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    Clinical Trial Results:
    Bevacizumab And Combination Chemotherapy in rectal cancer Until Surgery: A Phase II, Multicentre, Open-label, Randomised Study of Neoadjuvant Chemotherapy and Bevacizumab in Patients with MRI defined High-Risk Cancer of the Rectum

    Summary
    EudraCT number
    		 2010-022754-17
    Trial protocol
    		 GB  
    Global end of trial date
    14 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2019
    First version publication date
    22 Dec 2019
    Other versions
    Summary report(s)
    		 BACCHUS

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/09/0176
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01650428
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    90 Tottenham Court Road, London, United Kingdom,
    Public contact
    Sarah Pearce, University College London, 0207 6799392, ctc.bacchus@ucl.ac.uk
    Scientific contact
    Sarah Pearce, University College London, 0207 6799392, ctc.bacchus@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The principal research question is to see how effective the two different treatment arms are. Efficacy will be measured by examining tissue removed at surgery to see how many patients have a pathological complete response; that is - how many patients do not have any visible tumour left, even when looking through a microscope.
    Protection of trial subjects
    The risks for patients in this trial were similar to those for any patient undergoing chemotherapy treatment. The chemotherapy regimens used were new and intense but consideration was given to this when writing the protocol. The eligibility criteria were stringent to ensure patients were fit enough to receive treatment, assessments during and after trial treatment were comprehensive and detailed guidance was given in the protocol for dose modifications if/when toxicity from the chemotherapy occurred. Adverse events pertaining to the administration of these drugs were closely monitored throughout the trial. Each patient's GP was informed of their participation and asked to report all serious side effects immediately to the research team at site. Patient cards were also issued to the patients in case of emergencies, which contained information about the study. A risk assessment was performed for this trial and an appropriate level of monitoring was carried out including the monitoring of patient safety.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    16
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment start date: 29/05/2013 Recruitment end date: 08/09/2015 Total Number of sites: 15

    Pre-assignment
    Screening details
    		 522 patients screened. Patients were excluded for 1 of the following reasons: not 18-70 years of age, not 18-75 years of age (20/08/2014,age range extended) Pelvic MRI disease not meet eligibility criteria. Metastatic disease. Tumour not 4-12cm from anal verge. Previous radiotherapy. Recent surgery. WHO PS >1, Patient refusal. Clinical decision.

    Period 1
    Period 1 title
    Overall Trial (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
    Arm description
    		 FOLFOX + bevacizumab: • Bevacizumab 5 mg/kg IV over 30 – 90 minutes (cycles 1 – 5) • Oxaliplatin 85 mg/m2 IV over 2 hours • Folinic acid 350 mg IV over 2 hours • 5FU 3200 mg/m2 IV continuous infusion over 48 hours
    Arm type
    		 Active comparator

    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
    5 mg/kg on day 1 of each cycle, 25 mg/kg in total over 5 cycles

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m2 on day 1 of each cycle, 510 mg/m2 in total over 6 cycles

    Investigational medicinal product name
    Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3200 mg/m2 as continuous infusion over 48 hours starting on day 1 of each cycle, 19200 mg/m2 in total over 6 cycles

    Arm title
    		 Arm B
    Arm description
    		 FOLFOXIRI + Bevacizumab. Given every 2 weeks for 12 weeks (6 cycles) • Bevacizumab 5 mg/kg IV over 30 – 90* minutes (cycles 1 – 5 only) • Irinotecan 165 mg/m2 IV over 1 hour • Oxaliplatin 85 mg/m2 IV over 2 hours • 5FU 3200 mg/m2 IV continuous infusion over 48 hours
    Arm type
    		 Active comparator

    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
    5 mg/kg on day 1 of each cycle, 25 mg/kg in total over 5 cycles

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m2 on day 1 of each cycle, 510 mg/m2 in total over 6 cycles

    Investigational medicinal product name
    Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3200 mg/m2 as continuous infusion over 48 hours starting on day 1 of each cycle, 19200 mg/m2 in total over 6 cycles

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    165 mg/m2 on day 1 of each cycle, 990 mg/m2 in total over 6 cycles

    Number of subjects in period 1
    		Arm A Arm B
    Started
    10
    10
    Completed
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 12 12

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 FOLFOX + bevacizumab: • Bevacizumab 5 mg/kg IV over 30 – 90 minutes (cycles 1 – 5) • Oxaliplatin 85 mg/m2 IV over 2 hours • Folinic acid 350 mg IV over 2 hours • 5FU 3200 mg/m2 IV continuous infusion over 48 hours

    Reporting group title
    Arm B
    Reporting group description
    		 FOLFOXIRI + Bevacizumab. Given every 2 weeks for 12 weeks (6 cycles) • Bevacizumab 5 mg/kg IV over 30 – 90* minutes (cycles 1 – 5 only) • Irinotecan 165 mg/m2 IV over 1 hour • Oxaliplatin 85 mg/m2 IV over 2 hours • 5FU 3200 mg/m2 IV continuous infusion over 48 hours

    Primary: Pathological complete response (pCR) in the histological specimen

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    End point title
    		 Pathological complete response (pCR) in the histological specimen
    End point description
    The primary endpoint for this trial is the pathological complete response rate (pCR). The proportion of patients in each arm who achieve a pCR will be presented, along with a 95% confidence interval (CI). pCR will be assessed after surgery. Within each group the achieved pCR rate will be compared to the rate achieved by radiotherapy alone (5%). The study is powered on the assumption that a substantial proportion of patients will have a pCR. It is well recognised that patients who have a complete clinical response both on imaging and clinical examination will from time to time refuse surgery. For the purpose of this study, patients who have a sustained clinical complete response at 12 months will be considered the same as a patient with a complete pathological response. In contrast, patients with a transient clinical response where local endoluminal or pelvic relapse is observed within this 12 month timeframe will not.
    End point type
    Primary
    End point timeframe
    pCR will be assessed after surgery.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10
    10
    Units: percentage
        pCR
    0
    2
        Non-pCR
    10
    8
    Statistical analysis title
    		 Pathological Complete response rate
    Statistical analysis description
    The primary endpoint for this trial is the pathological complete response rate (pCR). The proportion of patients in each arm who achieve a pCR will be presented, along with a 95% confidence interval (CI). pCR will be assessed after surgery. The analysis was not powered for a direct comparison between treatment groups. The analysis was powered to compare the pCR rates in each group with historical controls data (pCR rate in radiotherapy alone in historical controls is 5%).
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 single proportion in each treatment
    Parameter type
    		 single proportion in FOLFOXIRI arm
    Point estimate
    0.22
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.55
    Notes
    [1] - A’Hern single stage design, ie, single proportion test

    Secondary: RECIST response rate

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    End point title
    		 RECIST response rate
    End point description
    RECIST response rate will be presented as percentages with corresponding 95% CIs. Time to event outcomes will be estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    This will be assessed after chemotherapy has ended. Complete response and Partial response will be considered as responses. The best response during chemotherapy will be given for each patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    9 [2]
    10 [3]
    Units: Percentage
        Complete Response
    11
    30
        Partial Response
    88
    40
        Stable Disease
    0
    30
    Notes
    [2] - Measured in Percentage
    [3] - Measured in Percentage
    No statistical analyses for this end point

    Secondary: CRM negative resection rate

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    End point title
    		 CRM negative resection rate
    End point description
    CRM negative resection rate: those with a resection distance >1mm amongst those having surgery.
    End point type
    Secondary
    End point timeframe
    Post surgery. Those with a resection distance >1mm amongst those having surgery.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10
    10
    Units: percentage
        RO - Resection
    70
    100
        R2 Resection
    10
    0
        Not available
    20
    0
    No statistical analyses for this end point

    Secondary: T and N stage downstaging

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    End point title
    		 T and N stage downstaging
    End point description
    This will examine T and N stage to assess whether stage has worsened from baseline to post-treatment. A patient will be considered to have downstaged if i) both T and N stage decrease; or ii) either T or N stage decreases and the other remains stable.
    End point type
    Secondary
    End point timeframe
    From baseline to post-treatment.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10
    10
    Units: percentage
        Downstaged
    60
    70
        Maintained T and N Stage
    10
    10
        Not evaluable
    30
    20
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Defined as time from randomisation to disease progression or death, whichever occurs first. Disease progression will be assessed by the RECIST criteria at pre-cycle 4 and post-treatment.
    End point type
    Secondary
    End point timeframe
    Disease progression will be assessed at pre-cycle 4 and post-treatment.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10 [4]
    10 [5]
    Units: months
    number (not applicable)
        2 year Progresssion Free Survial
    80
    100
        Deaths
    20
    0
    Notes
    [4] - percentage
    [5] - percentage
    No statistical analyses for this end point

    Secondary: Disease free survival

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    End point title
    		 Disease free survival
    End point description
    Defined as the time from surgery with complete resections (R0) to the occurrence of relapse, second colorectal primary or death from any cause, whichever occurs first. Only subjects who have a complete resection (R0) will be included in this analysis. Patients who are alive, without recurrence and with no secondary colorectal cancer at the time of cut-off will be right-censored at the most recent date of assessment.
    End point type
    Secondary
    End point timeframe
    From surgery to the occurrence of relapse, second colorectal primary or death from any cause, whichever occurs first.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    7 [6]
    10 [7]
    Units: months
    number (not applicable)
        Disease Free Survival
    71
    100
    Notes
    [6] - measured as percentage
    [7] - measured as percentage
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Defined as the time from study entry until death. The OS of all subjects and of the subgroup who had complete resection (R0) will be calculated.
    End point type
    Secondary
    End point timeframe
    Randomisation to death.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10
    10
    Units: Months
    number (not applicable)
        Deaths
    20
    0
        Alive
    80
    100
    No statistical analyses for this end point

    Secondary: Local control

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    End point title
    		 Local control
    End point description
    This will be assessed just for those patients who attain a CRM negative resection. This will be measured from date of surgery until local failure.
    End point type
    Secondary
    End point timeframe
    This will be measured from date of surgery until local failure.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    7 [8]
    10 [9]
    Units: percentage
        Progressed
    28
    0
        Not Progressed
    71
    100
    Notes
    [8] - measured as percentage
    [9] - measured as percentage
    No statistical analyses for this end point

    Secondary: 1-year colostomy rate

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    End point title
    		 1-year colostomy rate
    End point description
    This will be assessed post-surgery. The proportion of patients with an unreversed stoma one-year after surgery will be considered to have a colostomy at 1-year.
    End point type
    Secondary
    End point timeframe
    Up to one year post surgery.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    4 [10]
    4 [11]
    Units: percentage
        Stoma
    0
    50
        No Stoma
    100
    50
    Notes
    [10] - measured as percentage
    [11] - measured as percentage
    No statistical analyses for this end point

    Secondary: Chemotherapy compliance

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    End point title
    		 Chemotherapy compliance
    End point description
    Dose reductions and dose delays to all chemotherapy agents will be recorded.
    End point type
    Secondary
    End point timeframe
    Start to end of treatment
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10
    10
    Units: percentage
        Dose Reduction (any reason)
    40
    60
        Dose Omission (any reason)
    10
    10
        Without Dose Omission
    90
    90
        Without Dose Reduction
    60
    40
    No statistical analyses for this end point

    Secondary: Tumour Regression Grade

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    End point title
    		 Tumour Regression Grade
    End point description
    End point type
    Secondary
    End point timeframe
    Results from the post-resection tumour sample
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    10
    10
    Units: percentage
        Total Response
    0
    10
        Good Regression
    20
    20
        Moderate Regression
    20
    40
        Minimal Regression
    30
    10
        No Regression
    10
    10
        Not Reported
    20
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred between informed consent and 3 months after surgery to remove the rectal tumour were recorded.
    Adverse event reporting additional description
    Adverse events pertaining to the study drugs were closely monitored throughout the trial. Patient's GP were informed of their participation and asked to report all serious side effects immediately to sites. Patient cards and diaries were also issued to patients and reviewed before each treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 -

    Reporting group title
    Arm B
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    4
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    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
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 10 (50.00%)
         occurrences all number
    2
    6
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Constipation
         subjects affected / exposed
    4 / 10 (40.00%)
    8 / 10 (80.00%)
         occurrences all number
    3
    8
    Fatigue
         subjects affected / exposed
    8 / 10 (80.00%)
    10 / 10 (100.00%)
         occurrences all number
    8
    10
    Fever
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Ejaculation disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pelvic pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Laryngospasm
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pharyngeal mucositis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    sore thoat
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    4
    4
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
         occurrences all number
    3
    3
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Creatinine urine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    5
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    3
    Lymphocyte count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    5 / 10 (50.00%)
    8 / 10 (80.00%)
         occurrences all number
    5
    8
    Platelet count decreased
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 10 (40.00%)
         occurrences all number
    3
    4
    Weight loss
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    3 / 10 (30.00%)
    5 / 10 (50.00%)
         occurrences all number
    3
    5
    Injury, poisoning and procedural complications
    Wound complication
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Wound dehiscence
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dysaesthesia
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 10 (40.00%)
         occurrences all number
    2
    4
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Paresthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 10 (40.00%)
         occurrences all number
    6
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    5
    10
    Bone Marrow Hypocellular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Leukocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Eye disorders
    Blurred Vision
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Abdominal Pain
         subjects affected / exposed
    5 / 10 (50.00%)
    9 / 10 (90.00%)
         occurrences all number
    6
    10
    Anal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Colonic obstruction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    7 / 10 (70.00%)
    8 / 10 (80.00%)
         occurrences all number
    7
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    mucositis oral
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
         occurrences all number
    4
    3
    Nausea
         subjects affected / exposed
    5 / 10 (50.00%)
    8 / 10 (80.00%)
         occurrences all number
    5
    8
    Rectal haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    rectal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Small intestine obstruction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    6 / 10 (60.00%)
    5 / 10 (50.00%)
         occurrences all number
    6
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 10 (40.00%)
         occurrences all number
    0
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Urinary retention
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Catheter infection
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Pelvic infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Sepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    Wound infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Anorexia nervosa
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 10 (40.00%)
         occurrences all number
    2
    5
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    3
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2013
    Minimum time from finishing bevacizumab treatment to having surgery changed from 6 wks to 8 wks. Volume of blood collected increased from 9mls to 24 mls at each time-point. Safety information for bevacizumab added for necrotising faciitis & thromboembolisms. PIS: Contraceptive advice clarified. Additional safety information added from updated SPCs. Information about MRI scans added ICF: Additional MRI scans are now optional for patients as sites with the facilities
    11 Jul 2014
    Inclusion criteria: Increased upper age limit of eligible patients from 70 to 75
    17 Nov 2014
    Inclusion criteria: To include T4b patients Exclusion Criteria: Bisphosphonates wording changed Bisphosphonates added to list of concomitant medications
    05 Mar 2015
    Inclusion criteria: T3 tumours extending (≥ 4 mm), beyond the muscularis propria N0–N2 Tumours (involving or threatening the peritoneal surface) OR presence of macroscopic extramural venous invasion (V2 disease) AND for tumours below the peritoneal reflection, the primary tumour or involved lymph node (on MRI) must be >1 mm from the mesorectal fascia Exclusion Criteria: Circumferential resection margins has been removed.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30258994
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