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    Clinical Trial Results:
    Phase II study of cabozantinib in patients with metastatic gastrointestinal stromal tumor (GIST) who progressed during neoadjuvant, adjuvant or palliative therapy with imatinib and sunitinib

    Summary
    EudraCT number
    		 2014-000501-13
    Trial protocol
    		 BE   DE   HU   GB  
    Global end of trial date
    12 Mar 2021

    Results information
    Results version number
    		 v1
    This version publication date
    25 Sep 2021
    First version publication date
    25 Sep 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    1317-STBSG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02216578
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for the Research and Treatment of Cancer (EORTC)
    Sponsor organisation address
    Avenue E. Mounierlaan 83/11, Brussels, Belgium, 1200
    Public contact
    Clinical Operations Department, European Organisation for the Research and Treatment of Cancer (EORTC), +32 2774, regulatory@eortc.be
    Scientific contact
    Clinical Operations Department, European Organisation for the Research and Treatment of Cancer (EORTC), +32 2774, regulatory@eortc.be
    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
    10 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to assess the safety and activity of cabozantinib in patients with metastatic GIST who have previously progressed on imatinib and sunitinib and have not been exposed yet to other KIT- or PDGFR-directed tyrosine kinase inhibitors such as regorafenib or similar agents.
    Protection of trial subjects
    The responsible investigator ensure that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinicalpractice_en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 7
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    27
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 50 patients were registered by 11 institutions between February 28, 2017 and August 31, 2018.

    Pre-assignment
    Screening details
    		 Eligible patients aged at least 18 years, had ECOG performance status (PS) of 0-1 and adequate bone marrow and organ function prior to receiving the first dose of study treatmentn. Histologically confirmed diagnosis of GIST that is metastatic. Failure on prior therapy with imatinib and sunitinib.

    Pre-assignment period milestones
    Number of subjects started
    		 50
    Number of subjects completed
    		 50

    Period 1
    Period 1 title
    Overall period - Full patient population
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Arm I
    Arm description
    		 Cabozantinib was provided by Exelixis Inc., Alameda (United States) as 60 mg and 20 mg yellow film-coated tablets. Tablets were taken once daily at a starting dose of 60 mg, and patients were instructed not to eat for at least 2 h before and at least 1 h after taking cabozantinib. One treatment cycle was defined as 21 d of continuous dosing. Treatment was continued until patients experienced no further benefit, became intolerant to the drug or wished to discontinue the treatment. Treatment beyond RECIST 1.1 progression was allowed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CABOZATINIB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib was adequately provided by Exelixis free of charge as 60-mg and 20-mg yellow film-coated tablets. The 60-mg tablets were oval and the 20-mg tablets were round. One cycle of treatment was defined as 21 days of continuous dosing. Cabozantinib tablets were administered once daily at a starting dose of 60 mg, and patients were instructed not to eat for at least 2 hours before and at least 1 hour after taking cabozantinib.

    Number of subjects in period 1
    		Arm I
    Started
    50
    Completed
    0
    Not completed
    50
         Still on treatment at analysis
    4
         Toxicity
    4
         Patient's decision
    2
         Lost to follow-up
    1
         Progression of disease
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period - Full patient population
    Reporting group description
    		 -

    Reporting group values
    		 Overall period - Full patient population Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 27 27
        From 65-84 years
    		 23 23
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (35 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 30 30
    Prior treatment for metastatic disease - Imatinib received
    Units: Subjects
        Yes
    		 50 50
        No
    		 0 0
    Prior treatment for metastatic disease - Sunitinib received
    Units: Subjects
        Yes
    		 50 50
        No
    		 0 0
    Prior treatment for metastatic disease - Surgery done
    Units: Subjects
        Yes
    		 47 47
        No
    		 3 3
    Prior treatment for metastatic disease - Radiotherapy received
    Units: Subjects
        Yes
    		 4 4
        No
    		 46 46
    ECOG Performance Status
    Units: Subjects
        ECOG 0
    		 38 38
        ECOG 1
    		 12 12

    End points

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    End points reporting groups
    Reporting group title
    Arm I
    Reporting group description
    		 Cabozantinib was provided by Exelixis Inc., Alameda (United States) as 60 mg and 20 mg yellow film-coated tablets. Tablets were taken once daily at a starting dose of 60 mg, and patients were instructed not to eat for at least 2 h before and at least 1 h after taking cabozantinib. One treatment cycle was defined as 21 d of continuous dosing. Treatment was continued until patients experienced no further benefit, became intolerant to the drug or wished to discontinue the treatment. Treatment beyond RECIST 1.1 progression was allowed.

    Subject analysis set title
    Decision rule - primary patient population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This clinical trial had a sample size that required 41 patients eligible and evaluable (this last one meaning that the patient started the study treatment and had an image assessment as baseline) for the primary analysis. To allow for a sufficient number of patients to be assessable for the decision rule of the primary endpoint, the screening continue beyond those 41 (to a maximum of 50 patients - resulting in the final number of patients in the study). For the "Decision rule - primary patient population", the first 41 eligible and evaluable patients were considered.

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients

    Primary: Progression free survival (PFS) at 12 weeks

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    End point title
    		 Progression free survival (PFS) at 12 weeks
    End point description
    PFS at 12 weeks was measured as a binary variable. Patients will be considered as a "success" if this radiological evaluation indicates either CR, PR or SD as defined by RECIST v1.1 (see hereunder); all other cases will be considered as failures (including patients who have progressed or died before the week 12 assessment, patients with unknown progression status at week 12, or patients who started new anti-tumor therapy in the absence of progressive disease).
    End point type
    Primary
    End point timeframe
    This will be based on the disease evaluation by the local investigator of the radiological images performed 12 weeks after start of treatment.
    End point values
    		 Decision rule - primary patient population All patients
    Number of subjects analysed
    41
    50
    Units: Subjects
        Success
    24
    30
        Failure
    17
    20
    Statistical analysis title
    		 Primary endpoint - A'Hern one stage design
    Statistical analysis description
    A'Hern one stage design was used considering the following decision rule: P0 was taken as 40% - success in ≤ 40% of the cases was considered as unacceptable. P1 was taken as 60%. If at least 21 out of 41 eligible and evaluable patients were progression-free at the week 12 assessment, the activity of cabozantinib in this trial would be deemed sufficient to warrant further exploration of the drug in metastatic GIST. Type I and type II errors were fixed at 10% (alpha = beta = 0.10).
    Comparison groups
    All patients v Decision rule - primary patient population
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0126 [2]
    Method
    		 Exact test, binomial proportion, 1-sided
    Parameter type
    		 Proportion estimate
    Point estimate
    0.585
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.74
    Notes
    [1] - For the primary endpoint, PFS rate at 12 weeks was estimated using the Clopper-Pearson method for the (95%) confidence limits estimation in the primary analysis population. This is a single arm test - two arms were provided due to EUDRACT reporting system limitation. The primary test is performed in the decision rule population only.
    [2] - The corresponding exact p-values for the binomial proportion test (considering P0 was taken as 40%) is 0.0126.

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS was estimated by the Kaplan-Meier (KM) method. Median PFS was provided with its 95% confidence interval. Patients alive and free from progression at the time of the analysis were censored at the date of last disease assessment.
    End point type
    Secondary
    End point timeframe
    PFS was computed from the date of start of treatment to the first documented date of progression (by central review of the radiological images based on RECIST v1.1) or death, whatever the cause, whichever occurs first.
    End point values
    		 Arm I All patients
    Number of subjects analysed
    50
    50
    Units: Months
        median (confidence interval 95%)
    5.5 (3.6 to 6.9)
    5.5 (3.6 to 6.9)
    Statistical analysis title
    		 PFS - Full patient population
    Statistical analysis description
    PFS was computed from the date of start of treatment to the first documented date of progression (by central review of the radiological images based on RECIST v1.1) or death, whatever the cause, whichever occurs first. Patients alive and free from progression at the time of the analysis were censored at the date of last disease assessment. PFS was estimated by the Kaplan-Meier (KM) method. Median PFS was provided with its 95% confidence interval.
    Comparison groups
    Arm I v All patients
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Median PFS estimate
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.6
         upper limit
    		 6.9
    Notes
    [3] - This is a single arm assessment - two arms were provided due to EUDRACT reporting system limitation

    Secondary: Overall survival - Full patient population

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    End point title
    		 Overall survival - Full patient population
    End point description
    OS was estimated by the Kaplan-Meier (KM) method. Median OS was provided with its 95% confidence interval.
    End point type
    Secondary
    End point timeframe
    OS was computed from the date of start of treatment to the date of death (due to any cause). Patients alive at the time of analysis were censored at the date of last follow-up.
    End point values
    		 Arm I All patients
    Number of subjects analysed
    50
    50 [4]
    Units: months
        median (confidence interval 95%)
    18.2 (14.3 to 22.3)
    18.2 (14.3 to 22.3)
    Notes
    [4] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation
    Statistical analysis title
    		 OS - Full patient population
    Statistical analysis description
    OS was computed from the date of start of treatment to the date of death (due to any cause). Patients alive at the time of analysis were censored at the date of last follow-up. OS was estimated by the Kaplan-Meier (KM) method. Median OS was provided with its 95% confidence interval.
    Comparison groups
    Arm I v All patients
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Median OS estimate
    Point estimate
    18.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.3
         upper limit
    		 22.3
    Notes
    [5] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Response criteria was essentially based on a set of measurable lesions identified at baseline as target lesions, and – together with other lesions that are denoted as non-target lesions – followed until disease progression.
    End point type
    Secondary
    End point timeframe
    ORR (Complete response + Partial response) was based on the best response recorded from the start of treatment until treatment discontinuation based on RECIST v1.1.
    End point values
    		 Arm I All patients
    Number of subjects analysed
    50
    50
    Units: Subjects
        Yes
    7
    7
        No
    43
    43
    Statistical analysis title
    		 ORR - Full patient population
    Statistical analysis description
    ORR (Complete response + Partial response) was based on the best response recorded from the start of treatment until treatment discontinuation based on RECIST v1.1. Response criteria was essentially based on a set of measurable lesions identified at baseline as target lesions, and – together with other lesions that are denoted as non-target lesions – followed until disease progression. ORR was estimated using the Clopper-Pearson method for the (95%) confidence limits estimation.
    Comparison groups
    Arm I v All patients
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Proportion estimate
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.27
    Notes
    [6] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation

    Secondary: Clinical benefit rate (CBR)

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    End point title
    		 Clinical benefit rate (CBR)
    End point description
    End point type
    Secondary
    End point timeframe
    CBR (Complete response + Partial response + Stable disease) was based on the best response recorded from the start of treatment until treatment discontinuation based on RECIST v1.1.
    End point values
    		 Arm I All patients
    Number of subjects analysed
    50
    50
    Units: Subjects
        Yes
    41
    41
        No
    9
    9
    Statistical analysis title
    		 CBR - Full patient population
    Statistical analysis description
    CBR (Complete response + Partial response + Stable disease) was based on the best response recorded from the start of treatment until treatment discontinuation based on RECIST v1.1. CBR was estimated using the Clopper-Pearson method for the (95%) confidence limits estimation.
    Comparison groups
    Arm I v All patients
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Proportion estimate
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 0.91
    Notes
    [7] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation

    Secondary: Total duration of treatment

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    End point title
    		 Total duration of treatment
    End point description
    Total duration of treatment was computed from the date of start of treatment to the date of discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. Patients alive and still on protocol treatment at the time of the analysis were censored at the date of last known treatment administration.
    End point type
    Secondary
    End point timeframe
    Total duration of treatment was computed from the date of start of treatment to the date of discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death.
    End point values
    		 Arm I All patients
    Number of subjects analysed
    50
    50
    Units: months
        median (confidence interval 95%)
    5.3 (4.0 to 8.5)
    5.3 (4.0 to 8.5)
    Attachments
    		 Total treatment duration - 50 patients
    Statistical analysis title
    		 Total treatment duration - Full patient population
    Statistical analysis description
    Total duration of treatment was computed from the date of start of treatment to the date of discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. Patients alive and still on protocol treatment at the time of the analysis were censored at the date of last known treatment administration. Total treatment duration was estimated by the Kaplan-Meier (KM) method. The median estimate was provided with its 95% confidence interval.
    Comparison groups
    Arm I v All patients
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Median estimate
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4
         upper limit
    		 8.5
    Notes
    [8] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start from day -14 prior to the first administration of the investigational agent until total resolution of all adverse events (AEs) and discontinuation of treatment with cabozantinib. Persistent AEs will be followed for at least 30 days (+/- 3 days).
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items. Both AEs and SAEs are evaluated using CTC grading. Note that AEs related to hematology and biochemistry lab values were not specifically collected and are not included in the table below.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Arm I
    Reporting group description
    		 Cabozantinib.

    Serious adverse events
    		 Arm I
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 50 (32.00%)
         number of deaths (all causes)
    25
         number of deaths resulting from adverse events
    0
    Investigations
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    ATRIOVENTRICULAR BLOCK
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    ENCEPHALOPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    GENERAL PHYSICAL HEALTH DETERIORATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PYREXIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ANAL FISTULA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    DIARRHOEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    GASTRIC ULCER PERFORATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    INTESTINAL OBSTRUCTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    URINARY TRACT OBSTRUCTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    HERPES ZOSTER OTICUS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm I
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    Vascular disorders
    DEEP VEIN THROMBOPHLEBITIS OF LEFT LOWER LIMB
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEMATOMA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HOT FLASHES
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    HYPERTENSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    23 / 50 (46.00%)
         occurrences all number
    125
    General disorders and administration site conditions
    ALTERATION GENERAL STATUS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ALTERATION OF GENERAL HEALTH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CHILLS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    EDEMA FACE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    EDEMA LIMBS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    FATIGUE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    26 / 50 (52.00%)
         occurrences all number
    54
    FEBRILE SYMPTOMS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    FEVER
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    FLU LIKE SYMPTOMS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NIGHT SWEATS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    5
    WORSENING OF GENERAL CONDITION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    VAGINAL PROLAPSE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    BRONCHIAL CONGESTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    COUGH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    DRY NOSE MUCOSA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DYSPNEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    EPISTAXIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HOARSENESS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    9
    PRODUCTIVE COUGH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RHINITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    SNEEZING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SORE THROAT
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Psychiatric disorders
    INSOMNIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Investigations
    CPK INCREASED
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    ELECTROCARDIOGRAM QT CORRECTED INTERVAL PROLONGED
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    WEIGHT GAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    WEIGHT LOSS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    29 / 50 (58.00%)
         occurrences all number
    71
    Injury, poisoning and procedural complications
    OMBILICAL HERNIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Cardiac disorders
    ATRIOVENTRICULAR BLOCK COMPLETE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    TACHYCARDIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Nervous system disorders
    ATAXIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    COGNITIVE DISTURBANCE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DIZZINESS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DYSGEUSIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    8
    ENCEPHALOPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEADACHE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    9
    NEURALGIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PERIPHERAL MOTOR NEUROPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SYNCOPE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    EAR PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEARING IMPAIRED
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    VERTIGO
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Eye disorders
    FULL THICKNESS MACULAR HOLE RIGHT
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    VISUAL ACUITY DECLINED
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    VITROMACULAR TRACTION LEFT EYE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ABDOMINAL PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    14 / 50 (28.00%)
         occurrences all number
    17
    ANAL FISSURE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    ANAL FISTULA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    ANAL PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ANUSITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    BLOATING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CONSTIPATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    DENTAL ABSTRACTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DIARRHEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    39 / 50 (78.00%)
         occurrences all number
    109
    DRY MOUTH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    DYSPEPSIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    ESOPHAGITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    FLATULENCE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    FOOD POISONING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTRIC PERFORATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROESOPHAGEAL REFLUX DISEASE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    HEMORRHOIDS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    15
    INTESTINAL OBSTRUCTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    MUCOSITIS ORAL
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    18 / 50 (36.00%)
         occurrences all number
    23
    NAUSEA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    15
    ORAL DYSESTHESIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ORAL PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PAIN EPIGASTRIC
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PERIODONTAL DISEASE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    STOMACH CRAMPS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    STOMACH PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    TOOTH DEVELOPMENT DISORDER
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    TOOTHACHE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    VOMITING
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    6
    Hepatobiliary disorders
    BILE DUCT STENOSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    BILIARY TRACT OCCLUSION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CHOLECYSTITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEPATIC CYTOLYSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DRY SKIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    DRY SKIN (BODY)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DRY SKIN (FACE)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ECZEMATOUS RASH LEFT LOWER LEG
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ERYTHEMA MULTIFORME
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ERYTHEMA OF THE RIGTH HAND II-IV FINGER
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HAIR DISCOLORATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    HAIR HYPOPIGMENTATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    HAND HYPERSENSITIVITY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HORNY FEET
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    32 / 50 (64.00%)
         occurrences all number
    51
    PERIORBITAL EDEMA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PHOTOSENSITIVITY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PRURITUS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    RASH
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RASH MACULO-PAPULAR
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    SCALP PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Renal and urinary disorders
    CYSTITIS NONINFECTIVE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DYSURIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEMATURIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NEPHROTIC COLITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PROTEINURIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    9
    URINARY INFLAMMATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    URINARY TRACT OBSTRUCTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    URINARY URGENCY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    URINE INFLAMMATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Endocrine disorders
    HYPERTHYROIDISM
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPOTHYROIDISM
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    10 / 50 (20.00%)
         occurrences all number
    12
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    9
    ARTHRITIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    BACK PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    BONE PAIN
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    CRAMP IN THE CALF
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GENERALIZED MUSCLE WEAKNESS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    MUSCLE CRAMPS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    MYALGIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    9
    PAIN (ACHILLES HEEL)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    PAIN IN EXTREMITY
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Infections and infestations
    BRONCHIAL INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    FLU
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HERPES ZOSTER OTICUS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTION NOS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    MYCOBACTERIUM TUBERCULOSIS
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RHINITIS INFECTIVE
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    TOOTH INFECTION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    ANOREXIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    14 / 50 (28.00%)
         occurrences all number
    21
    DEHYDRATION
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPOKALEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPOPHOSPHATEMIA
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2016
    oAdministrative changes: Changes to sponsor signatory page EORTC: change of PM STBSG: change of chairman and secretary Update of reference pathologists Reformatting of all references for publications and one additional reference added as published recently Other administrative changes oStatistics part: The design of the study has been simplified from a two-stage to a one-stage setup. End-points have been clarified to be more comprehensive The end of study definition has been updated to reflect standard EORTC notation oScientific part: Further to document provided by Exelixis (master protocol template): Drug specific patient selection criteria, dose and schedule modification and drug specific side effects have been updated. The patient information sheet has been updated based on the Summary of product Characteristics (last update Feb 2016). Drop of translational imaging research project about Choi Criteria due to lack of interest and funding. Motivation/rationale: Simplify the statistical design of the study from a two-stage design without interruption of accrual to a one-stage A’Hern design. Taking into account 12 weeks for the primary endpoint assessment of the 18th patient and approximately 1 month for obtaining and validating the information, it would take up to 4 months to conclude whether to stop or proceed to the next stage of the study. With 5 patients expected to be entered in the study every month, an additional 20 patients would have been enrolled prior to reaching this decision, making the interim look futile. We propose to switch to a one-stage design. This proposal was justified based on the available pre-clinical data, in combination with the molecular targeting profile of cabozantinib, showing that it was very likely that the study drug would show a level of efficacy in GIST similar to that obtained by related compounds such as sunitinib and regorafenib, at the time, the only treatment approved by FDA and EMA for this indication.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32470848
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