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    Clinical Trial Results:
    Phase II clinical trial of capecitabine and oxaliplatin plus bevacizumab as neoadjuvant treatment for patients with previously untreated unresectable liver-only metastases from colorectal cancer

    Summary
    EudraCT number
    2005-004505-29
    Trial protocol
    GB  
    Global end of trial date
    10 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Sep 2016
    First version publication date
    25 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2676
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Royal Marsden NHS Foundation Trust
    Sponsor organisation address
    Downs Road, Sutton, London, United Kingdom, sm2 5pt
    Public contact
    Jacqui Oates, Royal Marsden NHS Foundation Trust, 0208 661 3279, jacqui.oates@rmh.nhs.uk
    Scientific contact
    Dr Khurum Khan, Royal Marsden NHS Foundation Trust , 0208 661 3279 , jacqui.oates@rmh.nhs.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
    01 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the response rate of patients with previously untreated unresectable liver-only metastases from colorectal cancer treated with neoadjuvant capecitabine and oxaliplatin plus bevacizumab.
    Protection of trial subjects
    The rate of liver resection correlated significantly with objective response rates (ORRs) of neoadjuvant chemotherapy . FOLFOXIRI (5-FU–LV–oxaliplatin–irinotecan) as well as the addition of cetuximab to FOLFOX or FOLFIRI (LV–5-FU–irinotecan) in Kras wild-type population resulted in a higher response rate compared with two-drug chemotherapy regimens . These improved response rates led to an increased rate of surgical metastases resection. Bevacizumab did not significantly improve ORR when added to oxaliplatin–fluoropyrimidine compared with oxaliplatin or fluoropyrimidine alone, and there were no statistically significant differences in resection rates in patients treated with bevacizumab compared with placebo . Nevertheless, these are subgroup (post hoc) analyses nested in large randomised, controlled trials of unselected patients not limited to liver-only metastases. As prospective bevacizumab data were lacking in this setting, a multicentre study of CAPOX (capecitabine–oxaliplatin) plus bevacizumab in patients with high-risk colorectal liver-only metastases (CLMs) considered to be unsuitable for upfront liver resection in order to assess the efficacy and safety of this approach was conducted. In our BOXER (bevacizumab, oxaliplatin, xeloda in unresectable liver metastases) study, CAPOX plus bevacizumab was used as it was considered an accepted first-line treatment of advanced CRC , and high-risk disease was based on large size, poorly located, multinodular, and synchronous presentation of liver metastases. This was considered standard approach at the time and thus no additonal safety risks were anticipated. However, all the routine safety procedures such as standard dose reductions or interruptions were conducted according to standrard hospital policies; moreover, a Trial Management Group (TMG) examined the safety of the study on regular basis. Ref: http://annonc.oxfordjournals.org.ezproxy.icr.ac.uk/content/22/9/2042.long
    Background therapy
    Oxaliplatin (130 mg/m2) and bevacizumab (7.5 mg/kg) were administered i.v. on day 1 every 3 weeks. Capecitabine was given orally at a dose of 1700 mg/m2/day divided into two split doses for 14 days followed by 7 days' rest repeated every 3 weeks. Dose adjustment was made in the event of toxicity assessed according to National Cancer Institute—Common Terminology Criteria for Adverse Events (NCI–CTCAE) version 3.0. Operability was reassessed every four cycles (12 weeks) with CT and MRI scans and this would then be rediscussed at liver MDT meetings. Nonprogressors who remained unresectable would proceed to a further four cycles of treatment. surgery. Patients deemed to be resectable would undergo surgery at an 8-week interval from last dose of bevacizumab (6 weeks from last dose of chemotherapy). Patients with in situ primary tumours could have either synchronous or staged resection of primary tumour and liver metastases as per local practice. postoperative chemotherapy. After recovery from surgery, patients received another 12 weeks of CAPOX plus bevacizumab at the same dose schedule as preoperative block.
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jun 2006
    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: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    26
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Appropriate patients were identified through multi-disciplinary meetings, which included representation from all disciplines including oncology, radiotherapy, surgery, histopathology and radiology. Patients were also idenfitied from new patient clinics by the sub-investigators.

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

    Arms
    Arm title
    All Patients
    Arm description
    capecitabine & oxaliplatin with bevacizumab
    Arm type
    single arm study

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 7.5mg/kg every 3 weeks

    Number of subjects in period 1
    All Patients
    Started
    46
    Completed
    45
    Not completed
    1
         Patient not eligible
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    -

    Reporting group values
    Treatment Total
    Number of subjects
    46 46
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    63 (29 to 78) -
    Gender categorical
    Units: Subjects
        Female
    17 17
        Male
    29 29

    End points

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    End points reporting groups
    Reporting group title
    All Patients
    Reporting group description
    capecitabine & oxaliplatin with bevacizumab

    Primary: Overall Response Rate

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    End point title
    Overall Response Rate [1]
    End point description
    Sum of complete and partial responses
    End point type
    Primary
    End point timeframe
    Best observed response rate
    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: This is a phase II study with only one arm, so no statistical comparisons can be made. This phase II study was designed using the optimal two-stage design with A'Hern exact P value. The primary end point was the best achieved ORR, calculated as the sum of observed complete and partial responses. An ORR rate of 60% was considered acceptable (p1) and ORR rate of 40% was ruled out as unacceptable (p0).
    End point values
    All Patients
    Number of subjects analysed
    45
    Units: Patients
    35
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment to 30 days post treatment end
    Adverse event reporting additional description
    Grade 3-5 related to treatment
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    No dictionary
    Dictionary version
    0
    Reporting groups
    Reporting group title
    All Patients
    Reporting group description
    All subjects receiving a study drug

    Serious adverse events
    All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 46 (15.22%)
         number of deaths (all causes)
    20
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Infection
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 46 (52.17%)
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4
    Nervous system disorders
    Peripheral neuropathy
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    5
    General disorders and administration site conditions
    Lethargy
         subjects affected / exposed
    11 / 46 (23.91%)
         occurrences all number
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 46 (13.04%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Hand and foot syndrome
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2006
    dose of capecitabine/oxaliplatin in combination chemotherapy reduced to 1700mg/m2 in two divided doses D1-14 in keeping with hospital guidelines
    01 Nov 2007
    dose adjustements for chemotherapy in patients above 75 years of age in keeping with the local guildelines
    02 Sep 2009
    clarification on follow up details on the study and additional PIS for patients participating in translational substudy

    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.
    single arm non-randomised syudy with no comparatar arm

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/2128
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