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    Clinical Trial Results:
    A randomized phase II of bevacizumab, capecitabine and radiation therapy with or without oxaliplatin in the preoperative treatment of locally advanced rectal cancer

    Summary
    EudraCT number
    		 2007-007177-23
    Trial protocol
    		 BE  
    Global end of trial date

    Results information
    Results version number
    		 v3(current)
    This version publication date
    13 Jul 2018
    First version publication date
    03 Aug 2017
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Correction of threshold for incidence of adverse events; correction of timepoint of onset of some adverse events
    Summary report(s)
    		 Synopsis from FSR
    Consort chart

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    s51104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00828672
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZLeuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Prof. Dr. Eric Van Cutsem, UZ Leuven, 0032 16 34 42 25, eric.vancutsem@uzleuven.be
    Scientific contact
    Prof. Dr. Eric Van Cutsem, UZ Leuven, 0032 16 34 42 25, eric.vancutsem@uzleuven.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
    Interim
    Date of interim/final analysis
    20 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Apr 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess the activity of bevacizumab (Avastin) in combination with capecitabine (Xeloda) and radiation therapy with or without oxaliplatin (Eloxatin) in the pre-operative treatment of locally advanced rectal cancer, followed by TME resection, in a multicenter setting.
    Protection of trial subjects
    Ethics review and approval, informed consent, prophylactic anti-emetic medication administered prior to oxaliplatin infusions in Arm A, dummy run for radiation therapy for appropriate treatment planning for each patient, supportive care and routine monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jun 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    58
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Eighty-four patients were included. First patient enrolled: 22-Jun-2009. Last patient enrolled: 29-Sep-2013. Participating sites: UZ Leuven, Erasme Hospital Bruxelles, Cliniques Universitaires St-Luc Bruxelles, AZ St. Lucas Brugge, AZ Groeninge Kortrijk, CHU Sart-Tilman Liege, OLVZ Aalst, H. Hart Ziekenhuis Roeselare, Clinique Saint Elisabeth Namur

    Pre-assignment
    Screening details
    		 Target population was represented by patients with locally advanced rectal cancer (tumour beyond mesorectal fascia (T4) or tumour ≤ 2 mm from mesorectal fascia or T3 tumour < 5 cm from anal verge by MRI), histologically confirmed. Pts were screened as per incl and excl criteria per protocol. Screening failures were not recorded in the eCRF.

    Period 1
    Period 1 title
    Pre-treatment (baseline)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Eloxatin
    Investigational medicinal product code
    Other name
    Oxaliplatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode (In Arm A only): 50 mg/m2 via a 1-hour IV infusion, on days 15, 22, 29, 36 and 43, concurrently with radiotherapy.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Arm title
    		 Arm B
    Arm description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    43
    41
    Treatment start
    43
    41
    Completed
    43
    41
    Period 2
    Period 2 title
    Study treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Eloxatin
    Investigational medicinal product code
    Other name
    Oxaliplatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode (In Arm A only): 50 mg/m2 via a 1-hour IV infusion, on days 15, 22, 29, 36 and 43, concurrently with radiotherapy.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Arm title
    		 Arm B
    Arm description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Number of subjects in period 2
    		Arm A Arm B
    Started
    43
    41
    Completion chemoradiotherapy
    43
    40
    Surgery
    41
    39
    Completed
    41
    39
    Not completed
    2
    2
         Adverse event, non-fatal
    -
    1
         Clinical complete response, no surgery
    1
    1
         Lost to follow-up, surgery off protocol
    1
    -
    Period 3
    Period 3 title
    Post-surgery (<30 days)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Eloxatin
    Investigational medicinal product code
    Other name
    Oxaliplatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode (In Arm A only): 50 mg/m2 via a 1-hour IV infusion, on days 15, 22, 29, 36 and 43, concurrently with radiotherapy.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Arm title
    		 Arm B
    Arm description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Number of subjects in period 3
    		Arm A Arm B
    Started
    41
    39
    Pathological central review
    41
    38
    Completed
    41
    38
    Not completed
    0
    1
         Central review materials NA
    -
    1
    Period 4
    Period 4 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Eloxatin
    Investigational medicinal product code
    Other name
    Oxaliplatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode (In Arm A only): 50 mg/m2 via a 1-hour IV infusion, on days 15, 22, 29, 36 and 43, concurrently with radiotherapy.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Arm title
    		 Arm B
    Arm description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose, frequency & treatment mode: 5 mg/kg via a 1-hour IV infusion, on days 1, 15, 29 and 43, concurrently with radiotherapy. Bevacizumab administration precedes the oxaliplatin infusion in Arm A.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Other name
    Capecitabine
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose, frequency & treatment mode: twice-daily 825 mg/m2 (equivalent to a total daily dose of 1650 mg/m2) days 15-47, 5 days per week, concurrently with radiotherapy.

    Number of subjects in period 4
    		Arm A Arm B
    Started
    41
    38
    Completed
    42
    41
    Joined
    1
    3
         Toxicity during CRT, surgery off protocol, in FU
    -
    1
         No central review materials, had surgery, in FU
    -
    1
         Clinical CR, no surgery, in FU
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 43 41 84
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 29 29 58
        From 65-84 years
    		 14 12 26
    Age continuous
    Exact age value at start of treatment was considered. No split per age group was performed.
    Units: years
        median (full range (min-max))
    		 61 (26 to 77) 59 (35 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 14 12 26
        Male
    		 29 29 58
    ECOG PS
    PS – Performance status
    Units: Subjects
        PS=0
    		 36 37 73
        PS=1
    		 7 4 11
    Distance from tumour to anal verge (colonoscopy)
    Distance from tumour to anal verge in cm - measuered by colonoscopy
    Units: Subjects
        <5cm
    		 18 15 33
        >= 5 cm
    		 13 15 28
        NA
    		 12 11 23
    Distance to CRM (MRI)
    Distance to circumferential margin - in mm - measured by MRI scan
    Units: Subjects
        0 mm
    		 21 24 45
        < 2mm
    		 6 2 8
        >= 2 mm
    		 9 10 19
        NA
    		 7 5 12
    Tumour stage
    Units: Subjects
        T2
    		 2 2 4
        T3
    		 34 31 65
        T4
    		 7 8 15
    Nodal stage
    Units: Subjects
        N0
    		 7 5 12
        N1
    		 15 18 33
        N2
    		 20 17 37
        Nx
    		 1 1 2
    Subject analysis sets

    Subject analysis set title
    Intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients that were randomized. In this study ITT set = per protocol (all patients that started treatment per protocol) = safety population (started treatment and had at least one dose)

    Subject analysis set title
    Efficacy set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients with pathologic assessment of microscopic preoperative response (patients in whom preoperative chemoradiotherapy was completed and surgical resection was performed as per protocol).

    Subject analysis set title
    Centrally reviewed efficacy set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients with pathologic assessment of microscopic preoperative response that was centrally reviewed (patients with post-surgical materials available for central review)

    Subject analysis sets values
    		 Intent to treat Efficacy set Centrally reviewed efficacy set
    Number of subjects
    84
    80
    79
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    58
        From 65-84 years
    26
    Age continuous
    Exact age value at start of treatment was considered. No split per age group was performed.
    Units: years
        median (full range (min-max))
    60 (26 to 78)
    Gender categorical
    Units: Subjects
        Female
    26
        Male
    58
    ECOG PS
    PS – Performance status
    Units: Subjects
        PS=0
    73
        PS=1
    11
    Distance from tumour to anal verge (colonoscopy)
    Distance from tumour to anal verge in cm - measuered by colonoscopy
    Units: Subjects
        <5cm
    33
        >= 5 cm
    28
        NA
    23
    Distance to CRM (MRI)
    Distance to circumferential margin - in mm - measured by MRI scan
    Units: Subjects
        0 mm
    45
        < 2mm
    8
        >= 2 mm
    19
        NA
    12
    Tumour stage
    Units: Subjects
        T2
    4
        T3
    65
        T4
    15
    Nodal stage
    Units: Subjects
        N0
    12
        N1
    33
        N2
    37
        Nx
    2

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Reporting group title
    Arm A
    Reporting group description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Reporting group title
    Arm A
    Reporting group description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).
    Reporting group title
    Arm A
    Reporting group description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Subject analysis set title
    Intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients that were randomized. In this study ITT set = per protocol (all patients that started treatment per protocol) = safety population (started treatment and had at least one dose)

    Subject analysis set title
    Efficacy set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients with pathologic assessment of microscopic preoperative response (patients in whom preoperative chemoradiotherapy was completed and surgical resection was performed as per protocol).

    Subject analysis set title
    Centrally reviewed efficacy set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients with pathologic assessment of microscopic preoperative response that was centrally reviewed (patients with post-surgical materials available for central review)

    Primary: Pathologic complete response (pCR) rate

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    End point title
    		 Pathologic complete response (pCR) rate
    End point description
    Pathologic complete response (ypT0N0) was concluded if the pathologist was unable to demonstrate any intact viable cancer cells within the operative specimen. The presence of mucin lakes without associated adjacent malignant cells could be defined as a pathologic complete response. Histopathologic assessments of tumour response post chemoradiotherapy provided by the investigators (as read by local pathologists) were reviewed centrally for all patients for whom surgical materials were available. The diagnosis of independent central reviewers primed.
    End point type
    Primary
    End point timeframe
    Post-surgery
    End point values
    		 Arm A Arm B Centrally reviewed efficacy set
    Number of subjects analysed
    41
    38
    79
    Units: Number of patients
        Dworak TRG=4 (Complete Response, no tumour left)
    14
    4
    18
        Dworak TRG=3-4 (good tumour regression)
    17
    9
    26
        Dworak TRG=0-1-2 (no or little tumour regression)
    24
    29
    53
    Attachments
    		 Tumour regression - main endpoint ypCR
    Statistical analysis title
    		 Counts of pathological complete response
    Statistical analysis description
    Descriptive. Counts of pathological complete response. Proportions with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 1 [2]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [1] - No comparison was performed between arms. Descriptive statistics only.
    [2] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Secondary: Histopathologic R0 resection rate (negative resection margins)

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    End point title
    		 Histopathologic R0 resection rate (negative resection margins)
    End point description
    Histopathologic R0 resection rate was defined as margins histologically negative for tumour involvement after resection. The circumferential resection margin (CRM) is considered to be involved if microscopic tumour is present <1mm from or at the inked circumferential or radial resection margin (51). Data on quality of mesorectal excision were expected but not collected consistently.
    End point type
    Secondary
    End point timeframe
    Post-surgery
    End point values
    		 Arm A Arm B Efficacy set Centrally reviewed efficacy set
    Number of subjects analysed
    41
    39 [3]
    80
    75
    Units: Number of cases
        Negative resection margins
    40
    37
    78
    71
        Positive resection margins
    1
    2
    2
    4
    Notes
    [3] - Pt that discontinued due to major toxicity and had surgery off protocol counted here as well
    Statistical analysis title
    		 Counts of patients with negative resection margins
    Statistical analysis description
    Descriptive. Counts of patients with negative resection margins in centrally reviewed efficacy set. Proportions with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 1 [5]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [4] - Descriptive
    [5] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Secondary: Pathologic downstaging rate and tumour regression rate

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    End point title
    		 Pathologic downstaging rate and tumour regression rate
    End point description
    Pathologic tumour response was assessed according to the TNM staging system and according to the grading system for tumour regression as described by Dworak. Grade 0: no regression Grade 1: dominant tumour mass with obvious fibrosis and/or vasculopathy Grade 2: dominantly fibrotic changes with few tumour cells or groups (easy to find) Grade 3: very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucous substance Grade 4: no tumour cells, only a fibrotic mass (total regression or complete response)
    End point type
    Secondary
    End point timeframe
    Post-surgery
    End point values
    		 Arm A Arm B Centrally reviewed efficacy set
    Number of subjects analysed
    41
    38
    79
    Units: Number of patients
        Dworak TRG 4 (complete response, no tumor left)
    14
    4
    18
        Dworak TRG 3-4 (good tumor regression)
    17
    9
    26
        Dworak TRG 0-1-2 (no or little tumor regression)
    24
    29
    53
    Statistical analysis title
    		 Counts of tumour regression grades
    Statistical analysis description
    Descriptive. Counts of patients with different tumour regression grades after treatment. Proportions with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 1 [7]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [6] - Descriptive
    [7] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Secondary: Clinical response rate

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    End point title
    		 Clinical response rate
    End point description
    Baseline measurements were performed within 4 weeks prior to treatment start. The same methods of assessment (CT and/or MRI) and the same techniques were used for each measurable lesion, identified at baseline and during follow-up. • Complete Response (CR) is disappearance of all clinical and radiological evidence of tumour (both target and non-target lesions). • Partial Response (PR) is at least a 30% decrease in the sum of LD of target lesions, taking as reference the baseline sum LD. • Stable Disease (SD) is steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. • Progressive Disease (PD) is at least a 20% increase in the sum of LD of measured lesions taking as references the smallest sum LD recorded since the treatment started. Appearance of new lesions will also constitute progressive disease. In exceptional circumstances, unequivocal progression of non-target lesions may be accepted as evidence of disease progressi
    End point type
    Secondary
    End point timeframe
    Pre-surgery
    End point values
    		 Arm A Arm B Intent to treat
    Number of subjects analysed
    43
    41
    84
    Units: Number of patients
        CR
    3
    5
    8
        PR
    24
    17
    41
        SD
    9
    13
    22
        PD
    0
    1
    1
        NA
    7
    5
    12
    Statistical analysis title
    		 Counts of clinical response
    Statistical analysis description
    Descriptive. Counts of clinical response. Rates of different types of response (CRR; OR; DCR) with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 1 [9]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [8] - Descriptive
    [9] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Secondary: Disease status (recurrence)

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    End point title
    		 Disease status (recurrence)
    End point description
    Recurrence of disease (local or distant) and disease free survival at 3 and 5 years
    End point type
    Secondary
    End point timeframe
    Post-treatment + 5 years
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    42
    41
    Units: Number of patients
        Recurred
    9
    8
        Not recurred
    33
    33
        Lost to follow-up
    0
    0
    Statistical analysis title
    		 Counts of disease recurrence
    Statistical analysis description
    1. Counts of patients with disease recurrence. Proportions with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request. 2. Kaplan-Meier survival analysis (median disease free survival time not yet reached as of 20-Feb-2017) Analysis to be redone at 5 years post study (expected March 2019)
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 1 [11]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [10] - Kaplan-Meier
    [11] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Secondary: Survival

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    End point title
    		 Survival
    End point description
    Deaths and overall survival at 3 and 5 years.
    End point type
    Secondary
    End point timeframe
    Post treatment + 5 years
    End point values
    		 Arm A Arm B Intent to treat
    Number of subjects analysed
    42
    41
    84
    Units: Number of patients
        Deceased
    4
    5
    9
        Alive
    38
    36
    74
        Lost to FU
    0
    0
    1
    Statistical analysis title
    		 Counts of patients deceased
    Statistical analysis description
    1. Counts of patients deceased. Proportions with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request. 2. Kaplan-Meier survival analysis (median overall survival time not yet reached as of 20-Feb-2017) Analysis to be redone at 5 years post study (expected March 2019)
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 1 [13]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [12] - Kaplan-Meier
    [13] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Secondary: Safety

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    End point title
    		 Safety
    End point description
    Adverse events graded as per NCI CTCAE (US National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0 All Serious Adverse Events occurences are reported; all Adverse Events related and not related to study treatment are reported; all severe laboratory events (hematology and biochemistry Gr 3 and higher) are reported; all severe postoperative complications (Gr 3 and higher) occured within the first month post surgery are reported.
    End point type
    Secondary
    End point timeframe
    All safety events (serious and non serious) from signature of informed consent to +30 days after surgery
    End point values
    		 Arm A Arm B Intent to treat
    Number of subjects analysed
    43
    41
    84
    Units: Number of cases and rates
        Serious Adverse Events
    22
    12
    34
        All Adverse Events
    564
    426
    990
        Severe lab events
    27
    16
    43
        Postoperative complications at 1 month
    14
    9
    23
    Statistical analysis title
    		 Counts of safety events
    Statistical analysis description
    Descriptive. Counts of safety events. Proportions with confidence intervals were calculated per arm. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 1 [15]
    Method
    		 Descriptive. No comparison
    Confidence interval
    Notes
    [14] - No comparison was performed between arms. Descriptive statistics only.
    [15] - This is a fictive value. P-value is not applicable. There is no comparison between arms.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signature of ICF to 30 days post surgery with follow-up for residual toxicity after this period if applicable
    Adverse event reporting additional description
    All SAE occurrences are reported and displayed below. Only Gr 3-4-5 non-serious adverse events are reported in this database.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTC AE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Oxaliplatin + Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine + Bevacizumab + Radiotherapy followed by surgery (TME).

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 43 (48.84%)
    12 / 41 (29.27%)
         number of deaths (all causes)
    4
    5
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Lung embolism
    Additional description: Lung embolism Gr 5 Postoperative
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Neuropathy motor
    Additional description: Neuropathy, motor (cranial, palate, pharynx) Gr 3 (swallowing problems) During chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
    Additional description: Seizure Gr 2 in a patient with epileptic background During chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
    Additional description: Fever Gr 1 During chemoradiotherapy
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
    Additional description: Rectal haemorrhage Gr 2 following rectal biopsy During chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhea Gr 3 During chemoradiotherapy
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
    Additional description: Rectovaginal fistula Gr 2 Postoperative
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leak
    Additional description: Anastomotic leak Gr 3 ; 2 in arm A and 3 in arm B - all events also SAE Timepoint of onset = Postoperative
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction
    Additional description: Obstruction GI Gr 2 and Gr 3, both in arm A Postoperative
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presacral hematoma
    Additional description: Presacral hematoma Gr 2 Postoperative
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
    Additional description: Depression Gr 3 During chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Febrile neutropenia
    Additional description: Febrile neutropenia Gr 3 During chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
    Additional description: Catheter related infection Gr 4 During chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: 2 Urinary tract infection Gr 2 (1 in each arm) and 1 Urinary tract infection Gr 3 in arm A During chemoradiotherapy
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
    Additional description: Catheter site infection Gr 3 with positive hemocultures Postoperative
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
    Additional description: 5 peri-anal wound infections Gr 3 (4 in arm A; 1 in arm B) ; 1 wound infection with evisceration Gr 4 in arm A; 1 Gr 5 wound infection in a patient with tumor break during surgery in arm B
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 43 (41.86%)
    15 / 41 (36.59%)
    Vascular disorders
    Deep venous thrombosis
    Additional description: DVT Gr 3 Timepoint of onset = Postoperative
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Embolism
    Additional description: Embolism Gr 4 and embolism Gr 5 both in arm B
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
    Additional description: Fatigue Gr 3 (2 pts in arm A and 1 pt in arm B - also an SAE for this pt) Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Sweating
    Additional description: Sweating Gr 3 Timepoint of onset = Postoperative
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pain pulmonary/respiratory
    Additional description: Sore throat Gr 3 and laryngeal pain Gr 3 in one patient in arm B Timepoint of onset = Follow up post end of treatment visit
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Depression
    Additional description: Depression Gr 3 - also an SAE Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Cardiac disorders
    Hypertension baseline
    Additional description: Hypertension Gr 3 Timepoint of onset = baseline
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Hypertension
    Additional description: Hypertension Gr 3 in 2 pts in arm B Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Cardiopulmonary arrest
    Additional description: Cardiopulmonary arrest Gr 5 Timepoint of onset = Follow up post end of treatment visit
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Nervous system disorders
    Neuropathy sensory
    Additional description: Neuropathy sensory Gr 3 Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Syncope
    Additional description: Syncope Gr 3 Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Neuropathy - cranial
    Additional description: Neuropathy - cranial Gr 3 (also an SAE) Timepoint of onset = Follow up post end of treatment visit
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Platelet count decreased
    Additional description: Platelet count decreased Gr 3 Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Disseminated Intravascular Coagulation
    Additional description: Disseminated Intravascular Coagulation Gr3 Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Haemorrhage
    Additional description: Hemorrhage wih surgery Gr 3 Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Hematoma postoperative
    Additional description: Hematoma Gr 3 in 1 pt in arm B (also SAE) Timepoint of onset = postoperative
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Meniere's disease
    Additional description: Pt with baseline Meniere's disease Gr3 (since 1999) Timepoint of onset = baseline
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Anorexia
    Additional description: Anorexia Gr 3
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Diarrhea
    Additional description: Diarrhea Gr 3 in 4 pts in arm A (three episodes were an SAE) Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    Anal pain
    Additional description: Pain gastro-intestinal - anal pain Gr 3 Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Leak GI
    Additional description: Leak GI Gr 3 Timepoint of onset = Postoperative
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 41 (7.32%)
         occurrences all number
    2
    3
    Obstruction GI
    Additional description: Onstruction GI Gr 3 in 2 pts in arm A (for 1 also an SAE) and in 1 pt in arm B (also an SAE) Timepoint of onset = Postoperative
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Pain GI
    Additional description: Stomach pain Gr 3 and pain due to leak Gr 3 Timepoint of onset = Postoperative
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Discharge from the anus
    Additional description: Purulent discharge from the anus Gr 3 Tiempoint of onset = postoperative
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Ascites
    Additional description: Ascites Gr 5 Timepoint of onset = Follow up post end of treatment visit
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Dysphagia
    Additional description: Dysphagia Gr 3 Timepoint of onset = Follow up post end of treatment visit
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
    Additional description: Dermatitis associated with radiotherapy Gr 3 Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    Rash
    Additional description: Rash Gr 3 Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Leak, GU
    Additional description: Leak, GU Gr 5 Timepoint of onset = follow-up
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain muskuloskeletal
    Additional description: Pain muskuloskeletal Gr 3 Timepoint of onset = Postoperative
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Febrile neutropenia
    Additional description: Febrile neutropenia Gr 3 (also an SAE) Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Catheter site infection
    Additional description: Catheter site infection Gr 3 (also an SAE) Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Sepsis
    Additional description: Sepsis Gr 3 and septic shock Gr 4 Timepoint of onset = during chemoradiotherapy
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Wound infection
    Additional description: 5 peri-anal wound infections Gr 3 (4 in arm A; 1 in arm B) ; 1 wound infection with evisceration Gr 4 in arm A; 1 Gr 5 wound infection in a patient with tumor break during surgery in arm B Timepoint of onset : postoperative
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 41 (4.88%)
         occurrences all number
    5
    2
    Peritonitis
    Additional description: Peritonitis Gr 5 (tumor break during surgery) - part of SAE Timepoint of onset = follow-up
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Infection due to leak of anastomosis
    Additional description: Infection due to leak of anastomosis Gr 3 (part of an SAE) Timepoint of onset = follow-up
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypocalcemia
    Additional description: Hypocalcemia Gr 3 Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Hypokalemia
    Additional description: Hypokalemia Gr 3 Timepoint of onset - during chemoradiotherapy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Hyponatremia
    Additional description: Hyponatremia Gr 3 Timepoint of onset = Postoperative
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2011
    The amendment consisted mainly in corrections and clarifications of the procedures. The Informed Consent form was not changed.
    07 Dec 2011
    The amendment consisted mainly in changes regarding the investigational capecitabine (declaration of change of drug production site). The Informed Consent Form was not changed.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was not powered to allow for formal statistical comparisons between arms. Descriptive statistics only. Use of a surrogate main endpoint (pCR rate) instead of clinical efficacy end-points

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25867261
    http://www.ncbi.nlm.nih.gov/pubmed/23997939
    http://www.ncbi.nlm.nih.gov/pubmed/24876730
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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