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    Clinical Trial Results:
    A Phase I Trial of Capecitabine Rapidly Disintegrating Tablets and Concomitant Radiation Therapy in Children with Newly Diagnosed Brainstem Gliomas and High Grade Gliomas

    Summary
    EudraCT number
    		 2016-000758-37
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    04 Oct 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Nov 2016
    First version publication date
    10 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NO18517
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00532948
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH 4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Oct 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the maximum tolerated dose (MTD) of capecitabine administered concurrently with radiation therapy (RT) to children with newly diagnosed non-disseminated, intrinsic brainstem gliomas or newly diagnosed non-disseminated high-grade gliomas.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all participants and/or their legally authorized representative. Participants signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug. The Pediatric Brain Tumor Consortium (PBTC) Monitoring Committee reviewed all reported toxicities on a weekly basis and communicated any areas of concern to the Study Chair. The study progress was reported in the PBTC semi-annual meeting book. The PBTC Data Safety Monitoring Board reviewed the protocol’s progress at least semi-annually.
    Background therapy
    		 Radiation therapy for 6 weeks
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    24 May 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    20
    Adolescents (12-17 years)
    4
    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
    		 All 24 participants in the study were enrolled at Pediatric Brain Tumor Consortium (PBTC) institutions in the United States of America (USA), from 24 May 2007 through 27 October 2009.

    Pre-assignment
    Screening details
    		 The study consisted of two periods of dosing: A dose-finding treatment period of 11 weeks and a post radiation treatment phase that lasted for 9 weeks.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Capecitabine 500 milligrams per square meter (mg/m^2)
    Arm description
    		 Capecitabine 500 mg/m^2 was administered twice daily (b.i.d) orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine RDT
    Investigational medicinal product code
    Ro 09-1978
    Other name
    Xeloda RDT
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 500 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Arm title
    		 Capecitabine 650 mg/m^2
    Arm description
    		 Capecitabine 650 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine RDT
    Investigational medicinal product code
    Ro 09-1978
    Other name
    Xeloda RDT
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 650 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Arm title
    		 Capecitabine 850 mg/m^2
    Arm description
    		 Capecitabine 850 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine RDT
    Investigational medicinal product code
    Ro 09-1978
    Other name
    Xeloda RDT
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 850 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Number of subjects in period 1
    		Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Started
    4
    14
    6
    Completed
    0
    9
    2
    Not completed
    4
    5
    4
         Failure to return
    -
    1
    -
         Death
    3
    3
    4
         Violation of selection criteria at entry
    -
    1
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Capecitabine 500 milligrams per square meter (mg/m^2)
    Reporting group description
    		 Capecitabine 500 mg/m^2 was administered twice daily (b.i.d) orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group title
    Capecitabine 650 mg/m^2
    Reporting group description
    		 Capecitabine 650 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group title
    Capecitabine 850 mg/m^2
    Reporting group description
    		 Capecitabine 850 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2 Total
    Number of subjects
    		 4 14 6 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 4 13 3 20
        Adolescents (12-17 years)
    		 0 1 3 4
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.5 ( 1.73 ) 8.4 ( 2.65 ) 13 ( 3.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 12 2 15
        Male
    		 3 2 4 9

    End points

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    End points reporting groups
    Reporting group title
    Capecitabine 500 milligrams per square meter (mg/m^2)
    Reporting group description
    		 Capecitabine 500 mg/m^2 was administered twice daily (b.i.d) orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group title
    Capecitabine 650 mg/m^2
    Reporting group description
    		 Capecitabine 650 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group title
    Capecitabine 850 mg/m^2
    Reporting group description
    		 Capecitabine 850 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all eligible patients who received at least one dose of capecitabine.

    Primary: Maximum Tolerated Dose of Capecitabine

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    End point title
    		 Maximum Tolerated Dose of Capecitabine [1]
    End point description
    The Maximum Tolerated Dose (MTD) was the dose level at which 6 evaluable patients had been treated and at most one patient experienced a dose limiting toxicity (DLT) and the next highest dose level was too toxic. Dose escalation occurred if 0 out of 3 or at most 1 out of 6 patients experienced DLT while being treated at a dose level; otherwise the dose was declared unsafe and thus above the MTD. Safety population was used for analysis of this end point.
    End point type
    Primary
    End point timeframe
    Up to 11 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis has been specified for this end point.
    End point values
    		 Safety Population
    Number of subjects analysed
    22
    Units: milligrams
    650
    No statistical analyses for this end point

    Primary: Number of Participants with Dose Limiting Toxicities

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    End point title
    		 Number of Participants with Dose Limiting Toxicities [2]
    End point description
    Dose limiting toxicity (DLT) was defined as any of the events which occurred during the 11 week dose-finding period: any event that leads to interruption of planned radiation for 5 consecutive days or 10 days total; Grade 4 neutropenia or thrombocytopenia; Grade 3 thrombocytopenia that required a platelet transfusion on 2 or more occasions; any Grade 3 or 4 non-hematologic toxicity (with the exception of Grade 3 nausea or vomiting of < 5 days duration, Grade 3 transaminases that returned to baseline value within 7 days of study drug interruption and that did not recur upon re-challenge with study drug, and/or Grade 3 fever or infection of <5 days duration); Grade 2 non-hematologic toxicities that persisted for >7 days and required treatment interruption, or any other capecitabine-related adverse events (AE) that required need for dose reduction or discontinuation of therapy. Safety population was used for analysis of this end point.
    End point type
    Primary
    End point timeframe
    Up to 11 weeks
    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: No statistical analysis has been specified for this end point.
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    4
    12
    6
    Units: Participants
    0
    3
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events

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    End point title
    		 Number of Participants With Adverse Events
    End point description
    An AE is an unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Toxicity was monitored and graded according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Adverse events that were not included in the CTCAE version 3.0 were reported and graded under the other AE within the appropriate category. Safety population was used for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Up to 06 years
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    4
    12
    6
    Units: Participants
    3
    12
    6
    No statistical analyses for this end point

    Secondary: Number of Participants With Baseline Shift From Normal to Low or High in Hematology Parameters

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    End point title
    		 Number of Participants With Baseline Shift From Normal to Low or High in Hematology Parameters
    End point description
    For hematology, the parameters assessed were: Hemoglobin, hematocrit, platelet count, RBC, WBC, lymphocytes, monocytes, granulocytes (blasts), neutrophils (segs, bands), eosinophils, and basophils. The safety population consisted of all eligible patients who received at least one dose of capecitabine. Participants available at a particular time point were included in analysis.
    End point type
    Secondary
    End point timeframe
    Up to 06 years
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    4
    2
    6
    Units: Participants
        Haematocrit, normal to low, n=3,1,5
    2
    1
    4
        Haematocrit, normal to high, n=3,1,5
    0
    0
    0
        Hemoglobin, normal to low, n=4,2,6
    0
    0
    2
        Hemoglobin, normal to high, n=4,2,6
    0
    0
    0
        White blood cell, normal to low, n=3,1,5
    0
    0
    0
        White blood cell, normal to high, n=3,1,5
    1
    1
    1
        Platelets, normal to low, n=4,2,6
    0
    1
    0
        Platelets, normal to high, n=4,2,6
    0
    0
    1
        Red blood cells, normal to low, n=3,1,3
    2
    0
    1
        Red blood cells, normal to high, n=3,1,3
    0
    1
    0
        Neutrophils (segmented), normal to low , n=3,0,5
    0
    0
    0
        Neutrophils (segmented), normal to high, n=3,0,5
    0
    0
    0
        Basophils (relative), normal to low, n=0,1,2
    0
    0
    0
        Basophils (relative), normal to high, n=0,1,2
    0
    1
    2
        Lymphocytes (relative), normal to low, n=3,1,5
    0
    0
    0
        Lymphocytes (relative), normal to high, n=3,1,5
    0
    0
    0
        Monocytes (relative), normal to low, n=3,1,4
    0
    0
    0
        Monocytes (relative), normal to high, n=3,1,4
    1
    0
    3
        Eosinophils (relative), normal to low, n=1,1,3
    0
    1
    0
        Eosinophils (relative), normal to high, n=1,1,3
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Baseline Shift From Normal to Low or High in Blood Chemistry Parameters

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    End point title
    		 Number of Participants With Baseline Shift From Normal to Low or High in Blood Chemistry Parameters
    End point description
    For blood chemistry, the parameters assessed were: Sodium, potassium, calcium, magnesium, chloride, bicarbonate, total protein, albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), Lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, indirect bilirubin, creatinine (serum creatinine or creatinine clearance), glucose. The safety population consisted of all eligible patients who received at least one dose of capecitabine. Participants available at a particular time point were included in analysis.
    End point type
    Secondary
    End point timeframe
    Up to 06 years
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    4
    2
    6
    Units: Participants
        Lactic dehydrogenase, normal to low, n=0,0,0
    0
    0
    0
        Lactic dehydrogenase, normal to high, n=0,0,0
    0
    0
    0
        Indirect bilirubin, normal to low, n=1,1,1
    0
    0
    0
        Indirect bilirubin, normal to high, n=1,1,1
    0
    1
    0
        BUN, normal to low, n=3,1,5
    0
    0
    2
        BUN, normal to high, n=3,1,5
    0
    1
    1
        Alkaline phosphatase, normal to low, n=1,1,4
    0
    0
    1
        Alkaline phosphatase, normal to high, n=1,1,4
    0
    0
    0
        Direct bilirubin, normal to low, n=2,1,1
    0
    0
    0
        Direct bilirubin, normal to high, n=2,1,1
    0
    0
    0
        Total bilirubin, normal to low, n=4,2,6
    0
    0
    0
        Total bilirubin, normal to high, n=4,2,6
    0
    0
    0
        Fasting glucose, normal to low, n=1,0,4
    0
    0
    0
        Fasting glucose, normal to high, n=1,0,4
    0
    0
    0
        Protein, normal to low, n=1,0,2
    1
    0
    1
        Protein, normal to high, n=1,0,2
    0
    0
    0
        Serum albumin, normal to low, n=3,1,5
    2
    0
    1
        Serum albumin, normal to high, n=3,1,5
    0
    0
    0
        Serum creatinine, normal to low, n=4,2,6
    0
    0
    0
        Serum creatinine, normal to high, n=4,2,6
    0
    0
    2
        ASAT (SGOT), normal to low, n=1,0,4
    0
    0
    0
        ASAT (SGOT), normal to high, n=1,0,4
    0
    0
    2
        ALAT (SGPT), normal to low, n=4,2,6
    0
    0
    0
        ALAT (SGPT), normal to high, n=4,2,6
    2
    2
    4
        Calcium, normal to low, n=3, 1,5
    1
    1
    0
        Calcium, normal to high, n=3,1,5
    0
    0
    1
        Phosphate, normal to low, n=3,1,5
    1
    0
    1
        Phosphate, normal to high, n=3,1,5
    0
    0
    1
        Potassium, normal to low, n=3, 1,5
    2
    0
    0
        Potassium, normal to high, n=3,1,5
    0
    1
    0
        Sodium, normal to low, n=3,1,5
    1
    1
    3
        Sodium, normal to high, n=3,1,5
    0
    0
    0
        Magnesium, normal to low, n=3,1,5
    0
    0
    0
        Magnesium, normal to high, n=3,1,5
    1
    1
    0
        Chloride, normal to low, n=3,1,5
    0
    0
    1
        Chloride, normal to high, n=3,1,5
    0
    1
    1
        Bicarbonate, normal to low, n=3,0,5
    0
    0
    0
        Bicarbonate, normal to high, n=3,0,5
    0
    0
    3
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration of Capecitabine and Its Metabolites (5’-Deoxy-5-Fluorocytidine [5’-DFCR], 5’-Deoxy-5-Fluorouridine [5’-DFUR], 5-Fluorouracil [5-FU] and Alpha-fluoro-beta-alanine [FBAL])

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    End point title
    		 Maximum Observed Plasma Concentration of Capecitabine and Its Metabolites (5’-Deoxy-5-Fluorocytidine [5’-DFCR], 5’-Deoxy-5-Fluorouridine [5’-DFUR], 5-Fluorouracil [5-FU] and Alpha-fluoro-beta-alanine [FBAL])
    End point description
    The maximum observed plasma concentration (Cmax) of capecitabine and its metabolites. Participants who consented to participating in the Pharmacokinetic (PK) studies were randomized to either sampling Series A or Series B. The collection time points included 2 different series, Series A (Baseline [pre-dose], 10 mins, 30 mins, 1, 2.5, 6, 8 and 10 hours after dosing) and Series B (Baseline [pre-dose], 15 minutes, 45 minutes, 1.5, 4, 8 and 10 hours after dosing). The safety population consisted of all eligible patients who received at least one dose of capecitabine. Participants available at a particular time point were included in analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    2
    4
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Capecitabine, Day 1, n= 2, 4, 3
    1440 ( 750 )
    3080 ( 1340 )
    1890 ( 1420 )
        Capecitabine, Day 14, n=2,2,2
    2100 ( 1770 )
    5440 ( 3270 )
    3710 ( 156 )
        5’-DFCR, Day 1, n=2,4,3
    2050 ( 813 )
    2190 ( 626 )
    2180 ( 1690 )
        5’-DFCR, Day 14, n=2,2,2
    2980 ( 2020 )
    3500 ( 1470 )
    3200 ( 233 )
        5’-DFUR, Day 1, n=2,4,3
    1910 ( 834 )
    2640 ( 1700 )
    3770 ( 3300 )
        5’-DFUR, Day 14, n=2,2,2
    3300 ( 2800 )
    3120 ( 445 )
    5020 ( 1220 )
        5-FU, Day 1, n=2,4,3
    47.8 ( 23.9 )
    77.3 ( 52.7 )
    178 ( 205 )
        5-FU, Day 14, n=2,2,2
    183 ( 196 )
    95.4 ( 27.8 )
    257 ( 107 )
        FBAL, Day 1, n=2,4,3
    1350 ( 134 )
    1740 ( 365 )
    2050 ( 1640 )
        FBAL, Day 14, n=2,2,2
    1770 ( 410 )
    2430 ( 84.9 )
    2140 ( 304 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration of Capecitabine and Its Metabolites (5’-DFCR, 5’-DFUR, 5-FU and FBAL)

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    End point title
    		 Time to Maximum Plasma Concentration of Capecitabine and Its Metabolites (5’-DFCR, 5’-DFUR, 5-FU and FBAL)
    End point description
    Time to maximum plasma concentration (Tmax) is the corresponding time at which Cmax occurs of capecitabine and its metabolites. Participants who consented to participating in the PK studies were randomized to either sampling Series A or Series B. The collection time points included 2 different series, Series A (Baseline [pre-dose], 10 mins, 30 mins, 1, 2.5, 6, 8 and 10 hours after dosing) and Series B (Baseline [pre-dose], 15 minutes, 45 minutes, 1.5, 4, 8 and 10 hours after dosing). Safety population were analysed for this endpoint. Participants available at a particular time point were included in analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    2
    4
    3
    Units: hour
    median (full range (min-max))
        Capecitabine, Day 1, n= 2, 4, 3
    0.58 (0.17 to 1)
    0.63 (0.25 to 1)
    0.85 (0.83 to 10)
        Capecitabine, Day 14, n=2,2,2
    1.33 (0.17 to 2.48)
    0.82 (0.8 to 0.83)
    0.61 (0.5 to 0.72)
        5’-DFCR, Day 1, n=2,4,3
    1 (1 to 1)
    0.75 (0.5 to 2.5)
    1.55 (0.85 to 10)
        5’-DFCR, Day 14, n=2,2,2
    1.49 (0.5 to 2.48)
    1.18 (0.5 to 1.53)
    0.61 (0.5 to 1.53)
        5’-DFUR, Day 1, n=2,4,3
    1 (1 to 1)
    0.9 (0.7 to 2.5)
    1.5 (0.75 to 10)
        5’-DFUR, Day 14, n=2,2,2
    1.5 (0.5 to 2.5)
    0.82 (0.8 to 0.83)
    0.61 (0.5 to 0.72)
        5-FU, Day 1, n=2,4,3
    1 (1 to 1)
    0.75 (0.5 to 2.5)
    1.5 (0.75 to 10)
        5-FU, Day 14, n=2,2,2
    1.5 (0.5 to 2.5)
    0.83 (0.8 to 0.83)
    1 (0.5 to 1.5)
        FBAL, Day 1, n=2,4,3
    2.53 (2.5 to 2.53)
    1.5 (1.5 to 2.5)
    1.55 (1.42 to 10)
        FBAL, Day 14, n=2,2,2
    1.74 (1 to 2.5)
    2.2 (1.5 to 2.8)
    2.03 (1.57 to 2.5)
    No statistical analyses for this end point

    Secondary: The Area Under the Plasma Concentration-time Curve From Time of Dosing to the Last Measurable Concentration of Capecitabine and Its Metabolites (5’-DFCR, 5’-DFUR, 5-FU and FBAL)

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    End point title
    		 The Area Under the Plasma Concentration-time Curve From Time of Dosing to the Last Measurable Concentration of Capecitabine and Its Metabolites (5’-DFCR, 5’-DFUR, 5-FU and FBAL)
    End point description
    The area under the plasma concentration-time curve from time of dosing to the last measurable concentration (AUC last) of capecitabine and its metabolites are reported. Participants who consented to participating in the PK studies were randomized to either sampling Series A or Series B. The collection time points included 2 different series, Series A (Baseline [pre-dose], 10 mins, 30 mins, 1, 2.5, 6, 8 and 10 hours after dosing) and Series B (Baseline [pre-dose], 15 minutes, 45 minutes, 1.5, 4, 8 and 10 hours after dosing). The safety population was used for this analysis. Participants available at a particular time point were included in analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    2
    4
    3
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Capecitabine, Day 1, n= 2, 4, 3
    3370 ( 607 )
    5160 ( 3700 )
    3470 ( 1170 )
        Capecitabine, Day 14, n=2,2,2
    2890 ( 655 )
    9660 ( 3340 )
    5670 ( 971 )
        5’-DFCR, Day 1, n=2,4,3
    5250 ( 755 )
    5140 ( 3440 )
    4180 ( 2380 )
        5’-DFCR, Day 14, n=2,2,2
    4300 ( 27.2 )
    9250 ( 1400 )
    6520 ( 452 )
        5’-DFUR, Day 1, n=2,4,3
    4790 ( 784 )
    4300 ( 1600 )
    6650 ( 3740 )
        5’-DFUR, Day 14, n=2,2,2
    4240 ( 929 )
    8010 ( 1890 )
    10500 ( 445 )
        5-FU Day 1, n=2,4,3
    81.6 ( 29.7 )
    114 ( 40.9 )
    271 ( 205 )
        5-FU Day 14, n=2,2,2
    181 ( 84.7 )
    253 ( 16.3 )
    499 ( 78.8 )
        FBAL, Day 1, n=2,4,3
    5990 ( 951 )
    8110 ( 1640 )
    7010 ( 4490 )
        FBAL, Day 14, n=2,2,2
    5720 ( 690 )
    10700 ( 574 )
    10400 ( 1760 )
    No statistical analyses for this end point

    Secondary: Anti Tumor Activity

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    End point title
    		 Anti Tumor Activity
    End point description
    Tumor response refers to the best response prior to failure (disease progression, death or second malignancy). Information concerning response and tumor measurements are only partially available and thus analysis is not performed. Efficacy data of the present study (NO18517 - NCT00532948) were pre-specified to be combined with efficacy data of the Phase 2 portion of this Study, NO21125 (NCT01118377) for analysis. Results are currently posted in the record of Study NO21125. No data displayed because Outcome Measure has zero total participants analyzed. Safety population was used for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Up to 06 years
    End point values
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: Participants
    Notes
    [3] - No data displayed because Outcome Measure has zero total participants analyzed.
    [4] - No data displayed because Outcome Measure has zero total participants analyzed.
    [5] - No data displayed because Outcome Measure has zero total participants analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 6 years
    Adverse event reporting additional description
    The safety population consisted of all eligible patients who received at least one dose of capecitabine RDT.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Capecitabine 500 milligrams per square meter (mg/m^2)
    Reporting group description
    		 Capecitabine 500 mg/m^2 was administered twice daily (b.i.d) orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group title
    Capecitabine 650 mg/m^2
    Reporting group description
    		 Capecitabine 650 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Reporting group title
    Capecitabine 850 mg/m^2
    Reporting group description
    		 Capecitabine 850 mg/m^2 was administered b.i.d orally for 14 days, followed by 7 day rest. The treatment was administered for 3 cycles with radiation therapy period and 3 cycles without radiation therapy.

    Serious adverse events
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 12 (8.33%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    3
    3
    4
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin exfoliation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Capecitabine 500 milligrams per square meter (mg/m^2) Capecitabine 650 mg/m^2 Capecitabine 850 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    12 / 12 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    5
    2
    Surgical and medical procedures
    Oculomotor nerve operation
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Trochlear nerve operation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 4 (75.00%)
    7 / 12 (58.33%)
    3 / 6 (50.00%)
         occurrences all number
    6
    7
    6
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    Chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Oedema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Penile erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Apnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Personality change
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Euphoric mood
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Psychotic disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    10 / 12 (83.33%)
    3 / 6 (50.00%)
         occurrences all number
    3
    22
    6
    Haemoglobin
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 12 (41.67%)
    4 / 6 (66.67%)
         occurrences all number
    3
    10
    6
    Neutrophil count
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    5
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 4 (50.00%)
    5 / 12 (41.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    8
    0
    Weight increased
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 12 (25.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    5
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    3
    2
    Blood bicarbonate decreased
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 12 (8.33%)
    2 / 6 (33.33%)
         occurrences all number
    3
    1
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    0
    Gamma−glutamyltransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    2
    Blood chloride increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Radiation mucositis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Thermal burn
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Radiation skin injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    3 / 4 (75.00%)
    8 / 12 (66.67%)
    1 / 6 (16.67%)
         occurrences all number
    4
    8
    1
    Facial nerve disorder
         subjects affected / exposed
    3 / 4 (75.00%)
    8 / 12 (66.67%)
    1 / 6 (16.67%)
         occurrences all number
    4
    9
    1
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
    6 / 12 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    4
    8
    3
    VIth nerve disorder
         subjects affected / exposed
    2 / 4 (50.00%)
    5 / 12 (41.67%)
    0 / 6 (0.00%)
         occurrences all number
    4
    6
    0
    Speech disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    1
    Vagus nerve disorder
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    3
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    3
    2
    1
    Glossopharyngeal nerve disorder
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Hyperreflexia
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 12 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    Nystagmus
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Convulsion
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    3
    Cognitive disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Hypoglossal nerve disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Trigeminal nerve disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Cerebellar syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cranial nerve disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    3 / 4 (75.00%)
    10 / 12 (83.33%)
    3 / 6 (50.00%)
         occurrences all number
    13
    36
    7
    Leukopenia
         subjects affected / exposed
    3 / 4 (75.00%)
    9 / 12 (75.00%)
    2 / 6 (33.33%)
         occurrences all number
    4
    14
    5
    Eye disorders
    Diplopia
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Vision blurred
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Extraocular muscle disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 4 (75.00%)
    8 / 12 (66.67%)
    2 / 6 (33.33%)
         occurrences all number
    7
    19
    2
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 12 (25.00%)
    3 / 6 (50.00%)
         occurrences all number
    4
    3
    3
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 12 (25.00%)
    4 / 6 (66.67%)
         occurrences all number
    0
    3
    5
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    4 / 6 (66.67%)
         occurrences all number
    1
    3
    4
    Diarrhoea
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    3
    2
    1
    Stomatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Skin exfoliation
         subjects affected / exposed
    1 / 4 (25.00%)
    8 / 12 (66.67%)
    4 / 6 (66.67%)
         occurrences all number
    1
    12
    5
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 12 (25.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    3
    3
    Alopecia
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    1
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Acne
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Gingival infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    2
    Otitis media
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    2
    Gastrointestinal candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Oral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 12 (16.67%)
    3 / 6 (50.00%)
         occurrences all number
    3
    2
    3
    Hyponatraemia
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 12 (41.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    8
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 12 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    4
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    5
    1
    Hypermagnesaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    5
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    4
    2
    2
    Hypercalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    2
    Decreased appetite
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jun 2008
    Text was updated in protocol page 28, Section 5.6.3.Non – Hematological Toxicity, sub section 5.6.3.1 General toxicities to clarify for dose modification due to Nonhematological Toxicity –DLT.

    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
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