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    Clinical Trial Results:
    Induction FOLFOX with or without Aflibercept followed by chemoradiation in High Risk Locally Advanced Rectal Cancer. Phase II randomized, multicenter, open label trial

    Summary
    EudraCT number
    		 2014-002063-14
    Trial protocol
    		 ES  
    Global end of trial date
    04 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2021
    First version publication date
    26 Mar 2021
    Other versions
    Summary report(s)
    		 RIA ICH3 Synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GEMCAD-1402
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02340949
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)
    Sponsor organisation address
    Pau Alsina, 64-68.Esc.B, entlo. 5ª, Barcelona, Spain,
    Public contact
    Federico Nepote, MFAR Clinical Research, investigacion@mfar.net
    Scientific contact
    Federico Nepote, MFAR Clinical Research, investigacion@mfar.net
    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
    31 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of induction therapy with mFOLFOX6 +/- aflibercept followed by CT/RT in terms of pathological Complete Responses (pCR)
    Protection of trial subjects
    The protocol, through the schedule of visits and procedures, establishes measures to ensure the minimal risk to patients enrolled in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 180
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    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)
    180
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Locally advanced high-risk rectum adenocarcinoma patients were recruited in 22 centers in Spain

    Pre-assignment
    Screening details
    		 Random assignment of treatment will be stratified by T3 versus T4 stage for all patients. Patients will be allocated in a 2:1 ratio to the experimental or active comparator arms respectively.

    Period 1
    Period 1 title
    Baseline and Randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 mFOLFOX6 + Aflibercept
    Arm description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, ove
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days.

    Investigational medicinal product name
    FOLFOX6 regimen
    Investigational medicinal product code
    Other name
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m².

    Arm title
    		 mFOLFOX6
    Arm description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FOLFOX6 regimen
    Investigational medicinal product code
    Other name
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m².

    Number of subjects in period 1
    		mFOLFOX6 + Aflibercept mFOLFOX6
    Started
    115
    65
    Completed
    115
    65
    Period 2
    Period 2 title
    Study treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 mFOLFOX6 + Aflibercept
    Arm description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, ove
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days.

    Investigational medicinal product name
    FOLFOX6 regimen
    Investigational medicinal product code
    Other name
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m².

    Arm title
    		 mFOLFOX6
    Arm description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FOLFOX6 regimen
    Investigational medicinal product code
    Other name
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m².

    Number of subjects in period 2
    		mFOLFOX6 + Aflibercept mFOLFOX6
    Started
    115
    65
    Completed treatment as per protocol
    99
    61
    Completed
    99
    61
    Not completed
    16
    4
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    2
    -
         Physician decision
    1
    -
         Adverse event, non-fatal
    4
    2
         Lack of efficacy
    6
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    mFOLFOX6 + Aflibercept
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, ove

    Reporting group title
    mFOLFOX6
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU

    Reporting group values
    		 mFOLFOX6 + Aflibercept mFOLFOX6 Total
    Number of subjects
    		 115 65 180
    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
        arithmetic mean (standard deviation)
    		 58.4 ( 10.4 ) 62.2 ( 9.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 38 26 64
        Male
    		 77 39 116
    Clinical stage Tumor-nodes-metastasis (TNM)
    TNM clinical stage. The T refers to the size and extent of the main tumor. The main tumor is usually called the primary tumor. The higher the number after the T, the larger the tumor or the more it has grown into nearby tissues. The range is from T0 to T4. T's may be further divided to provide more detail, such as T3a and T3b.
    Units: Subjects
        Mising
    		 1 1 2
        mrT2
    		 1 0 1
        mrT3
    		 17 12 29
        mrT3B
    		 8 8 16
        mrT3A
    		 1 0 1
        mrT3C
    		 47 22 69
        mrT3D
    		 7 4 11
        mrT4
    		 9 6 15
        mrT4A
    		 16 7 23
        mrT4B
    		 8 5 13
    Clinical Stage TNM Nodes (n2)
    Used to describe regional lymph node involvement of the tumor. Lymph nodes function as biologic filters, as fluid from body tissues are absorbed into lymphatic capillaries and flows to the lymph nodes.[1] N0 indicates no regional nodal spread, while N1-N3 indicates some degree of nodal spread, with a progressively distal spread from N1 to N3.
    Units: Subjects
        N2
    		 115 65 180
    Location
    Location of primary tumor in the rectum
    Units: Subjects
        Distal
    		 30 18 48
        Middle
    		 84 46 130
        Missing
    		 1 1 2
    Histology
    Type of tumor cell composition found by histopathology analysis.
    Units: Subjects
        Adenocarcinoma
    		 115 65 180
        Other
    		 0 0 0
    Mesorectal Fascia (FMR)
    Distance from tumor to mesorectal fascia grouped in two categories depending on the distances: close (distance <=1 mm) or distal (NR).
    Units: Subjects
        FMR + (distance <=1 mm)
    		 68 37 105
        NR
    		 47 28 75
    EMVI score
    Extramural vascular invasion (EMVI) is the direct invasion of a blood vessel (usually a vein) by a tumor. In rectal cancer, this can occur on a macroscopic level and be detected on staging MRI. It is a significant prognostic factor, being a predictor of haematogenous spread. Score range from 0 to 4. Higher score means higher risk of distant metastasis.
    Units: Subjects
        Score 0/1/2
    		 60 34 94
        Score 3/4
    		 55 31 86

    End points

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    End points reporting groups
    Reporting group title
    mFOLFOX6 + Aflibercept
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, ove

    Reporting group title
    mFOLFOX6
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
    Reporting group title
    mFOLFOX6 + Aflibercept
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, ove

    Reporting group title
    mFOLFOX6
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU

    Primary: Number of Patients Achieving pCR

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    End point title
    		 Number of Patients Achieving pCR
    End point description
    To analyze the number of patients achieving pCR after induction therapy with mFOLFOX6 +/- aflibercept followed by CT/RT. pCR will be defined as the absence of viable tumor cells in the primary tumor and in the lymph nodes (ypT0N0)
    End point type
    Primary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115
    65
    Units: Patients
        Yes
    25
    9
        No
    90
    56
    Statistical analysis title
    		 Chi square test
    Comparison groups
    mFOLFOX6 v mFOLFOX6 + Aflibercept
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1938
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Efficacy: R0 Resection

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    End point title
    		 Efficacy: R0 Resection
    End point description
    To determine R0 resection rates. Number of patients achieving a R0, optimal surgical outcome.
    End point type
    Secondary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115
    65
    Units: Patients
        Yes
    101
    60
        No
    2
    2
        Not Available
    12
    3
    No statistical analyses for this end point

    Secondary: TRG; residual tumor after preoperative therapy

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    End point title
    		 TRG; residual tumor after preoperative therapy
    End point description
    TRG; residual tumor after preoperative therapy will be semiquantitatively evaluated according to the 5-point regression grading scale established by Mandard.
    End point type
    Secondary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115
    65
    Units: Patients
        Yes
    59
    30
        No
    56
    35
        Not available
    0
    0
    No statistical analyses for this end point

    Secondary: CRM≤ 1

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    End point title
    		 CRM≤ 1
    End point description
    CRM will be defined as tumor ≤ 1 mm from the resection margin. Number of patients with CRM≤ 1
    End point type
    Secondary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115
    65
    Units: Patients
        Yes
    3
    3
        No
    96
    56
        Not available
    16
    6
    No statistical analyses for this end point

    Secondary: To evaluate the relationship between MRI changes with outcome.

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    End point title
    		 To evaluate the relationship between MRI changes with outcome.
    End point description
    T Downstaging: defined as a lower pathologic T stage compared to pre-treatment mrT stage.
    End point type
    Secondary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115
    65
    Units: Patients
        Yes
    68
    46
        No
    47
    19
    No statistical analyses for this end point

    Secondary: Safety and Tolerability of mFOLFOX6 +/- Aflibercept Followed Chemoradiation

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    End point title
    		 Safety and Tolerability of mFOLFOX6 +/- Aflibercept Followed Chemoradiation
    End point description
    The safety and tolerability of the study therapy will be assessed by means of AEs and changes in laboratory data. AEs will be coded and evaluated using the NCI-CTCAE v4.0 toxicity criteria (if NCI-CTCAE are not applicable, MedDRA will be used).
    End point type
    Secondary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115 [1]
    65 [2]
    Units: Patients
        At least one AE
    115
    65
        At least one Grade 3-4 AE
    83
    31
        At least one AE that lead to treatment discontinua
    20
    4
        At least one AE that lead to death
    3
    0
        At least one Serious Adverse Event (SAE)
    45
    16
        At least one treatment-related AE
    105
    59
        At least one treatment-related AE Grade 3-4
    64
    17
        At least one treatment-related AE that led to deat
    0
    0
        At least one treatment-related AE that led to perm
    17
    3
        At least one treatment-related Serious Adverse Eve
    25
    3
    Notes
    [1] - Each row is independent (one patient may suffer more than one event on the row list)
    [2] - Each row is independent (one patient may suffer more than one event on the row list)
    No statistical analyses for this end point

    Secondary: To Determine the Rate of 30 Days Surgical Complications (Assessed by Means of AEs Reported)

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    End point title
    		 To Determine the Rate of 30 Days Surgical Complications (Assessed by Means of AEs Reported)
    End point description
    Surgical complications will be assessed by means of AEs reported during 30 days post surgery.
    End point type
    Secondary
    End point timeframe
    Until 2 years and 2 months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115 [3]
    65 [4]
    Units: Patients
        Postoperative AEs
    3
    1
        Postoperative AEs Grade 3-4
    2
    0
        Complications
    60
    30
        Anastomosis fistula
    4
    1
        wound infection
    5
    5
        intraabdominal infection
    10
    1
        Stoma complications
    2
    0
        Reoperation
    9
    5
    Notes
    [3] - Each row is independent (one patient may suffer more than one event and count in several rows)
    [4] - Each row is independent (one patient may suffer more than one event and count in several rows)
    No statistical analyses for this end point

    Secondary: To Evaluate the 3 Years Local Recurrence and DFS

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    End point title
    		 To Evaluate the 3 Years Local Recurrence and DFS
    End point description
    To determine the rate of local recurrence and DFS at 3-years after completing the Study treatment.
    End point type
    Secondary
    End point timeframe
    Until 5 years and two months
    End point values
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Number of subjects analysed
    115
    65
    Units: Percentage of patients
        arithmetic mean (confidence interval 95%)
    75.2 (66.1 to 82.2)
    81.5 (69.8 to 89.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study. Approximately 3 years
    Adverse event reporting additional description
    For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    mFOLFOX6 + Aflibercept
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, ove

    Reporting group title
    mFOLFOX6
    Reporting group description
    		 - mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusión in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU

    Serious adverse events
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 115 (39.13%)
    16 / 65 (24.62%)
         number of deaths (all causes)
    12
    7
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral neuropathy
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 115 (3.48%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    34 / 115 (29.57%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    34 / 34
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 115 (6.96%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    8 / 8
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    4 / 115 (3.48%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 115 (2.61%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Stomatitis
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 mFOLFOX6 + Aflibercept mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    115 / 115 (100.00%)
    65 / 65 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 115 (19.13%)
    3 / 65 (4.62%)
         occurrences all number
    22
    3
    Epistaxis
         subjects affected / exposed
    17 / 115 (14.78%)
    1 / 65 (1.54%)
         occurrences all number
    17
    1
    Nervous system disorders
    Peripheral neuropathy
         subjects affected / exposed
    48 / 115 (41.74%)
    30 / 65 (46.15%)
         occurrences all number
    48
    30
    Dysaesthesia
         subjects affected / exposed
    15 / 115 (13.04%)
    10 / 65 (15.38%)
         occurrences all number
    15
    10
    Paraesthesia
         subjects affected / exposed
    11 / 115 (9.57%)
    11 / 65 (16.92%)
         occurrences all number
    11
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    65 / 115 (56.52%)
    38 / 65 (58.46%)
         occurrences all number
    65
    38
    Nausea
         subjects affected / exposed
    37 / 115 (32.17%)
    23 / 65 (35.38%)
         occurrences all number
    37
    23
    Abdominal pain
         subjects affected / exposed
    16 / 115 (13.91%)
    5 / 65 (7.69%)
         occurrences all number
    16
    5
    Dysphonia
         subjects affected / exposed
    19 / 115 (16.52%)
    1 / 65 (1.54%)
         occurrences all number
    19
    1
    Pyrexia
         subjects affected / exposed
    14 / 115 (12.17%)
    4 / 65 (6.15%)
         occurrences all number
    14
    4
    Dysgeusia
         subjects affected / exposed
    11 / 115 (9.57%)
    8 / 65 (12.31%)
         occurrences all number
    11
    8
    Musculoskeletal pain
         subjects affected / exposed
    11 / 115 (9.57%)
    7 / 65 (10.77%)
         occurrences all number
    11
    7
    Aphonia
         subjects affected / exposed
    14 / 115 (12.17%)
    0 / 65 (0.00%)
         occurrences all number
    14
    0
    Abdominal pain upper
         subjects affected / exposed
    10 / 115 (8.70%)
    3 / 65 (4.62%)
         occurrences all number
    10
    3
    Fatigue
         subjects affected / exposed
    7 / 115 (6.09%)
    5 / 65 (7.69%)
         occurrences all number
    7
    5
    Headache
         subjects affected / exposed
    8 / 115 (6.96%)
    1 / 65 (1.54%)
         occurrences all number
    8
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    14 / 115 (12.17%)
    4 / 65 (6.15%)
         occurrences all number
    14
    4
    Thrombocytopenia
         subjects affected / exposed
    9 / 115 (7.83%)
    7 / 65 (10.77%)
         occurrences all number
    9
    7
    Anaemia
         subjects affected / exposed
    6 / 115 (5.22%)
    7 / 65 (10.77%)
         occurrences all number
    6
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    42 / 115 (36.52%)
    22 / 65 (33.85%)
         occurrences all number
    42
    22
    Mucosal inflammation
         subjects affected / exposed
    48 / 115 (41.74%)
    14 / 65 (21.54%)
         occurrences all number
    48
    14
    Vomiting
         subjects affected / exposed
    21 / 115 (18.26%)
    13 / 65 (20.00%)
         occurrences all number
    21
    13
    Decreased appetite
         subjects affected / exposed
    25 / 115 (21.74%)
    9 / 65 (13.85%)
         occurrences all number
    25
    9
    Constipation
         subjects affected / exposed
    13 / 115 (11.30%)
    9 / 65 (13.85%)
         occurrences all number
    13
    9
    Proctalgia
         subjects affected / exposed
    11 / 115 (9.57%)
    6 / 65 (9.23%)
         occurrences all number
    11
    6
    Rectal haemorrhage
         subjects affected / exposed
    14 / 115 (12.17%)
    3 / 65 (4.62%)
         occurrences all number
    14
    3
    Anal inflammation
         subjects affected / exposed
    10 / 115 (8.70%)
    0 / 65 (0.00%)
         occurrences all number
    10
    0
    Rectal tenesmus
         subjects affected / exposed
    8 / 115 (6.96%)
    1 / 65 (1.54%)
         occurrences all number
    8
    1
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    13 / 115 (11.30%)
    8 / 65 (12.31%)
         occurrences all number
    13
    8
    Infections and infestations
    Stomatitis
         subjects affected / exposed
    14 / 115 (12.17%)
    3 / 65 (4.62%)
         occurrences all number
    14
    3
    Cystitis
         subjects affected / exposed
    9 / 115 (7.83%)
    7 / 65 (10.77%)
         occurrences all number
    9
    7

    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
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