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    Clinical Trial Results:
    A phase Ib/II, multi-center, study of oral LGH447 in combination with oral BYL719 in patients with relapsed and refractory multiple myeloma Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2013-004959-21
    Trial protocol
    		 DE   IT  
    Global end of trial date
    28 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2018
    First version publication date
    18 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLGH447X2103C
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02144038
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH- 4002, Basel, Switzerland,
    Public contact
    Novartis Pharma AG, NOVARTIS Pharma AG, 41 613241111,
    Scientific contact
    Clinical Novartis Pharma AG, 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
    28 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase Ib: to estimate the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) for LGH447 in combination with BYL719 in patients with relapsed and refractory multiple myeloma.
    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
    23 Jul 2014
    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
    Australia: 3
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    20
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    14
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 It was expected that 20-25 patients were to be enrolled in this Phase Ib portion of the study. The actual number of patients could be adapted by results obtained during the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LGH 200mg + BYL 100mg
    Arm description
    		 Patients in this arm received 200 mg qd LGH447 and 100 mg qd BYL719
    Arm type
    		 Experimental

    Investigational medicinal product name
    LGH447
    Investigational medicinal product code
    LGH477
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    LGH477 was an investigational drug and was supplied as 10 mg, 50 mg, and 200 mg hard gelatin capsules for oral use. LGH477 was dosed prior to BYL719 on a flat scale of mg/day and was not adjusted to body weight or body surface area.

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    alpelisib
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BYL719 was an investigational drug and was supplied as 10 mg, 50 mg, and 100 mg film-coated tablets for oral use. BYL719 was dosed immediately following LGH447 on a flat scale of mg/day and was not adjusted to body weight or body surface area.

    Arm title
    		 LGH 150mg + BYL 150mg
    Arm description
    		 Patients in this arm received doses of 150 mg qd LGH447 and 150 mg qd BYL719
    Arm type
    		 Experimental

    Investigational medicinal product name
    LGH447
    Investigational medicinal product code
    LGH477
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    LGH477 was an investigational drug and was supplied as 10 mg, 50 mg, and 150 mg hard gelatin capsules for oral use. LGH477 was dosed prior to BYL719 on a flat scale of mg/day and was not adjusted to body weight or body surface area.

    Investigational medicinal product name
    alpelisib
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BYL719 was an investigational drug and was supplied as 10 mg, 50 mg, and 150 mg film-coated tablets for oral use. BYL719 was dosed immediately following LGH447 on a flat scale of mg/day and was not adjusted to body weight or body surface area.

    Arm title
    		 LGH 200mg + BYL 200mg
    Arm description
    		 Patients in this arm received doses of 200 mg qd LGH447 and 200 mg qd BYL719
    Arm type
    		 Experimental

    Investigational medicinal product name
    LGH447
    Investigational medicinal product code
    LGH477
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    LGH477 was an investigational drug and was supplied as 10 mg, 50 mg, and 200 mg hard gelatin capsules for oral use. LGH477 was dosed prior to BYL719 on a flat scale of mg/day and was not adjusted to body weight or body surface area.

    Investigational medicinal product name
    alpelisib
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BYL719 was an investigational drug and was supplied as 10 mg, 50 mg, and 200 mg film-coated tablets for oral use. BYL719 was dosed immediately following LGH447 on a flat scale of mg/day and was not adjusted to body weight or body surface area.

    Number of subjects in period 1
    		LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Started
    7
    4
    9
    Completed
    0
    0
    0
    Not completed
    7
    4
    9
         Subject withdrew consent
    1
    -
    -
         Physician decision
    -
    1
    -
         Disease progression
    2
    3
    4
         Adverse event, non-fatal
    3
    -
    3
         Death
    -
    -
    1
         Subject/guardian decision
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LGH 200mg + BYL 100mg
    Reporting group description
    		 Patients in this arm received 200 mg qd LGH447 and 100 mg qd BYL719

    Reporting group title
    LGH 150mg + BYL 150mg
    Reporting group description
    		 Patients in this arm received doses of 150 mg qd LGH447 and 150 mg qd BYL719

    Reporting group title
    LGH 200mg + BYL 200mg
    Reporting group description
    		 Patients in this arm received doses of 200 mg qd LGH447 and 200 mg qd BYL719

    Reporting group values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg Total
    Number of subjects
    		 7 4 9 20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 4 6 14
        From 65-84 years
    		 3 0 3 6
    Age continuous
    Units: years
        median (standard deviation)
    		 58.9 ( 9.32 ) 60.8 ( 1.5 ) 62.2 ( 61 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 3 3 8
        Male
    		 5 1 6 12

    End points

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    End points reporting groups
    Reporting group title
    LGH 200mg + BYL 100mg
    Reporting group description
    		 Patients in this arm received 200 mg qd LGH447 and 100 mg qd BYL719

    Reporting group title
    LGH 150mg + BYL 150mg
    Reporting group description
    		 Patients in this arm received doses of 150 mg qd LGH447 and 150 mg qd BYL719

    Reporting group title
    LGH 200mg + BYL 200mg
    Reporting group description
    		 Patients in this arm received doses of 200 mg qd LGH447 and 200 mg qd BYL719

    Primary: Maximum Tolerted dose (MTD) or Recommended Phase 2 Dose (RP2D)

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    End point title
    		 Maximum Tolerted dose (MTD) or Recommended Phase 2 Dose (RP2D) [1]
    End point description
    The study was terminated prematurely and no maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) was declared.
    End point type
    Primary
    End point timeframe
    Cycle 1 = 28 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    7
    4
    9
    Units: Pariticipants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Primary PK Paramenter for LGH447: AUC0-24

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    End point title
    		 Primary PK Paramenter for LGH447: AUC0-24
    End point description
    Pharmacokinetics (PK) parameters were estimated and reported, when feasible, by noncompartmental analysis of LGH447 and BYL719 concentration versus time data. Only PK blood samples with dates and times and for which the dose dates and times were adequately recorded were included in the PK analyses. Samples taken from patients who vomited within 4 hours of dosing were excluded from summary statistics. AUC0-24: Area under the plasma concentration-time curve calculated from time zero to 24 hour.
    End point type
    Secondary
    End point timeframe
    C1D1, C1D15
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    6
    4
    8
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (C1D1)
    22700 ( 14000 )
    14200 ( 14700 )
    25000 ( 12900 )
        Cycle 1, Day 15 (C1, D15)
    78100 ( 38600 )
    32500 ( 15300 )
    61700 ( 21400 )
    No statistical analyses for this end point

    Secondary: Primary PK parameters for LGH447: Cmax

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    End point title
    		 Primary PK parameters for LGH447: Cmax
    End point description
    Pharmacokinetics (PK) parameters were estimated and reported, when feasible, by noncompartmental analysis of LGH447 and BYL719 concentration versus time data. Only PK blood samples with dates and times and for which the dose dates and times were adequately recorded were included in the PK analyses. Samples taken from patients who vomited within 4 hours of dosing were excluded from summary statistics. Cmax = Maximum (peak) observed plasma drug concentration (mass x volume-1).
    End point type
    Secondary
    End point timeframe
    C1D1, C1D15
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    6
    4
    8
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1
    1580 ( 957 )
    885 ( 788 )
    1490 ( 729 )
        C1D15
    3840 ( 1730 )
    1810 ( 665 )
    3160 ( 1050 )
    No statistical analyses for this end point

    Secondary: Primary PK paramenters for LGH447: Tmax

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    End point title
    		 Primary PK paramenters for LGH447: Tmax
    End point description
    Pharmacokinetics (PK) parameters were estimated and reported, when feasible, by noncompartmental analysis of LGH447 and BYL719 concentration versus time data. Only PK blood samples with dates and times and for which the dose dates and times were adequately recorded were included in the PK analyses. Samples taken from patients who vomited within 4 hours of dosing were excluded from summary statistics. Following oral dose of both study drugs, mean peak plasma concentrations were achieved at Tmax ranging from 2 to 5 hr post-dose. Tmax: Time to reach maximum (peak) plasma drug concentration (time).
    End point type
    Secondary
    End point timeframe
    C1D1, C1D15
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    6
    4
    8
    Units: hr
    median (full range (min-max))
        C1D1
    2.51 (1.92 to 6)
    4.15 (3.03 to 5.02)
    3.96 (2 to 24.3)
        C1D15
    4.95 (4 to 6)
    2.45 (1.98 to 2.92)
    4 (2.98 to 7.75)
    No statistical analyses for this end point

    Secondary: Primary PK parameter for BYL719: AUC0-24

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    End point title
    		 Primary PK parameter for BYL719: AUC0-24
    End point description
    Pharmacokinetics (PK) parameters were estimated and reported, when feasible, by noncompartmental analysis of LGH447 and BYL719 concentration versus time data. Only PK blood samples with dates and times and for which the dose dates and times were adequately recorded were included in the PK analyses. Samples taken from patients who vomited within 4 hours of dosing were excluded from summary statistics. AUC0-24: Area under the plasma concentration-time curve calculated from time zero to 24 hour.
    End point type
    Secondary
    End point timeframe
    C1D1, C1D15
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    6
    3
    8
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (C1D1)
    8970 ( 3960 )
    4970 ( 1730 )
    12900 ( 4790 )
        Cycle 1, Day 15 (C1D15)
    6650 ( 3300 )
    7850 ( 999.99 )
    17900 ( 5960 )
    No statistical analyses for this end point

    Secondary: Primary PK parameter for BYL719: Cmax

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    End point title
    		 Primary PK parameter for BYL719: Cmax
    End point description
    Pharmacokinetics (PK) parameters were estimated and reported, when feasible, by noncompartmental analysis of LGH447 and BYL719 concentration versus time data. Only PK blood samples with dates and times and for which the dose dates and times were adequately recorded were included in the PK analyses. Samples taken from patients who vomited within 4 hours of dosing were excluded from summary statistics. Cmax = Maximum (peak) observed plasma drug concentration (mass x volume-1).
    End point type
    Secondary
    End point timeframe
    C1D1, C1D15
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    6
    3
    8
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1
    1040 ( 483 )
    439 ( 152 )
    1230 ( 400 )
        C1D15
    535 ( 298 )
    674 ( 99.99 )
    1500 ( 453 )
    No statistical analyses for this end point

    Secondary: Primary PK parameter for BYL719: Tmax

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    End point title
    		 Primary PK parameter for BYL719: Tmax
    End point description
    Pharmacokinetics (PK) parameters were estimated and reported, when feasible, by noncompartmental analysis of LGH447 and BYL719 concentration versus time data. Only PK blood samples with dates and times and for which the dose dates and times were adequately recorded were included in the PK analyses. Samples taken from patients who vomited within 4 hours of dosing were excluded from summary statistics. Following oral dose of both study drugs, mean peak plasma concentrations were achieved at Tmax ranging from 2 to 5 hr post-dose. Tmax: Time to reach maximum (peak) plasma drug concentration (time).
    End point type
    Secondary
    End point timeframe
    C1D1, C1D15
    End point values
    		 LGH 200mg + BYL 100mg LGH 150mg + BYL 150mg LGH 200mg + BYL 200mg
    Number of subjects analysed
    6
    3
    8
    Units: hr
    median (full range (min-max))
        C1D1
    2.01 (1.92 to 2.92)
    3.95 (2.08 to 5.02)
    3.46 (2 to 5.08)
        C1D15
    4 (1.97 to 5)
    2.92 (2.92 to 2.92)
    2.96 (2.05 to 6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    LGH 200mg + BYL 100mg
    Reporting group description
    		 LGH 200mg + BYL 100mg

    Reporting group title
    LGH 200mg + BYL 200mg
    Reporting group description
    		 LGH 200mg + BYL 200mg

    Reporting group title
    LGH 150mg + BYL 150mg
    Reporting group description
    		 LGH 150mg + BYL 150mg

    Serious adverse events
    		 LGH 200mg + BYL 100mg LGH 200mg + BYL 200mg LGH 150mg + BYL 150mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 9 (44.44%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    0
    2
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (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
    White blood cell count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (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
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (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
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (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
    Pseudomonas infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (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
    Sepsis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (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
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LGH 200mg + BYL 100mg LGH 200mg + BYL 200mg LGH 150mg + BYL 150mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    9 / 9 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmacytoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    5 / 7 (71.43%)
    4 / 9 (44.44%)
    3 / 4 (75.00%)
         occurrences all number
    5
    4
    3
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 9 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    5
    4
    2
    Temperature intolerance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    1
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 9 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    5
    9
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Glutamate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Lipase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 9 (44.44%)
    0 / 4 (0.00%)
         occurrences all number
    5
    5
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Spinal compression fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Hypersomnia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    2
    Hypogeusia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Sensory loss
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    6 / 9 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    12
    14
    2
    Increased tendency to bruise
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    7
    3
    Neutropenia
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 9 (55.56%)
    2 / 4 (50.00%)
         occurrences all number
    10
    15
    7
    Thrombocytopenia
         subjects affected / exposed
    2 / 7 (28.57%)
    6 / 9 (66.67%)
    3 / 4 (75.00%)
         occurrences all number
    5
    10
    3
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Photopsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
    4 / 9 (44.44%)
    2 / 4 (50.00%)
         occurrences all number
    8
    4
    2
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 9 (44.44%)
    2 / 4 (50.00%)
         occurrences all number
    1
    4
    2
    Oesophagitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    1
    Vomiting
         subjects affected / exposed
    6 / 7 (85.71%)
    4 / 9 (44.44%)
    0 / 4 (0.00%)
         occurrences all number
    10
    6
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Drug eruption
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    Erythema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Onychoclasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Palmar erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Polyuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Muscle twitching
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Cholecystitis infective
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Rhinitis
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Sinusitis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Hyperamylasaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 9 (44.44%)
    0 / 4 (0.00%)
         occurrences all number
    2
    6
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2014
    Amendment 1 introduced changes to the hematologic dose limiting toxicities (DLT) criteria for multiple myeloma patients.
    21 Aug 2014
    Amendment 2 introduced the changes relating to thrombocytopenia, and included the following: To better understand the mechanism of action and kinetics underlying LGH447-associated thrombocytopenia, which is the primary DLT seen to date in the LGH447X2101 study, this amendment adds the measurement of thrombopoietin (TPO) level in the blood to determine if LGH447 interferes with the production and differentiation of megakaryocytes; To update safety information for LGH447 to include a DLT of maculopapular rash and modify the monitoring and dose modification guidelines for skin rash; To update safety information to align with BYL719 Investigator Brochure Version 6; Inhibitors of BCRP were added to the list of medication to use with caution since the co-administration of BYL719 with BCRP inhibitors may increase local or systemic BY L719 exposure. Treatment with BCRP inhibitors should be kept as short as possible or fully avoided; Agents which modify gastric pH (H2 receptor antagonists, proton pump inhibitors and antacids) were added to the list of medication to use with caution since both LGH447 and BYL719 are characterized by pH dependent solubility. Therefore, agents that modify gastric pH may affect the absorption and bioavailability of BYL719 and LGH447.
    28 Jan 2015
    Amendment 3 introduced guidelines for management of pneumonitis.

    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.
    Enrollment to the study was permanently terminated based upon review of the available data and since termination occurred before completion of the dose -escalation part (Phase Ib), any analyses related to Phase II were not conducted.
    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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