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    Clinical Trial Results:
    A Phase I/II Study Of Sunitinib In Young Patients With Advanced Gastrointestinal Stromal Tumor

    Summary
    EudraCT number
    		 2011-002008-33
    Trial protocol
    		 HU   ES   Outside EU/EEA   CZ   PT   IT   GB   PL   AT   DE   FR   SK  
    Global end of trial date
    21 Aug 2017

    Results information
    Results version number
    		 v3(current)
    This version publication date
    20 Mar 2019
    First version publication date
    25 Feb 2018
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    A6181196
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01396148
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 110017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000342-PIP01-08
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the plasma pharmacokinetic (PK) profile of Sunitinib and its active metabolite SU012662 in children and young adults with advanced, unresectable Gastrointestinal Stromal Tumor (GIST).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jun 2012
    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
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    6
    EEA total number of subjects
    3
    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)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 4 centers in 3 countries between 12 June 2012 and 21 August 2017.

    Pre-assignment
    Screening details
    		 This was a single arm, multi-center, multi-national study where a total of 6 subjects were dosed based on the body surface area. The starting dose of Sunitinib was 15 milligram/ meter square (mg/m^2) per day administered orally, from Day 1 to 28 in each treatment cycle of 42 days.

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

    Arms
    Arm title
    		 Sunitinib
    Arm description
    		 Subjects received Sunitinib capsules orally at a dose based on body surface area (BSA) (minimum dose of 15 milligram/ meter square [mg/m^2] up to a maximum dose of 30 mg/m^2) once daily, from Day 1 to 28 in each treatment cycle of 42 days ( up to a maximum of 18 cycles) until completion of study treatment, disease progression, unacceptable toxicity, required a treatment rest (greater than [>4] weeks), withdrawal of subject consent, or if other withdrawal criteria were met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    SU011248
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sunitinib capsules orally at a dose based on body surface area (BSA) (minimum dose of 15 milligram/ meter square [mg/m^2] up to a maximum dose of 30 mg/m^2) once daily, from Day 1 to 28 in each treatment cycle of 42 days (up to a maximum of 18 cycles).

    Number of subjects in period 1
    		Sunitinib
    Started
    6
    Completed
    5
    Not completed
    1
         Subject decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    		 Subjects received Sunitinib capsules orally at a dose based on body surface area (BSA) (minimum dose of 15 milligram/ meter square [mg/m^2] up to a maximum dose of 30 mg/m^2) once daily, from Day 1 to 28 in each treatment cycle of 42 days ( up to a maximum of 18 cycles) until completion of study treatment, disease progression, unacceptable toxicity, required a treatment rest (greater than [>4] weeks), withdrawal of subject consent, or if other withdrawal criteria were met.

    Reporting group values
    		 Sunitinib Total
    Number of subjects
    		 6 6
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 6 6
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.3 ( 1.4 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 5 5
        Male
    		 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    		 5 5
        Asian|
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    		 Subjects received Sunitinib capsules orally at a dose based on body surface area (BSA) (minimum dose of 15 milligram/ meter square [mg/m^2] up to a maximum dose of 30 mg/m^2) once daily, from Day 1 to 28 in each treatment cycle of 42 days ( up to a maximum of 18 cycles) until completion of study treatment, disease progression, unacceptable toxicity, required a treatment rest (greater than [>4] weeks), withdrawal of subject consent, or if other withdrawal criteria were met.

    Subject analysis set title
    Sunitinib: Lower Exposure
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects who received Sunitinib capsules orally at a dose based on BSA (minimum dose of 15 mg/m^2 up to a maximum dose of 30 mg/m^2 once daily, from Day 1 to 28 in each treatment cycle of 42 days (up to a maximum of 18 cycles) and had total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) < the median Ctrough value

    Subject analysis set title
    Sunitinib: Higher Exposure
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects who received Sunitinib capsules orally at a dose based on BSA (minimum dose of 15 mg/m^2 up to a maximum dose of 30 mg/m^2 once daily, from Day 1 to 28 in each treatment cycle of 42 days (up to a maximum of 18 cycles) and had total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) >= the median Ctrough value

    Primary: Estimated Steady-State Maximum Plasma Concentration (Cmax,ss) of Sunitinib and its Metabolite

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    End point title
    		 Estimated Steady-State Maximum Plasma Concentration (Cmax,ss) of Sunitinib and its Metabolite [1]
    End point description
    Estimated steady-state maximum plasma concentration (Cmax,ss) of Sunitinib and its metabolite SU012662. Summarized data for all time points was reported. The PK population included all treated participants with at least one PK observation.
    End point type
    Primary
    End point timeframe
    pre-dose on Day 1, Day 12-18 and Day 25-29 of Cycle 1,2, 3 and 2, 4, 6, 8 hours post-dose on Day 1 Cycle 1
    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: Descriptive data analysis was planned for this endpoint.
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Sunitinib
    37.98 ( 12.91 )
        SU012662
    14.55 ( 3.04 )
    No statistical analyses for this end point

    Primary: Estimated Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC24) of Sunitinib and its Metabolite

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    End point title
    		 Estimated Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC24) of Sunitinib and its Metabolite [2]
    End point description
    Estimated area under the plasma concentration versus time curve from time zero to 24 hours post dose AUC(0-24) of Sunitinib and its metabolite SU012662. Summarized data for all time points was reported. The PK population included all treated participants with at least one PK observation.
    End point type
    Primary
    End point timeframe
    pre-dose on Day 1, Day 12-18 and Day 25-29 of Cycle 1,2, 3 and 2, 4, 6, 8 hours post-dose on Day 1 Cycle 1
    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: Descriptive data analysis was planned for this endpoint.
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: nanogram*hour per milliliter (ng*hr)/mL
    arithmetic mean (standard deviation)
        Sunitinib
    812.59 ( 273.37 )
        SU012662
    336.78 ( 74.15 )
    No statistical analyses for this end point

    Primary: Estimated Oral clearance (CL/F) of Sunitinib and its Metabolite

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    End point title
    		 Estimated Oral clearance (CL/F) of Sunitinib and its Metabolite [3]
    End point description
    SU012662 is the metabolite of Sunitinib. Oral clearance (CL/F) is a quantitative measure of the rate at which a drug substance is removed from the blood (CL) normalized by the oral bioavailability of the drug (F). Summarized data for all time points was reported. The PK population included all treated participants with at least one PK observation.
    End point type
    Primary
    End point timeframe
    pre-dose on Day 1, Day 12-18 and Day 25-29 of Cycle 1,2, 3 and 2, 4, 6, 8 hours post-dose on Day 1 Cycle 1
    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: Descriptive data analysis was planned for this endpoint.
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: Liters per hour (L/hr)
    arithmetic mean (standard deviation)
        Sunitinib
    26.37 ( 7.62 )
        SU012662
    12.85 ( 3.11 )
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) of Sunitinib and its Metabolite

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Sunitinib and its Metabolite [4]
    End point description
    SU012662 is the metabolite of Sunitinib. The pharmacokinetic (PK) population included all treated subjects with at least 1 PK observation.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
    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: Descriptive data analysis was planned for this endpoint.
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Sunitinib|
    17.58 ( 32 )
        SU012662|
    2.342 ( 18 )
    No statistical analyses for this end point

    Primary: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and its Metabolite

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    End point title
    		 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and its Metabolite [5]
    End point description
    SU012662 is the metabolite of Sunitinib. The PK population included all treated subjects with at least 1 PK observation.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
    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: Descriptive data analysis was planned for this endpoint.
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: hours
    median (full range (min-max))
        Sunitinib|
    8 (4 to 8)
        SU012662|
    8 (4 to 8)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours Post Dose AUC(0-8) for Sunitinib and its Metabolite

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    End point title
    		 Area Under the Plasma Concentration-Time Curve From Time Zero to 8 hours Post Dose AUC(0-8) for Sunitinib and its Metabolite [6]
    End point description
    AUC(0-8) was defined as area under the plasma concentration time-curve from time zero to 8 hours post dose. SU012662 is the metabolite of Sunitinib. The PK population included all treated subjects with at least 1 PK observation.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
    Notes
    [6] - 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: Descriptive data analysis was planned for this endpoint.
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: nanograms*hour per milliliter (ng*hr)/mL
    geometric mean (geometric coefficient of variation)
        Sunitinib|
    77.49 ( 42 )
        SU012662|
    10.11 ( 37 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged insubject hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to end of study (up to Cycle 18) that were absent before treatment or that worsened relative to pretreatment state. AEs included both non-serious adverse events (AEs) and SAEs. The as-treated population included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: subjects
        AEs|
    6
        SAEs|
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0
    End point description
    An AE is any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events+subject to be in imminent danger of death. Grade 5 events =death. Treatment-emergent events are events between first dose of study drug and up to end of study (up to Cycle 18) that were absent before treatment or that worsened relative to pretreatment state. Number of subjects with AEs of any of the Grade 3 or above (Grade 4, 5) were reported. The as-treated population included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: subjects
    5
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged insubject hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both non-serious adverse events (AEs) and SAEs. The as-treated population included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: subjects
        AEs|
    6
        SAEs|
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Clinically Significant Laboratory Abnormalities
    End point description
    Criteria for clinically significant laboratory abnormalities: Hemoglobin (Hb), hematocrit: less than (<) 0.8*lower limit of normal (LLN), platelet: <75 or greater than (>) 700*10^3/millimeter (mm)^3*upper limit of normal (ULN), leukocyte: <2.5 or >17.5*10^3/mm^3*ULN; total bilirubin 1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase: >3.0*ULN, total protein, albumin: <0.8*LLN or >1.2*ULN ;blood urea nitrogen, creatinine: >1.3*ULN, uric acid >1.2*ULN; sodium <0.95*LLN or >1.05*ULN, potassium, calcium: <0.9*LLN or >1.1*ULN, albumin, total protein <0.8*LLN or >1.2*ULN; glucose <0.6*LLN or >1.5*ULN, creatine kinase >2.0*ULN; urine (red blood cell, white blood cell >6/high power field). The as-treated population included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Objective Response

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    End point title
    		 Number of Subjects With Objective Response
    End point description
    Objective response in subjects was defined as the number of subjects with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Confirmed response were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and non-target). PR was defined as at least 30 percentage (%) decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. The full analysis set included all enrolled subjects regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: subjects
        Complete response|
    0
        Partial response|
    0
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response: Time (in months) from the first documentation of objective tumor response (confirmed CR or PR) to the first documentation of disease progression or death due to any cause. Confirmed response were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. CR: Disappearance of all lesions (target and non-target). PR: At least 30% decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. Progression: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). Analysis was performed on a subset of FAS which included subjects who had confirmed CR or PR. Since, none of the subjects had confirmed CR or PR, hence duration of response was not analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    0 [7]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [7] - None of the subjects were confirmed response,the analysis of duration of response was not analyzed.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression free survival was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The full analysis set included all enrolled subjects regardless of what treatment, if any, was received. The upper limit of 95% CI was not reached and has been denoted as 99999.
    End point type
    Secondary
    End point timeframe
    Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: months
        median (confidence interval 95%)
    5.8 (2.3 to 99999)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was defined as time (in months) from enrollment to the date of death due to any cause. Analysis was performed using Kaplan-Meier method. The full analysis set included all enrolled subjects regardless of what treatment, if any, was received. Data was not analyzed and has been denoted as 99999, since none of the subjects died.
    End point type
    Secondary
    End point timeframe
    Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6 [8]
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    Notes
    [8] - Data not analyzed, since none of the subjects died.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups

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    End point title
    		 Number of Subjects With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups
    End point description
    AE: any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. As per NCI CTCAE version 4.0, Grade1= asymptomatic or mild symptoms, Grade 2= Moderate; local or noninvasive intervention indicated; Grade 3 events=medically significant but not immediately life-threatening, require systemic drug therapy/other treatment, Grade 4 events =subject to be in imminent danger of death. Grade 5 events=death. Subjects with any of the Grade 1 to Grade 5 AEs were reported. The PK evaluable subjects were divided into 2 PK subgroups on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure). The PK subgroup analysis set included all treated subjects with at least 1 PK observation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days)
    End point values
    		 Sunitinib: Lower Exposure Sunitinib: Higher Exposure
    Number of subjects analysed
    3
    3
    Units: subjects
        Nausea|
    0
    2
        Vomiting|
    0
    1
        Diarrhoea|
    0
    2
        Fatigue|
    0
    1
        Palmar-Plantar Erythrodysaesthesia Syndrome|
    1
    0
        Neutropenia|
    2
    1
        Thrombocytopenia|
    1
    1
        Lymphopenia|
    0
    0
        Hypertension|
    0
    0
        Anaemia|
    1
    0
    No statistical analyses for this end point

    Secondary: Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration

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    End point title
    		 Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration
    End point description
    Pearson correlation coefficient between percent change from baseline in laboratory parameters with total drug (Sunitinib + SU012662) concentration were calculated on Day 28 of Cycles 1, 2, and 3. Laboratory parameters included absolute neutrophil count, platelet count, lymphocyte count and hemoglobin. The PK population included all treated subjects with at least one PK observation.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: correlation coefficient
    number (not applicable)
        Absolute Neutrophil Count: Cycle 1 Day 28|
    -0.1870
        Absolute Neutrophil Count: Cycle 2 Day 28|
    -0.5914
        Absolute Neutrophil Count: Cycle 3 Day 28|
    -0.5536
        Platelet Count: Cycle 1 Day 28|
    0.0329
        Platelet Count: Cycle 2 Day 28|
    -0.6424
        Platelet Count: Cycle 3 Day 28|
    -0.6604
        Lymphocyte Count: Cycle 1 Day 28|
    0.1509
        Lymphocyte Count: Cycle 2 Day 28|
    -0.4815
        Lymphocyte Count: Cycle 3 Day 28|
    -0.2931
        Hemoglobin: Cycle 1 Day 28|
    0.9107
        Hemoglobin: Cycle 2 Day 28|
    0.4368
        Hemoglobin: Cycle 3 Day 28|
    0.2095
    No statistical analyses for this end point

    Secondary: Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results with Total Drug (Sunitinib + SU012662) Concentration

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    End point title
    		 Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results with Total Drug (Sunitinib + SU012662) Concentration
    End point description
    Pearson correlation coefficient between percent change from baseline in vital sign results with total drug (Sunitinib + SU012662) concentration were calculated on Day 28 of Cycles 1, 2, and 3. Vital signs included systolic blood pressure and diastolic blood pressure. The PK population included all treated subjects with at least one PK observation.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days)
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: correlation coefficient
    number (not applicable)
        Systolic Blood Pressure: Cycle 1 Day 28|
    -0.3730
        Systolic Blood Pressure: Cycle 2 Day 28|
    -0.8146
        Systolic Blood Pressure: Cycle 3 Day 28|
    0.2768
        Diastolic Blood Pressure: Cycle 1 Day 28|
    0.6854
        Diastolic Blood Pressure: Cycle 2 Day 28|
    -0.3638
        Diastolic Blood Pressure: Cycle 3 Day 28|
    0.2634
    No statistical analyses for this end point

    Secondary: Number of Subjects With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups

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    End point title
    		 Number of Subjects With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups
    End point description
    SD:when there is no sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR:as at least 30% decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. CR:disappearance of all lesions (target and non-target). PD:at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. Subjects with SD, PR, CR and PD responses were assessed according to 2 PK subgroups created on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value < the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values >= the median Ctrough value(higher exposure). The PK subgroup analysis set included all treated subjects with at least 1 PK observation.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or discontinuation from the study, or death, whichever occurred first(maximum duration: up to Cycle 18; each cycle was of 42 days)
    End point values
    		 Sunitinib: Lower Exposure Sunitinib: Higher Exposure
    Number of subjects analysed
    3
    3
    Units: subjects
        Stable Disease|
    1
    2
        Partial Response|
    0
    0
        Complete Response|
    0
    0
        Progressive Disease|
    2
    1
    No statistical analyses for this end point

    Secondary: Progression Free Survival for PK Sub-groups

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    End point title
    		 Progression Free Survival for PK Sub-groups
    End point description
    Progression free survival was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The PK evaluable subjects were assessed according to 2 PK subgroups created on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure). The PK population included all treated subjects with at least one PK observation.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days)
    End point values
    		 Sunitinib: Lower Exposure Sunitinib: Higher Exposure
    Number of subjects analysed
    3
    3
    Units: months
        median (confidence interval 95%)
    2.6 (2.4 to 99999)
    9.0 (2.3 to 99999)
    No statistical analyses for this end point

    Secondary: Pearson Correlation Coefficient Between Progression Free Survival With Total Drug (Sunitinib + SU012662) Concentration

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    End point title
    		 Pearson Correlation Coefficient Between Progression Free Survival With Total Drug (Sunitinib + SU012662) Concentration
    End point description
    Pearson correlation coefficient between Progression Free Survival (PFS) with total drug (Sunitinib + SU012662) concentration at Day 28 of Cycle 1 was calculated. PFS was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The PK population included all treated subjects with at least one PK observation.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days
    End point values
    		 Sunitinib
    Number of subjects analysed
    6
    Units: correlation coefficient
        number (not applicable)
    0.5904
    No statistical analyses for this end point

    Secondary: Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for each Selected Efficacy Parameter (e.g., Sum of Largest Diameters for Target Tumors) was Observed

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    End point title
    		 Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for each Selected Efficacy Parameter (e.g., Sum of Largest Diameters for Target Tumors) was Observed
    End point description
    Due to low number of enrolled subjects (n=6), there was insufficient data to perform any type of pharmacokinetic/pharmacodynamic modeling to obtain EC50 values, hence data is not reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
    End point values
    		 Sunitinib
    Number of subjects analysed
    0 [9]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [9] - Data for this endpoint was not collected and summarized due to change in planned analysis.
    No statistical analyses for this end point

    Secondary: Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Safety Endpoint (e.g., Absolute Neutrophil Count) was Observed 

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    End point title
    		 Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Safety Endpoint (e.g., Absolute Neutrophil Count) was Observed 
    End point description
    Due to low number of enrolled subjects (n=6), there was insufficient data to perform any type of pharmacokinetic/pharmacodynamic modeling to obtain EC50 values, hence data is not reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
    End point values
    		 Sunitinib
    Number of subjects analysed
    0 [10]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [10] - Data for this endpoint was not collected and summarized due to change in planned analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    		 Subjects were dosed based on the body surface area. The starting dose of Sunitinib was 15 milligram/ meter square (mg/m^2) per day administered orally, from Day 1 to 28 in each treatment cycle of 42 days until completion of study treatment, disease progression, unacceptable toxicity, required a treatment rest (greater than [>4] weeks), withdrawal of subject consent, or if other withdrawal criteria were met.

    Serious adverse events
    		 Sunitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Sunitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Nasal congestion
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Amylase increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Blood phosphorus increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Blood alkaline phosphatase
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eosinophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    12
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    14
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 6 (66.67%)
         occurrences all number
    10
    Migraine
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    7
    Leukopenia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Lymphopenia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    23
    Thrombocytopenia
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    5
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    4
    Dyspepsia
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Impaired gastric emptying
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Lip discolouration
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    5
    Sensitivity of teeth
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Hepatobiliary disorders
    Hepatic haematoma
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Hair colour changes
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Muscle spasms
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    6
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    4
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Folliculitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Herpes simplex
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    3
    Hyperglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Hypermagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2012
    The purpose was to revise The Schedule of Activities and associated protocol sections to include growth and pubertal maturation assessments for paediatric subjects, a reduced mandatory visit schedule after Cycle 3, and clarification of standard tumor analysis requirements. The term “chemotherapy naïve” was removed from the study design and the associated secondary objective to study tolerability in pediatric subjects with GIST.
    31 Jul 2017
    The purpose was to reduce the numbers of subjects enrolled in the study (in the range of age from 6 to < 18) from 15 to 6 evaluable subjects. The centralized review of imaging (ie, MRI, CT scans etc) aimed to confirm the efficacy endpoint was no longer required. As this study is part of a PIP, both these changes had been agreed with EMA’s Pediatric Committee (PDCO) and are aligned with the PIP binding elements.

    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.
    Data for Estimated steady-state Cmax, AUC24 and CL/F will be estimated and reported separately as part of the Non-linear Mixed Effects Modeling analysis, and will be provided once available.
    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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