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    Clinical Trial Results:
    FOLFOX/bevacizumab with or without irinotecan in first-line treatment for metastatic colorectal cancer. A randomized phase II study.

    Summary
    EudraCT number
    		 2010-022162-27
    Trial protocol
    		 DE  
    Global end of trial date
    31 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2021
    First version publication date
    21 May 2021
    Other versions
    Summary report(s)
    		 Final Study Report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AIO0209
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01321957
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Martin-Luther-Universität Halle-Wittenberg
    Sponsor organisation address
    Magdeburger Str. 8, Halle (Saale), Germany, 06112
    Public contact
    Koordinierungszentrum für klinische Studien Halle/S., Koordinierungszentrum für klinische Studien Halle/S., +49 3455574903, aio0209@kks-halle.de
    Scientific contact
    Koordinierungszentrum für klinische Studien Halle/S., Koordinierungszentrum für klinische Studien Halle/S., +49 3455574903, aio0209@kks-halle.de
    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
    28 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of 5-Fluorouracil (5-FU), oxaliplatin and irinotecan (FOLFOXIRI-Regimen) with bevacizumab versus 5-FU and oxaliplatin (FOLFOX-Regimen) with bevacizumab in patients with metastatic colorectal cancer. Secondary objectives were safety and tolerability of the treatment as well as the progression free survival, overall survival, secondary resection rate, quality of life and the prognostic value of and the allocation to the clinical classification of patients. The addition of irinotecan might be more effective in terms of response and survival in bevacizumab insensitive compared to bevacizumab sensitive patients, therefore potential markers (VEGF-A, osteopontin, G-CSF, Ang-2, sVEGFR2, neuropilin, Dll4, CAIX/ HIF1a, etc.) were evaluated.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards consistent with Good Clinical Practice and applicable regulations. The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (from June 1964, Tokyo October 1975, Venice October 1983, Hong Kong September 1989, Somerset West October 1996 and Edinburgh amendments from 2000) or the laws and regulations. The protocol has been written, and the study has been conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice (reference: http://www.ifpma.org/pdfifpma/e6.pdf). The protocol was approved by Independent Ethics Committees.
    Background therapy
    		 Prevention of nausea/vomiting: NK1 receptor antagonist, 5-HT3 antagonists and dexamethasone were recommended for oxaliplatin-based CT. Delayed nausea/vomiting: oral dexamethasone; metoclopramide, alizapride, prochlorperazine at the discretion of the physician. Subjects had a supply of antiemetics available at home. Oral metoclopramide was recommended for capecitabine-induced nausea (5-HT3 antagonists at the discretion of the investigator. Diarrhoea and neutropenia: empiric use of antibiotics as prophylaxis against bowel sepsis was to be considered. Use of a quinolone was suggested. Anticoagulation: full dose anticoagulants as long as the INR or aPTT was within therapeutic limits and the patient had been on a stable dose for anticoagulants for at least two weeks at the time of registration. Monitoring of INR for oral anticoagulants was recommended. Antivirals and Antiprotozoals: Capecitabine should not be administered together with the halogenated antiviral drug sorivudine or its chemically related analogues. Caution in case of administration of metronidazole. Gastrointestinal Drugs: Care needed to be taken if a subject was taking both capecitabine and cimetidine. Allopurinol: Concomitant use of allopurinol with capecitabine and 5-FU should be avoided. Anti-epileptic Substances: Subjects taking phenytoin concomitantly with capecitabine had to be regularly monitored for increased phenytoin plasma concentrations and associated clinical symptoms. Growth factors: Haematopoietic growth factors (i.e., G- or GM-CSF) was used according to institutional guidelines to treat febrile neutropenia.
    Evidence for comparator
    		 Usually, bevacizumab and 5-FU are combined with either oxaliplatin or irinotecan. The chemotherapy regimen selected for this study (FOLFOX) was chosen on the basis of the higher response rates and survival durations as compared with other fluoropyrimidine-based regimens, and thus represent appropriate regimens for combination with bevacizumab. This therapy is therefore being used as a standard of care first-line therapy.
    Actual start date of recruitment
    28 Jul 2011
    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
    Germany: 250
    Worldwide total number of subjects
    250
    EEA total number of subjects
    250
    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)
    161
    From 65 to 84 years
    89
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Between July 28, 2011 and September 23, 2014, 250 patients were enrolled at 50 trial sites in Germany. The last patient finished the maintenance treatment in August 2017. Follow-up (LPV) was finished in August 2018.

    Pre-assignment
    Screening details
    		 All patients with metastatic colorectal carcinoma presenting at the participating trial sites with an indication for therapy were screened for inclusion/ exclusion criteria for this trial. All patients who met the inclusion/ exclusion criteria were offered participation in the study. There was no selection based on other criteria.

    Period 1
    Period 1 title
    CHARTA 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
    		 FOLFOX+beva
    Arm description
    		 Induction chemotherapy: FOLFOX (oxaliplatin, LV and 5-FU and bevacizumab, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab and 12 months of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-Fluoruracil
    Investigational medicinal product code
    5-FU
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3200 mg/sqm i.v. over 48 hours at day 1-3 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy and another 12 months in the maintainance therapy. Maximal treatment duration is 18 months.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    I-LV
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/sqm i.v. over two hours at day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy and another 12 months in the maintainance therapy. Maximal treatment duration is 18 months.

    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/sqm i.v. over two hours at day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    bevacizimab
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg i.v. over 30 to 90 min at day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Capecitabine
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1600 mg/sqm per day on day 1–14, every three weeks in the maintainance therapy (maximum for 12 months)

    Arm title
    		 FOLFOXIRI+beva
    Arm description
    		 Induction chemotherapy: FOLFOXIRI (oxaliplatin, LV and 5-FU and bevacizumab + irinotecan, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab + irinotecan + 12 M of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab + irinotecan (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-Fluoruracil
    Investigational medicinal product code
    5-FU
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3200 mg/sqm i.v. over 48 hours at day 1-3 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy and another 12 months in the maintainance therapy. Maximal treatment duration is 18 months. For the first cycle in the FOLFOXIRI+beva arm a dose reduction of 5-FU/LV to 75% was possible for patients who had an increased risk for severe toxicity as judged by the treating physician. If no significant toxicity occurs (e.g. diarrhea grade 3), treatment had to be continued with full dose. Upfront dose reduction and reescalation was at the discretion of the investigator.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    I-LV
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/sqm i.v. over two hours at day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy and another 12 months in the maintainance therapy. Maximal treatment duration is 18 months.

    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/sqm i.v. over two hours at day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    bevacizimab
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg i.v. over 30 to 90 min at day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy.

    Investigational medicinal product name
    Xeloda
    Investigational medicinal product code
    Capecitabine
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1600 mg/sqm per day on day 1–14, every three weeks in the maintainance therapy (maximum for 12 months)

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    IRI
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    165 mg/sqm i.v. over two hours on day 1 of each cycle for a maximum of 12 cycles (6 months) in the induction therapy. For the first cycle in the FOLFOXIRI+beva arm a dose reduction of irinotecan to 75% was possible for patients who had an increased risk for severe toxicity as judged by the treating physician. If no significant toxicity occurs (e.g. diarrhea grade 3), treatment had to be continued with full dose. Upfront dose reduction and reescalation was at the discretion of the investigator.

    Number of subjects in period 1
    		FOLFOX+beva FOLFOXIRI+beva
    Started
    126
    124
    Completed
    121
    121
    Not completed
    5
    3
         Consent withdrawn by subject
    3
    1
         Histologic diagnosis of neuroendocrinic tumor
    1
    1
         Randomisation failure - CTx before randomisation
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    FOLFOX+beva
    Reporting group description
    		 Induction chemotherapy: FOLFOX (oxaliplatin, LV and 5-FU and bevacizumab, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab and 12 months of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.

    Reporting group title
    FOLFOXIRI+beva
    Reporting group description
    		 Induction chemotherapy: FOLFOXIRI (oxaliplatin, LV and 5-FU and bevacizumab + irinotecan, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab + irinotecan + 12 M of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab + irinotecan (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.

    Reporting group values
    		 FOLFOX+beva FOLFOXIRI+beva Total
    Number of subjects
    		 126 124 250
    Age categorical
    Subjects not completed the trial were excluded from analysis - Not determined.
    Units: Subjects
        </= 30 year
    		 2 0 2
        31-40 years
    		 8 5 13
        41-50 years
    		 14 17 31
        51-60 years
    		 32 40 72
        61-70 years
    		 44 40 84
        71-80 years
    		 21 18 39
        > 80 years
    		 0 1 1
        Not determined (excl.)
    		 5 3 8
    Age continuous
    Subjects not completed the trial (see Subject disposition) were excluded from analysis. Arm FOLFOX+beva: n=121, excluded 5 Arm FOLFOXIRI+beva: n=121, excluded 3
    Units: years
        arithmetic mean (standard deviation)
    		 60 ( 11.4 ) 59.5 ( 9.9 ) -
    Gender categorical
    Subjects not completed the trial (see Subject disposition) were excluded from analysis - Not determined.
    Units: Subjects
        Female
    		 42 43 85
        Male
    		 79 78 157
        Not determined
    		 5 3 8
    ESMO clinical group - stratum
    group 1: liver and/or lung metastasis potentially resectable after downsizing, comorbidity allowing surgery group 2: multiple metastasis, rapid progression, risk of rapid deterioration, unlikely to become resectablepage group 3: not resectable and no symptoms or risk of deterioration *not determined for excluded subjects (see subject disposition)
    Units: Subjects
        group 1
    		 35 35 70
        group 2
    		 67 67 134
        group 3
    		 19 19 38
        not determined
    		 5 3 8
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 56 62 118
        ECOG 1
    		 56 52 108
        ECOG 2
    		 6 3 9
        not determined
    		 8 7 15
    BMI - categories acc. to WHO
    Units: Subjects
        < 18.5
    		 2 4 6
        18.5 - < 25
    		 55 50 105
        25 - < 30
    		 43 44 87
        30 - < 35
    		 14 17 31
        35 - < 40
    		 2 3 5
        >/= 40
    		 4 3 7
        not determined
    		 6 3 9
    BRAF mutation
    Units: Subjects
        wildtype
    		 91 85 176
        mutated
    		 5 8 13
        not done
    		 30 31 61
    all-RAS mutation, any exon
    Units: Subjects
        no mutation
    		 47 53 100
        mutation
    		 59 61 120
        not determined
    		 20 10 30
    Grading
    Units: Subjects
        G1
    		 6 4 10
        G2
    		 70 73 143
        G3
    		 30 33 63
        G4
    		 0 1 1
        Gx
    		 12 10 22
        not determined
    		 8 3 11
    Location of primary tumor
    Units: Subjects
        Colon
    		 60 69 129
        Rectum
    		 36 33 69
        Rectum and Colon
    		 21 18 39
        not determined
    		 9 4 13
    Tumor sideness : left vs. right
    Units: Subjects
        left colon or rectum
    		 88 84 172
        right colon
    		 28 36 64
        not determined
    		 10 4 14
    Stage of primary tumor
    at first diagnosis
    Units: Subjects
        0.
    		 2 0 2
        I.
    		 0 2 2
        IIA
    		 4 3 7
        IIB
    		 3 0 3
        IIIA
    		 2 1 3
        IIIB
    		 1 5 6
        IIIC
    		 3 6 9
        IV
    		 97 94 191
        not determined
    		 14 13 27
    TNM stage - T status
    Units: Subjects
        T1
    		 1 0 1
        T2
    		 9 4 13
        T3
    		 48 62 110
        T4
    		 38 32 70
        Tis
    		 0 0 0
        Tx
    		 20 17 37
        not determined
    		 10 9 19
    TNM stage - N status
    Units: Subjects
        N0
    		 27 15 42
        N1
    		 41 38 79
        N2
    		 34 38 72
        N3
    		 0 3 3
        Nx
    		 18 22 40
        not detemined
    		 6 8 14
    TNM stage - M status
    Units: Subjects
        M0
    		 8 8 16
        M1
    		 107 108 215
        Mx
    		 4 4 8
        not determined
    		 7 4 11
    Köhne Score
    Units: Subjects
        low risk
    		 11 9 20
        intermediate risk
    		 85 85 170
        high risk
    		 20 18 38
        not determined
    		 10 12 22
    Induction therapy: Max. number of cycles per patient
    Units: Subjects
        1 Cycle/n
    		 1 4 5
        2 Cycle/n
    		 2 5 7
        3 Cycle/n
    		 4 4 8
        4 Cycle/n
    		 7 9 16
        5 Cycle/n
    		 12 5 17
        6 Cycle/n
    		 6 3 9
        7 Cycle/n
    		 1 2 3
        8 Cycle/n
    		 9 5 14
        9 Cycle/n
    		 4 4 8
        10 Cycle/n
    		 2 3 5
        11 Cycle/n
    		 9 5 14
        12 Cycle/n
    		 61 72 133
        not determined
    		 8 3 11
    Maintenence therapy: Number of treatment cycles - by categories
    FOLFOX+beva: n=58 FOLFOXIRI+beva: n=66
    Units: Subjects
        up to 6 cycles
    		 24 26 50
        up to 12 cycles
    		 14 16 30
        up to 18 cycles
    		 11 9 20
        up to 24 cycles
    		 7 13 20
        > 24 cycles
    		 2 2 4
        not received maintenence therapy
    		 63 55 118
        not determined
    		 5 3 8
    Height
    FOLFOX+beva: n=120 FOLFOXIRI+beva: n=121
    Units: cm
        arithmetic mean (standard deviation)
    		 172.9 ( 9.1 ) 171.9 ( 9.0 ) -
    Weight
    FOLFOX+beva: n=120 FOLFOXIRI+beva: n=121
    Units: kg
        arithmetic mean (standard deviation)
    		 78.5 ( 18.6 ) 77.5 ( 15.9 ) -
    Body mass index (BMI)
    FOLFOX+beva: n=120 FOLFOXIRI+beva: n=121
    Units: Index
        arithmetic mean (standard deviation)
    		 26.2 ( 5.5 ) 26.2 ( 5.2 ) -
    Duration of therapy
    Units: days
        arithmetic mean (standard deviation)
    		 147.8 ( 63.3 ) 155.6 ( 68.6 ) -
    Duration of induction therapy
    Units: Days
        median (full range (min-max))
    		 168 (14 to 392) 168 (14 to 307) -
    Induction therapy: Dose intensity in % of calculated full dose - fluoropyrimidin
    FOLFOX+beva: n=119 FOLFOXIRI+beva: n=121
    Units: [%]
        median (full range (min-max))
    		 97.9 (52.8 to 112.5) 94.8 (53.3 to 106.3) -
    Induction therapy: Dose intensity in % of calculated full dose - oxaliplatin
    FOLFOX+beva: n=120 FOLFOXIRI+beva: n=121
    Units: [%]
        median (full range (min-max))
    		 97.7 (51.9 to 107.8) 93.9 (24.7 to 105.8) -
    Induction therapy: Dose intensity in % of calculated full dose - bevacizumab
    FOLFOX+beva: n=120 FOLFOXIRI+beva: n=121
    Units: [%]
        median (full range (min-max))
    		 98.9 (0 to 141.7) 96.9 (0 to 115.5) -
    Induction therapy: Dose intensity in % of calculated full dose - leucovorin
    FOLFOX+beva: n=120 FOLFOXIRI+beva: n=121
    Units: [%]
        median (full range (min-max))
    		 99.4 (40 to 216.5) 97.1 (54.2 to 194.8) -
    Induction therapy: Dose intensity in % of calculated full dose - irinotecan
    FOLFOX+beva: n=0 FOLFOXIRI+beva: n=121
    Units: [%]
        median (full range (min-max))
    		 0 (0 to 0) 92.7 (13 to 105.7) -
    Induction therapy: Mean dose intensity over 3* (arm A) or 4* (arme B) substances
    FOLFOX+beva (arm A): n=120 -- *5-FU/Lv, Oxaliplatoin, Bevacizumab FOLFOXIRI+beva (armB): n=121 -- *5-FU/Lv, Oxaliplatin, Bevacizumab, Irinotecan
    Units: [%]
        median (full range (min-max))
    		 95.6 (63.2 to 107.1) 90.7 (46.1 to 108.3) -
    Maintenance therapy: Number of treatment cycles
    FOLFOX+beva: n=58 FOLFOXIRI+beva: n=66
    Units: [n]
        median (full range (min-max))
    		 8 (1 to 26) 8 (1 to 26) -
    Maintenence therapy: Duration
    FOLFOX+beva: n=58 FOLFOXIRI+beva: n=66
    Units: weeks
        median (full range (min-max))
    		 21.4 (0.3 to 53.1) 22.6 (0.3 to 75.1) -

    End points

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    End points reporting groups
    Reporting group title
    FOLFOX+beva
    Reporting group description
    		 Induction chemotherapy: FOLFOX (oxaliplatin, LV and 5-FU and bevacizumab, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab and 12 months of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.

    Reporting group title
    FOLFOXIRI+beva
    Reporting group description
    		 Induction chemotherapy: FOLFOXIRI (oxaliplatin, LV and 5-FU and bevacizumab + irinotecan, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab + irinotecan + 12 M of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab + irinotecan (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.

    Primary: Progression free survival rate at 9 months (absolute)

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    End point title
    		 Progression free survival rate at 9 months (absolute)
    End point description
    End point type
    Primary
    End point timeframe
    9 months after start of study therapy
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    121
    121
    Units: Subjects
        Progression-free at 9 months
    68
    81
        Progression at 9 months
    48
    37
        Not assessable
    5
    3
    Statistical analysis title
    		 PFS@9 - stratified logistic regression
    Statistical analysis description
    The absolute progression rate was compared by different statistical tests, first by applying a logistic regression method, stratified by the clinical stage of patients at baseline, which was the test method prospectively defined in the protocol.
    Comparison groups
    FOLFOXIRI+beva v FOLFOX+beva
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 PFS@9 - Fisher's exact test
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    242
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.135
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 PFS@9 - Chi^2-Test
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    242
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.145
    Method
    		 Chi-squared
    Confidence interval

    Primary: Progression free survival rate at 9 months (Kaplan-Meier)

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    End point title
    		 Progression free survival rate at 9 months (Kaplan-Meier)
    End point description
    The PFS rate at 9 months was also revealed by the Kaplan-Meier-Method. This method takes also the available information for censored patients into account.
    End point type
    Primary
    End point timeframe
    9 months after start of study therapy
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    121
    121
    Units: Percentage
        number (confidence interval 95%)
    58 (49 to 67)
    69 (61 to 78)
    Statistical analysis title
    		 PFS@9 - Kaplan-Meier
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.082
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression events (according to RECIST assessment)
    End point type
    Secondary
    End point timeframe
    From Start of study therapy until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    121
    121
    Units: Subjects
        progression events
    108
    112
        censored
    13
    9
    Attachments
    		 Untitled (Filename: PFS-Kaplan-Meier.JPG)
    Statistical analysis title
    		 PFS - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.08

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Death events
    End point type
    Secondary
    End point timeframe
    from start of study therapy until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    121
    121
    Units: Subjects
        death events
    98
    96
        censored
    23
    25
    Attachments
    		 Overall Survival
    Statistical analysis title
    		 OS- Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.09

    Secondary: Best response to treatment

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    End point title
    		 Best response to treatment
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    114
    114
    Units: Subjects
        CR
    6
    6
        PR
    63
    73
        SD
    29
    25
        PD
    16
    10
    No statistical analyses for this end point

    Secondary: Best response by categories

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    End point title
    		 Best response by categories
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    114
    114
    Units: Subjects
        response (CR+PR)
    69
    79
        failure (SD+PD)
    45
    35
    Statistical analysis title
    		 Best response - Fisher's exact test
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Resection of primary tumor - before randomization

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    End point title
    		 Resection of primary tumor - before randomization
    End point description
    End point type
    Secondary
    End point timeframe
    before randomization
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    121
    121
    Units: Subjects
        no resection
    65
    72
        primary resected
    56
    49
    No statistical analyses for this end point

    Secondary: Secondary resection of primary tumor - after randomization

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    End point title
    		 Secondary resection of primary tumor - after randomization
    End point description
    End point type
    Secondary
    End point timeframe
    from randomization until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    121
    121
    Units: Subjects
        secondary resection
    13
    9
    No statistical analyses for this end point

    Secondary: Secondary resection of metastases

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    End point title
    		 Secondary resection of metastases
    End point description
    End point type
    Secondary
    End point timeframe
    from randomization until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    120
    121
    Units: Subjects
        no secondary resection of metastases
    95
    91
        secondary resection of metastases
    25
    30
    Statistical analysis title
    		 Secundary resection of metastases - Fisher's exact
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.54
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Number of sec. metastases resection by patient

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    End point title
    		 Number of sec. metastases resection by patient
    End point description
    End point type
    Secondary
    End point timeframe
    from randomization until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    25
    30
    Units: Subjects
        1 met. resection
    22
    20
        2 met. resections
    3
    8
        > 2 met. resections
    0
    2
    No statistical analyses for this end point

    Secondary: Location of sec. metastases resections

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    End point title
    		 Location of sec. metastases resections
    End point description
    End point type
    Secondary
    End point timeframe
    from randomization until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    25
    30
    Units: Subjects
        liver
    23
    29
        lung
    2
    1
        peritoneum
    0
    2
        other
    3
    4
    No statistical analyses for this end point

    Secondary: EORTC-QLQ C30 - Global health status

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    End point title
    		 EORTC-QLQ C30 - Global health status
    End point description
    n: Number of subjects with completed questionnaire FOLFOX+Beva: Baseline n=109, Cycle 5 n=82, Cycle 9 n= 61, MT cycle 1 n=39, End of therapy n=56 FOLFOXIRI+Beva: Baseline n=109, Cycle 5 n=79, Cycle 9 n= 67, MT cycle 1 n=45, End of therapy n=52
    End point type
    Secondary
    End point timeframe
    From randomitation until end of therapy
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    109
    109
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    58 ( 22 )
    54.8 ( 21.5 )
        Cycle 5
    61.2 ( 21.6 )
    57 ( 22.3 )
        Cycle 9
    57 ( 22.5 )
    62.4 ( 18.9 )
        MT cycle 1
    62.2 ( 15.3 )
    60.9 ( 19.8 )
        End of Therapy
    56 ( 20.5 )
    56.9 ( 25.5 )
    No statistical analyses for this end point

    Secondary: EORTC-QLQ CIPN20 - Sensory Scale

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    End point title
    		 EORTC-QLQ CIPN20 - Sensory Scale
    End point description
    n: Number of subjects with completed questionnaire FOLFOX+Beva: Baseline n=105, Cycle 5 n=78, Cycle 9 n= 58, MT cycle 1 n=35, End of therapy n=53 FOLFOXIRI+Beva: Baseline n=101, Cycle 5 n=73, Cycle 9 n= 64, MT cycle 1 n=45, End of therapy n=45 When presenting score level data, the scoring instructions for the CIPN-20 module highly recommends calculation of Cronbach's alpha coefficient as indicator for reliability of the multi-item score levels. That coefficient should preferably be above 0.70 for any given multi-item scale. The values of Cronbach's alpha for each scale for the CHARTA data are: Sensory scale 0.86, Motor scale 0.83, Autonomic scale 0.59. Since Cronbach’s alpha for the autonomic scale is less than 0.7 in this study, only the score values for both sensory scale and motor scale are presented.
    End point type
    Secondary
    End point timeframe
    from randomization until end of therapy
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    105
    101
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    4.7 ( 8.4 )
    5.5 ( 10.5 )
        Cycle 5
    19.1 ( 18.1 )
    15.8 ( 16 )
        Cycle 9
    20.6 ( 16.5 )
    20.4 ( 17.3 )
        MT Cycle 1
    33.5 ( 21.1 )
    33.8 ( 21.3 )
        End of therapy
    29 ( 23.1 )
    25.3 ( 20.8 )
    No statistical analyses for this end point

    Secondary: EORTC-QLQ CIPN20 - Motor Scale

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    End point title
    		 EORTC-QLQ CIPN20 - Motor Scale
    End point description
    n: Number of subjects with completed questionnaire FOLFOX+Beva: Baseline n=76, Cycle 5 n=56, Cycle 9 n= 41, MT cycle 1 n=24, End of therapy n=34 FOLFOXIRI+Beva: Baseline n=79, Cycle 5 n=54, Cycle 9 n= 45, MT cycle 1 n=30, End of therapy n=32
    End point type
    Secondary
    End point timeframe
    from randomization until end of therapy
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    76
    79
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    4.1 ( 7.5 )
    3.4 ( 6.3 )
        Cycle 5
    7.4 ( 12.4 )
    8.3 ( 12.9 )
        Cycle 9
    9.5 ( 14.9 )
    9.3 ( 10.5 )
        MT Cycle 1
    11.6 ( 12.3 )
    14.3 ( 13 )
        End of therapy
    12.9 ( 13.7 )
    11.5 ( 16.8 )
    No statistical analyses for this end point

    Secondary: Response rate - RAS wildtype

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    End point title
    		 Response rate - RAS wildtype
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study therapy until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    41
    44
    Units: Subjects
        response
    24
    30
        failure
    17
    14
    Statistical analysis title
    		 Response rate RAS wildtype - Fisher's exact
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response rate - RAS mutated

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    End point title
    		 Response rate - RAS mutated
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    58
    57
    Units: Subjects
        response
    36
    41
        failure
    22
    16
    Statistical analysis title
    		 Response rate RAS mutated - Fisher's exact
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response rate - BRAF mutated

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    End point title
    		 Response rate - BRAF mutated
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    5
    6
    Units: Subjects
        response
    4
    5
        failure
    1
    1
    Statistical analysis title
    		 Response rate BRAF mutated - Fisher's exact
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response rate - Clinical group 1

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    End point title
    		 Response rate - Clinical group 1
    End point description
    Clinical group (stratum) 1: (liver and/or lung metastasis potentially resectable after downsizing, comorbidity allowing surgery
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    32
    34
    Units: Subjects
        response
    18
    23
        failure
    14
    11
    Statistical analysis title
    		 Response rate Stratum 1 - Fisher's exact
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response rate - Clinical group 2

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    End point title
    		 Response rate - Clinical group 2
    End point description
    Clinical group (stratum) 2: multiple metastasis, rapid progression, risk of rapid deterioration, unlikely to become resectable
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    64
    62
    Units: Subjects
        response
    40
    42
        failure
    24
    20
    Statistical analysis title
    		 Response rate Stratum 2 - Fisher's exact
    Comparison groups
    FOLFOXIRI+beva v FOLFOX+beva
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Response rate - Clinical group 3

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    End point title
    		 Response rate - Clinical group 3
    End point description
    Clinical group (stratum) 3: (not resectable and no symptoms or risk of deterioration
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    18
    18
    Units: Subjects
        response
    11
    14
        failure
    7
    4
    Statistical analysis title
    		 Response rate Stratum 3 - Fisher's exact
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Progression Free Survival - RAS wildtype

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    End point title
    		 Progression Free Survival - RAS wildtype
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    42
    45
    Units: Subjects
        events
    39
    43
    Attachments
    		 PFS - RAS wildtype
    Statistical analysis title
    		 PFS - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.15

    Secondary: Progression Free Survival - RAS mutated

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    End point title
    		 Progression Free Survival - RAS mutated
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    59
    61
    Units: Subjects
        events
    52
    55
    Attachments
    		 PFS - RAS mutated
    Statistical analysis title
    		 PFS - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.3

    Secondary: Progression Free Survival - BRAF mutated

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    End point title
    		 Progression Free Survival - BRAF mutated
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    5
    8
    Units: Subjects
        events
    4
    7
    Attachments
    		 PFS - BRAF mutated
    Statistical analysis title
    		 PFS - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.54

    Secondary: Progression free survival - Clinical group 1

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    End point title
    		 Progression free survival - Clinical group 1
    End point description
    Clinical group (stratum) 1: (liver and/or lung metastasis potentially resectable after downsizing, comorbidity allowing surgery
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    35
    35
    Units: Subjects
        events
    30
    30
    Attachments
    		 PFS - Stratum 1
    Statistical analysis title
    		 PFS - Stratum 1 - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.33

    Secondary: Progression free survival - Clinical group 2

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    End point title
    		 Progression free survival - Clinical group 2
    End point description
    Clinical group (stratum) 2: multiple metastasis, rapid progression, risk of rapid deterioration, unlikely to become resectable
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    67
    67
    Units: Subjects
        events
    60
    64
    Attachments
    		 PFS - Stratum 2
    Statistical analysis title
    		 PFS - Stratum 2 - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOXIRI+beva v FOLFOX+beva
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.32

    Secondary: Progression free survival - Clinical group 3

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    End point title
    		 Progression free survival - Clinical group 3
    End point description
    Clinical group (stratum) 3: (not resectable and no symptoms or risk of deterioration
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    19
    19
    Units: Subjects
        events
    18
    18
    Attachments
    		 PFS - Stratum 3
    Statistical analysis title
    		 PFS - Stratum 3 - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.12

    Secondary: Overall Survival - RAS wildtype

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    End point title
    		 Overall Survival - RAS wildtype
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    42
    45
    Units: Subjects
        events
    37
    35
    Attachments
    		 OS - RAS wildtype
    Statistical analysis title
    		 OS - RAS wildtype - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.24

    Secondary: Overall Survival - RAS mutated

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    End point title
    		 Overall Survival - RAS mutated
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    59
    61
    Units: Subjects
        events
    46
    48
    Attachments
    		 OS - RAS mutated
    Statistical analysis title
    		 OS - RAS mutated - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOXIRI+beva v FOLFOX+beva
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.24

    Secondary: Overall Survival - BRAF mutated

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    End point title
    		 Overall Survival - BRAF mutated
    End point description
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow-up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    5
    8
    Units: Subjects
        events
    4
    7
    Attachments
    		 OS - BRAF mutated
    Statistical analysis title
    		 OS - BRAF mutated - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 3.48

    Secondary: Overall survival - Clinical group 1

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    End point title
    		 Overall survival - Clinical group 1
    End point description
    Clinical group (stratum) 1: (liver and/or lung metastasis potentially resectable after downsizing, comorbidity allowing surgery
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    35
    35
    Units: Subjects
        events
    27
    22
    Attachments
    		 OS - Stratum 1
    Statistical analysis title
    		 OS - Stratum 1 - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOXIRI+beva v FOLFOX+beva
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.21

    Secondary: Overall survival - Clinical group 2

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    End point title
    		 Overall survival - Clinical group 2
    End point description
    Clinical group (stratum) 2: multiple metastasis, rapid progression, risk of rapid deterioration, unlikely to become resectable
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    67
    67
    Units: Subjects
        events
    54
    59
    Attachments
    		 OS - Stratum 2
    Statistical analysis title
    		 OS - Stratum 2 - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.3

    Secondary: Overall survival - Clinical group 3

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    End point title
    		 Overall survival - Clinical group 3
    End point description
    Clinical group (stratum) 3: (not resectable and no symptoms or risk of deterioration
    End point type
    Secondary
    End point timeframe
    from start of study treatment until end of follow up
    End point values
    		 FOLFOX+beva FOLFOXIRI+beva
    Number of subjects analysed
    19
    19
    Units: Subjects
        events
    17
    15
    Attachments
    		 OS - Stratum 3
    Statistical analysis title
    		 OS - Stratum 3 - Hazard ratio, CI and p-value
    Comparison groups
    FOLFOX+beva v FOLFOXIRI+beva
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.43

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start date occurred during treatment plus 30 days, or between end of induction and start of maintenance. Any events after start of maintenance were counted for this part of therapy, also with a wash-out-period of 30 days.
    Adverse event reporting additional description
    All subjects received at least one dose of study treatment were analysed for safety. One subject received irinotecan in the first cycle although being randomised to arm A; subject was included in safety analysis as being randomised to arm B according to protocol.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    FOLFOX+beva
    Reporting group description
    		 Induction chemotherapy: FOLFOX (oxaliplatin, LV and 5-FU and bevacizumab, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab and 12 months of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.

    Reporting group title
    FOLFOXIRI+beva
    Reporting group description
    		 Induction chemotherapy: FOLFOX (oxaliplatin, LV and 5-FU and bevacizumab + irinotecan, biweekly), until progression, intolerable toxicity, and secondary resection or for a max. of 12 cycles (6 months). Maintenance therapy: either 5-FU/LV and bevacizumab (beweekly) or capecitabine and bevacizumab (5-FU or capecitabine at the investigators discretion) for up to 12 months until progression or intolerable toxicity. Maximum treatment duration: 18 months (6 months of FOLFOX and bevacizumab + irinotecan + 12 M of maintenance). In case of secondary resection treatment had to be resumed 4–8 weeks postoperatively for a total of 6 months FOLFOX and bevacizumab + irinotecan (pre- and post-op treatment), followed by maintenance treatment for total treatment duration of up to 12 months in the absence of progression or intolerable toxicity.

    Serious adverse events
    		 FOLFOX+beva FOLFOXIRI+beva
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 119 (23.53%)
    37 / 123 (30.08%)
         number of deaths (all causes)
    98
    96
         number of deaths resulting from adverse events
    2
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour progression
         subjects affected / exposed
    3 / 119 (2.52%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         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
    Disease progression
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever of unknown origin
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reduced general condition
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death unexplained
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic hypoplasia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         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
    Radiation pneumonitis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femural neck fracture
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic complication
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular fibrillation
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Organic brain syndrome
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroleptic malignant syndrome
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 119 (1.68%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic fever
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 119 (4.20%)
    9 / 123 (7.32%)
         occurrences causally related to treatment / all
    5 / 5
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon perforation
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 119 (2.52%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emesis
         subjects affected / exposed
    2 / 119 (1.68%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Biloma
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (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
    5 / 119 (4.20%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 119 (0.84%)
    4 / 123 (3.25%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Febrile infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 119 (2.52%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary infection
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic complication
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 FOLFOX+beva FOLFOXIRI+beva
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 119 (100.00%)
    123 / 123 (100.00%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    6 / 119 (5.04%)
    2 / 123 (1.63%)
         occurrences all number
    6
    2
    Weight decreased
         subjects affected / exposed
    8 / 119 (6.72%)
    6 / 123 (4.88%)
         occurrences all number
    8
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 119 (5.88%)
    17 / 123 (13.82%)
         occurrences all number
    7
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 119 (9.24%)
    9 / 123 (7.32%)
         occurrences all number
    11
    9
    Dysgeusia
         subjects affected / exposed
    13 / 119 (10.92%)
    13 / 123 (10.57%)
         occurrences all number
    13
    13
    Headache
         subjects affected / exposed
    13 / 119 (10.92%)
    5 / 123 (4.07%)
         occurrences all number
    13
    5
    Neuropathy peripheral
         subjects affected / exposed
    10 / 119 (8.40%)
    7 / 123 (5.69%)
         occurrences all number
    10
    7
    Paraesthesia
         subjects affected / exposed
    12 / 119 (10.08%)
    14 / 123 (11.38%)
         occurrences all number
    12
    14
    Peripheral sensory neuropathy
         subjects affected / exposed
    7 / 119 (5.88%)
    2 / 123 (1.63%)
         occurrences all number
    7
    2
    Polyneuropathy
         subjects affected / exposed
    47 / 119 (39.50%)
    39 / 123 (31.71%)
         occurrences all number
    47
    39
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 119 (7.56%)
    16 / 123 (13.01%)
         occurrences all number
    9
    16
    Leukopenia
         subjects affected / exposed
    9 / 119 (7.56%)
    24 / 123 (19.51%)
         occurrences all number
    9
    24
    Neutropenia
         subjects affected / exposed
    17 / 119 (14.29%)
    38 / 123 (30.89%)
         occurrences all number
    17
    38
    Thrombocytopenia
         subjects affected / exposed
    16 / 119 (13.45%)
    17 / 123 (13.82%)
         occurrences all number
    16
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 119 (5.88%)
    12 / 123 (9.76%)
         occurrences all number
    7
    12
    Fatigue
         subjects affected / exposed
    31 / 119 (26.05%)
    26 / 123 (21.14%)
         occurrences all number
    31
    26
    General physical health deterioration
         subjects affected / exposed
    7 / 119 (5.88%)
    5 / 123 (4.07%)
         occurrences all number
    7
    5
    Mucosal inflammation
         subjects affected / exposed
    18 / 119 (15.13%)
    18 / 123 (14.63%)
         occurrences all number
    18
    18
    Pain
         subjects affected / exposed
    8 / 119 (6.72%)
    5 / 123 (4.07%)
         occurrences all number
    8
    5
    Pyrexia
         subjects affected / exposed
    14 / 119 (11.76%)
    12 / 123 (9.76%)
         occurrences all number
    14
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 119 (10.08%)
    13 / 123 (10.57%)
         occurrences all number
    12
    13
    Abdominal pain upper
         subjects affected / exposed
    3 / 119 (2.52%)
    10 / 123 (8.13%)
         occurrences all number
    3
    10
    Diarrhoea
         subjects affected / exposed
    43 / 119 (36.13%)
    71 / 123 (57.72%)
         occurrences all number
    43
    71
    Nausea
         subjects affected / exposed
    54 / 119 (45.38%)
    55 / 123 (44.72%)
         occurrences all number
    54
    55
    Stomatitis
         subjects affected / exposed
    11 / 119 (9.24%)
    14 / 123 (11.38%)
         occurrences all number
    11
    14
    Vomiting
         subjects affected / exposed
    26 / 119 (21.85%)
    30 / 123 (24.39%)
         occurrences all number
    26
    30
    Respiratory, thoracic and mediastinal disorders
    Constipation
         subjects affected / exposed
    19 / 119 (15.97%)
    9 / 123 (7.32%)
         occurrences all number
    19
    9
    Epistaxis
         subjects affected / exposed
    22 / 119 (18.49%)
    9 / 123 (7.32%)
         occurrences all number
    22
    9
    Oropharyngeal pain
         subjects affected / exposed
    7 / 119 (5.88%)
    1 / 123 (0.81%)
         occurrences all number
    7
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 119 (10.08%)
    27 / 123 (21.95%)
         occurrences all number
    12
    27
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    8 / 119 (6.72%)
    4 / 123 (3.25%)
         occurrences all number
    8
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 119 (5.88%)
    1 / 123 (0.81%)
         occurrences all number
    7
    1
    Infections and infestations
    Infection
         subjects affected / exposed
    9 / 119 (7.56%)
    5 / 123 (4.07%)
         occurrences all number
    9
    5
    Nasopharyngitis
         subjects affected / exposed
    14 / 119 (11.76%)
    7 / 123 (5.69%)
         occurrences all number
    14
    7
    Urinary tract infection
         subjects affected / exposed
    7 / 119 (5.88%)
    5 / 123 (4.07%)
         occurrences all number
    7
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 119 (12.61%)
    16 / 123 (13.01%)
         occurrences all number
    15
    16
    Hyperkalaemia
         subjects affected / exposed
    7 / 119 (5.88%)
    13 / 123 (10.57%)
         occurrences all number
    7
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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/22897915
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    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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