95 (2 to 4.2)
    2.25 (2 to 49.8)
    3.03 (0.467 to 7.78)
        Day 15 (n=2,3,5,3,6,4,8,2,5,6)
    5.93 (4 to 7.85)
    4.02 (1 to 4.83)
    4.05 (2.13 to 8)
    3 (2.17 to 3.02)
    2.59 (1.58 to 4.03)
    2.55 (1.87 to 3.15)
    2.98 (1 to 7.62)
    5.25 (3 to 7.5)
    2.17 (2.05 to 3.15)
    2.18 (2 to 4.15)
    No statistical analyses for this end point

    Secondary: Elimination Half-life (T1/2) of LTT462

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    End point title
    		 Elimination Half-life (T1/2) of LTT462
    End point description
    T1/2 is the Elimination half-life. PAS included of all Subjects who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn’t vomit within 4 hours postdose, had at least 1 primary PK parameter. Here ‘N’ number of Subjects analyzed signifies number of Subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    1
    2
    4
    2
    3
    6
    7
    2
    2
    9
    Units: Hours
        median (full range (min-max))
    27.9 (27.9 to 27.9)
    39.2 (28.8 to 49.5)
    20.8 (13.4 to 24.5)
    16.8 (16.7 to 16.8)
    15.2 (14.9 to 19.6)
    14.0 (12.0 to 18.7)
    17.6 (16.1 to 18.9)
    13.2 (11.8 to 14.5)
    16.2 (13.3 to 19.1)
    17.1 (11.6 to 41.1)
    No statistical analyses for this end point

    Secondary: Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of LTT462

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    End point title
    		 Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of LTT462
    End point description
    AUCtau is the area under the curve calculated to the end of a dosing interval (tau) at steady-state calculated by formula amount *time * volume^-1. PAS included of all Subjects who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn’t vomit within 4 hours post-dose, had at least 1 primary PK parameter. Here ‘N’ number of Subjects analyzed signifies number of Subjects who were evaluable for this outcome measure. Here, '99999' signifies data was not calculated due to single subject in the arm.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    1
    1
    4
    3
    5
    4
    4
    1
    5
    4
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    3010 ( 99999 )
    6370 ( 99999 )
    8660 ( 50.0 )
    14600 ( 96.5 )
    13100 ( 81.6 )
    25400 ( 74.3 )
    35400 ( 94.8 )
    6760 ( 99999 )
    11100 ( 59.5 )
    18600 ( 85.2 )
    No statistical analyses for this end point

    Secondary: Accumulation Ratio (Racc) of LTT462

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    End point title
    		 Accumulation Ratio (Racc) of LTT462
    End point description
    Racc is the accumulation ratio calculated by AUCtau ratio Day 15 versus Day 1. PAS included of all Subjects who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn’t vomit within 4 hours post-dose, had at least 1 primary PK parameter. Here ‘N’ number of Subjects analyzed signifies number of Subjects who were evaluable for this outcome measure. Here, '99999' signifies data was not calculated due to single subject in the arm. Here, '99999' signifies data was not calculated due to single subject in the arm.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    1
    1
    4
    3
    4
    4
    3
    0 [26]
    4
    4
    Units: Ratio
        geometric mean (geometric coefficient of variation)
    3.01 ( 99999 )
    3.35 ( 99999 )
    5.09 ( 72.7 )
    2.74 ( 46.9 )
    1.49 ( 25.1 )
    1.73 ( 62.4 )
    1.44 ( 73.4 )
    ( )
    3.19 ( 50.2 )
    6.89 ( 84.3 )
    Notes
    [26] - No subject was evaluable in this arm
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Relative Quantity (RQ) of Dual Specificity Phosphatase 6 (DUSP6) in Blood sample

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    End point title
    		 Changes From Baseline in Relative Quantity (RQ) of Dual Specificity Phosphatase 6 (DUSP6) in Blood sample
    End point description
    Assessment of Pharmacodynamic (PD) effects of LTT462 in tumor, pre- and post- treatment tumor biopsies were examined for expression of DUSP6. For assessment of PD effects in blood, levels of DUSP6 were measured in blood samples. The full analysis set included all subjects who had received at least one dose of LTT462. Here, '99999' signifies data was not calculated due to single subject in the arm.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2, 3, 15 and 16
    End point values
    		 LTT462 45 mg QD LTT462 100 mg QD LTT462 150 mg QD LTT462 200 mg QD LTT462 300 mg QD LTT462 400 mg QD LTT462 450 mg QD LTT462 600 mg QD LTT462 150 mg BID LTT462 200 mg BID
    Number of subjects analysed
    2
    3
    6
    4
    8
    6
    12
    6
    6
    12
    Units: Ratio
    arithmetic mean (standard deviation)
        Tumor Sample (n=1,2,4,1,4,1,4,1,2,3)
    -0.2 ( 99999 )
    0.8 ( 1.11 )
    -1.1 ( 29.46 )
    -28.8 ( 99999 )
    -31.0 ( 31.06 )
    -56.5 ( 99999 )
    -22.2 ( 28.67 )
    -79.9 ( 99999 )
    -61.8 ( 4.16 )
    -14.4 ( 22.27 )
        Blood Sample (n=2,3,6,3,8,6,12,6,6,11)
    -50.8 ( 6.14 )
    -66.1 ( 40.22 )
    -35.2 ( 27.33 )
    -34.7 ( 22.02 )
    -42.5 ( 16.56 )
    -43 ( 13.67 )
    -40.1 ( 9.92 )
    -40.4 ( 21.04 )
    -39.2 ( 12.98 )
    -32.9 ( 18.71 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were evaluated from screening until at least 30 days after the discontinuation of study treatment (Up to 2.8 years)
    Adverse event reporting additional description
    The Safety Set included all subjects who had received at least one dose of LTT462.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    All LTT462 QD
    Reporting group description
    		 All subjects who received 45 to 600 mg LTT462 QD as oral capsules

    Reporting group title
    All LTT462 BID
    Reporting group description
    		 Subjects received 150 and 200 mg LTT462 BID as oral capsules.

    Serious adverse events
    		 All LTT462 QD All LTT462 BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 47 (48.94%)
    8 / 18 (44.44%)
         number of deaths (all causes)
    6
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Biliary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All LTT462 QD All LTT462 BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 47 (97.87%)
    18 / 18 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 18 (0.00%)
         occurrences all number
    6
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 18 (11.11%)
         occurrences all number
    8
    2
    Fatigue
         subjects affected / exposed
    8 / 47 (17.02%)
    6 / 18 (33.33%)
         occurrences all number
    9
    7
    Mucosal haemorrhage
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    6 / 47 (12.77%)
    2 / 18 (11.11%)
         occurrences all number
    7
    2
    Pyrexia
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Swelling
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Dyspnoea
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 47 (19.15%)
    1 / 18 (5.56%)
         occurrences all number
    9
    1
    Amylase increased
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 18 (16.67%)
         occurrences all number
    2
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 47 (21.28%)
    5 / 18 (27.78%)
         occurrences all number
    11
    6
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 47 (14.89%)
    1 / 18 (5.56%)
         occurrences all number
    8
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 18 (11.11%)
         occurrences all number
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 47 (14.89%)
    3 / 18 (16.67%)
         occurrences all number
    9
    4
    Blood creatinine increased
         subjects affected / exposed
    9 / 47 (19.15%)
    2 / 18 (11.11%)
         occurrences all number
    10
    3
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Gamma-glutamyltransferase
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 18 (11.11%)
         occurrences all number
    8
    2
    Lipase
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Liver function test
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 18 (5.56%)
         occurrences all number
    7
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 47 (38.30%)
    4 / 18 (22.22%)
         occurrences all number
    22
    6
    Leukocytosis
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Leukopenia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Neutropenia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 18 (5.56%)
         occurrences all number
    2
    2
    Thrombocytopenia
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Chorioretinopathy
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 18 (11.11%)
         occurrences all number
    11
    3
    Cystoid macular oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Macular oedema
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Retinal detachment
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 18 (16.67%)
         occurrences all number
    6
    3
    Retinal pigment epitheliopathy
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Retinopathy
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 18 (16.67%)
         occurrences all number
    5
    3
    Vision blurred
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 18 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    Abdominal pain
         subjects affected / exposed
    6 / 47 (12.77%)
    0 / 18 (0.00%)
         occurrences all number
    7
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Ascites
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Constipation
         subjects affected / exposed
    6 / 47 (12.77%)
    1 / 18 (5.56%)
         occurrences all number
    6
    1
    Diarrhoea
         subjects affected / exposed
    22 / 47 (46.81%)
    6 / 18 (33.33%)
         occurrences all number
    30
    7
    Gingival bleeding
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    21 / 47 (44.68%)
    7 / 18 (38.89%)
         occurrences all number
    26
    10
    Vomiting
         subjects affected / exposed
    19 / 47 (40.43%)
    7 / 18 (38.89%)
         occurrences all number
    25
    10
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Jaundice
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Portal vein thrombosis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Alopecia
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Dermatitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    6 / 47 (12.77%)
    2 / 18 (11.11%)
         occurrences all number
    6
    2
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Hyperkeratosis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    8 / 47 (17.02%)
    4 / 18 (22.22%)
         occurrences all number
    9
    4
    Rash
         subjects affected / exposed
    14 / 47 (29.79%)
    7 / 18 (38.89%)
         occurrences all number
    20
    7
    Rash maculo-papular
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Myalgia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rash pustular
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 47 (29.79%)
    3 / 18 (16.67%)
         occurrences all number
    14
    4
    Hypercalcaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Hyperphosphataemia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 47 (17.02%)
    1 / 18 (5.56%)
         occurrences all number
    11
    1
    Hypocalcaemia
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 18 (0.00%)
         occurrences all number
    5
    0
    Hypomagnesaemia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Hyponatraemia
         subjects affected / exposed
    5 / 47 (10.64%)
    4 / 18 (22.22%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jul 2016
    - Added laboratory evaluation for inorganic phosphorus to blood chemistry panel
    14 Aug 2017
    - Changed description of LTT462 from having mild phototoxic potential to no phototoxic potential and removed requirement for sun protection precautions
    13 Mar 2018
    - Reduced the minimum age of prospective subjects from ≥18 years to ≥12 years. - Amended biopsy inclusion criterion to allow adolescent subjects to participate without having to provide the required new biopsy at screening or on treatment if not feasible.

    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.
    The study was stopped due to limited clinical activity at the end of the dose escalation phase. The dose expansion part was not opened.
    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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