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    Clinical Trial Results:
    Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in Locally Advanced Resectable Rectal Cancer: A Randomized, Non-Comparative Phase II Study

    Summary
    EudraCT number
    		 2006-003472-35
    Trial protocol
    		 FR  
    Global end of trial date
    23 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Apr 2017
    First version publication date
    29 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML19202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00865189
    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
    23 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of two preoperative therapeutic strategies including bevacizumab in participants with newly diagnosed locally advanced rectal cancer.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2007
    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
    France: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    62
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 92 participants with resectable rectal cancer were selected and 91 participants were randomized into the study. One participant was not randomized due to non-compliance with the inclusion/exclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Arm description
    		 In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (intravenous [IV] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at the fixed dose of 5 milligrams per kilogram (mg/kg) as an IV infusion over 30 to 90 minutes.

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Leucovorin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Folinic acid was administered at a dose of 200 mg/m^2 as a 2-hour IV infusion.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Eloxatine
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was administered at a dose of 85 milligrams per square meter (mg/m^2) as a 2-hour IV infusion.

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil was administered at a dose of 400 mg/m^2 as an IV bolus, then at a dose of 600 mg/m^2 as a continuous IV infusion for 22 hours in Phase 1, and was administered at a dose of 225 mg/m^2 as a 24-hour IV infusion, 5 days a week, for 5 weeks in Phase 2.

    Arm title
    		 Arm B (Bevacizumab, Chemoradiotherapy)
    Arm description
    		 In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil was administered at a dose of 400 mg/m^2 as an IV bolus, then at a dose of 600 mg/m^2 as a continuous infusion for 22 hours in Phase 1, and was administered at a dose of 225 mg/m^2 as a 24-hour infusion, 5 days a week, for 5 weeks in Phase 2.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at the fixed dose of 5 mg/kg as an IV infusion over 30 to 90 minutes.

    Number of subjects in period 1
    		Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Started
    46
    45
    Completed
    34
    26
    Not completed
    12
    19
         Consent withdrawn by subject
    1
    -
         Death
    4
    11
         Unspecified
    1
    2
         Lost to follow-up
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Reporting group description
    		 In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (intravenous [IV] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.

    Reporting group title
    Arm B (Bevacizumab, Chemoradiotherapy)
    Reporting group description
    		 In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.

    Reporting group values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy) Total
    Number of subjects
    		 46 45 91
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 29 62
        From 65-84 years
    		 13 16 29
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.38 ( 8.99 ) 60.71 ( 9.88 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 15 15 30
        Male
    		 31 30 61

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Reporting group description
    		 In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (intravenous [IV] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.

    Reporting group title
    Arm B (Bevacizumab, Chemoradiotherapy)
    Reporting group description
    		 In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.

    Primary: Percentage of Participants With Tumor Sterilization Defined by ypT0-N0

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    End point title
    		 Percentage of Participants With Tumor Sterilization Defined by ypT0-N0 [1]
    End point description
    Tumor sterilization was defined as the absence of residual tumor cells in the resected specimen including lymph nodes (ypT0-N0). The rate of sterilization of the tumoral specimen was assessed after surgery on the surgical specimen by local review. Analyses were performed for participants who have been operated as defined by the protocol (within the study and TME technique) and for all participants who have been operated. Reported is the percentage of participants with tumor sterilization. Intent to treat (ITT) population included all the randomized participants who received at least one dose of treatment. Here, number of participants analyzed = participants who were evaluable for this outcome.
    End point type
    Primary
    End point timeframe
    After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
    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: Statistical analysis not reported due to a limitation of EudraCT application as the application does not allow the capture of a statistical analysis performed within a group.
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    42
    44
    Units: percentage of participants
        number (confidence interval 95%)
    23.8 (12.1 to 39.5)
    11.4 (3.8 to 24.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Tumor Down-Staging (ypT0-pT2)

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    End point title
    		 Percentage of Participants With Tumor Down-Staging (ypT0-pT2)
    End point description
    A participant with a downstaging was defined as a participant with T3 (T describes the size of the original [primary] tumor) at inclusion and T2 or T1 or T0 after surgery, or with N+ (N describes lymph nodes involvement) at inclusion and N- after surgery and if T is equal at inclusion and after surgery. The clinical tumor-node-metastasis (cTNM) classification was used at inclusion and the pathological staging tumor and nodes (ypTN) classification after surgery. Reported is the percentage of participants with tumor downstaging of the surgical specimen according to the local review and centralized review. ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome. “n” = participants who were evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    41
    44
    Units: percentage of participants
    number (confidence interval 95%)
        Downstaging, local review (n=41, 44)
    65.9 (51.3 to 80.4)
    54.5 (39.8 to 69.3)
        Downstaging, centralized review (n=39, 43)
    64.1 (49 to 79.2)
    55.8 (41 to 70.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Local and Distant Recurrences

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    End point title
    		 Percentage of Participants With Local and Distant Recurrences
    End point description
    The percentage of participants with a recurrence was described by type of recurrence (local and distant recurrence). ITT population.
    End point type
    Secondary
    End point timeframe
    After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: percentage of participants
    number (confidence interval 95%)
        Participants with a local recurrence
    2.2 (0.1 to 11.5)
    6.7 (1.4 to 18.3)
        Participants with a distant recurrence
    17.4 (7.8 to 31.4)
    13.3 (5.1 to 26.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death

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    End point title
    		 Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: percentage of participants
        number (not applicable)
    30.4
    33.3
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS)

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    End point title
    		 Disease-Free Survival (DFS)
    End point description
    The DFS was defined as the time from the first treatment intake to disease recurrence assessed (second primary cancer, local or distant recurrence, distant metastases) or death from any cause. The DFS was analyzed using Kaplan-Meier method. ITT population. Here, 9999 and 99999 indicates that median and upper limit of 95% CI, respectively, were not reached due to low number of DFS-events.
    End point type
    Secondary
    End point timeframe
    From first time of the treatment administration to the date of second cancer, local or regional recurrence, distant metastasis or death from any cause (up to approximately 6 years)
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: months
        median (confidence interval 95%)
    68.3 (68.3 to 99999)
    9999 (53 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    		 Percentage of Participants Who Died
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6 years
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: percentage of participants
        number (not applicable)
    8.7
    24.4
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    The overall survival was defined as the time from the first treatment intake to death from any cause. ITT population. Here, 9999, 999 and 99999 indicates that median and 95% CI were not reached due to the low number of deaths.
    End point type
    Secondary
    End point timeframe
    From the first treatment administration to the date of death (up to approximately 6 years)
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: months
        median (confidence interval 95%)
    9999 (999 to 99999)
    9999 (999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Cycles of Induction Chemotherapy

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    End point title
    		 Number of Cycles of Induction Chemotherapy [2]
    End point description
    ITT population. Only Arm A participants received induction treatment.
    End point type
    Secondary
    End point timeframe
    6 cycles (12 weeks; cycle length = 14 days)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable for Arm A
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Number of subjects analysed
    46
    Units: cycles
        arithmetic mean (standard deviation)
    5.8 ( 0.7 )
    No statistical analyses for this end point

    Secondary: Number of Cycles of Chemotherapy

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    End point title
    		 Number of Cycles of Chemotherapy
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: cycles
        arithmetic mean (standard deviation)
    4.4 ( 1.5 )
    4.8 ( 0.5 )
    No statistical analyses for this end point

    Secondary: Number of Cycles of Radiotherapy

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    End point title
    		 Number of Cycles of Radiotherapy
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: cycles
        arithmetic mean (standard deviation)
    4.5 ( 1.5 )
    5 ( 0 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Surgery

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    End point title
    		 Percentage of Participants With Surgery
    End point description
    The surgery involving a radical rectal excision using the TME technique. ITT population.
    End point type
    Secondary
    End point timeframe
    Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment
    End point values
    		 Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) Arm B (Bevacizumab, Chemoradiotherapy)
    Number of subjects analysed
    46
    45
    Units: percentage of participants
        number (not applicable)
    91.3
    97.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to approximately 6 years
    Adverse event reporting additional description
    The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Arm B (Bevacizumab, Chemoradiotherapy)
    Reporting group description
    		 In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.

    Reporting group title
    Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Reporting group description
    		 In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (intravenous [IV] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.

    Serious adverse events
    		 Arm B (Bevacizumab, Chemoradiotherapy) Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 45 (40.00%)
    21 / 46 (45.65%)
         number of deaths (all causes)
    11
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectoprostatic fistula
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal fistula
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic fistula
         subjects affected / exposed
    4 / 45 (8.89%)
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 46 (6.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic complication
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus arrhythmia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative abscess
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm B (Bevacizumab, Chemoradiotherapy) Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 45 (97.78%)
    46 / 46 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 45 (15.56%)
    11 / 46 (23.91%)
         occurrences all number
    10
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 45 (13.33%)
    17 / 46 (36.96%)
         occurrences all number
    7
    32
    Mucosal inflammation
         subjects affected / exposed
    4 / 45 (8.89%)
    7 / 46 (15.22%)
         occurrences all number
    4
    8
    Fatigue
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 46 (8.70%)
         occurrences all number
    2
    9
    Pyrexia
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 45 (4.44%)
    15 / 46 (32.61%)
         occurrences all number
    2
    17
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 45 (2.22%)
    12 / 46 (26.09%)
         occurrences all number
    1
    16
    Blood potassium decreased
         subjects affected / exposed
    1 / 45 (2.22%)
    5 / 46 (10.87%)
         occurrences all number
    1
    6
    Weight decreased
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    Injury, poisoning and procedural complications
    Anastomotic fistula
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    Wound dehiscence
         subjects affected / exposed
    5 / 45 (11.11%)
    2 / 46 (4.35%)
         occurrences all number
    6
    2
    Wound complication
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 46 (8.70%)
         occurrences all number
    1
    4
    Radiation skin injury
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    0 / 45 (0.00%)
    22 / 46 (47.83%)
         occurrences all number
    0
    30
    Paraesthesia
         subjects affected / exposed
    2 / 45 (4.44%)
    11 / 46 (23.91%)
         occurrences all number
    2
    16
    Headache
         subjects affected / exposed
    2 / 45 (4.44%)
    7 / 46 (15.22%)
         occurrences all number
    2
    8
    Dysaesthesia
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    24 / 45 (53.33%)
    25 / 46 (54.35%)
         occurrences all number
    28
    35
    Proctitis
         subjects affected / exposed
    18 / 45 (40.00%)
    21 / 46 (45.65%)
         occurrences all number
    19
    23
    Nausea
         subjects affected / exposed
    7 / 45 (15.56%)
    24 / 46 (52.17%)
         occurrences all number
    7
    38
    Constipation
         subjects affected / exposed
    3 / 45 (6.67%)
    15 / 46 (32.61%)
         occurrences all number
    3
    16
    Abdominal pain
         subjects affected / exposed
    5 / 45 (11.11%)
    7 / 46 (15.22%)
         occurrences all number
    5
    10
    Rectal haemorrhage
         subjects affected / exposed
    2 / 45 (4.44%)
    9 / 46 (19.57%)
         occurrences all number
    2
    10
    Abdominal pain upper
         subjects affected / exposed
    4 / 45 (8.89%)
    5 / 46 (10.87%)
         occurrences all number
    4
    5
    Anorectal discomfort
         subjects affected / exposed
    7 / 45 (15.56%)
    1 / 46 (2.17%)
         occurrences all number
    7
    1
    Proctalgia
         subjects affected / exposed
    3 / 45 (6.67%)
    4 / 46 (8.70%)
         occurrences all number
    3
    4
    Haemorrhoids
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 46 (8.70%)
         occurrences all number
    2
    4
    Vomiting
         subjects affected / exposed
    0 / 45 (0.00%)
    6 / 46 (13.04%)
         occurrences all number
    0
    6
    Rectal tenesmus
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    Stomatitis
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Abdominal pain lower
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Gingivitis
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    0
    5
    Alopecia
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Pruritus
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    13 / 45 (28.89%)
    20 / 46 (43.48%)
         occurrences all number
    18
    31
    Dysuria
         subjects affected / exposed
    10 / 45 (22.22%)
    12 / 46 (26.09%)
         occurrences all number
    10
    12
    Pollakiuria
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 45 (8.89%)
    2 / 46 (4.35%)
         occurrences all number
    4
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 45 (6.67%)
    6 / 46 (13.04%)
         occurrences all number
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2007
    The following changes were implemented: Minor modifications allowing to clarify some points and adding supplemental information in the inclusion and exclusion criteria, the follow-up of targeted events, the participant’s follow-up period in case of emergence of toxicity, modifications in the protocol and the participant’s information form for the ancillary study, and update of the list of Investigators.
    02 Jun 2008
    This amendment was implemented to update and clarify some exclusion criteria related to study treatments and disease, include the safety data of bevacizumab updated on November 2007. The last updates being incorporate in the protocol and the participant’s consent form.
    08 Sep 2015
    This amendment was implemented to change the secondary efficacy endpoint “progression-free survival” by “disease-free survival”.

    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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    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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