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    Clinical Trial Results:
    A Multi-Center, Randomized, Placebo-Controlled Phase II Study of Regorafenib in Combination With FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) Versus Placebo With FOLFIRI as Second-Line Therapy in Patients with Metastatic Colorectal Cancer.

    Summary
    EudraCT number
    		 2012-000709-59
    Trial protocol
    		 IE   GB  
    Global end of trial date
    05 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jun 2022
    First version publication date
    23 Jun 2022
    Other versions
    Summary report(s)
    		 LCCC1029_CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    LCCC1029
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01298570
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ICORG Study Number: ICORG 12-07
    Sponsors
    Sponsor organisation name
    Cancer Trials Ireland
    Sponsor organisation address
    Ardilaun House, Block B, 111 St Stephen's Green, Dublin 2, Ireland, D02 VN51
    Public contact
    Clinical Project Manager, Cancer Trials Ireland, 353 016677211, info@cancertrials.ie
    Scientific contact
    Clinical Project Manager, Cancer Trials Ireland, 353 016677211, info@cancertrials.ie
    Sponsor organisation name
    UNC Lineberger Comprehensive Cancer Centre
    Sponsor organisation address
    University of North Carolina, Chapel Hill, North Carolina, United States, 27599
    Public contact
    Maureen Tyan, RN, UNC Lineberger Comprehensive Cancer Centre, 919 8437039, maureen_tynan@med.unc.edu
    Scientific contact
    Maureen Tyan, RN, UNC Lineberger Comprehensive Cancer Centre, 919 8437039, maureen_tynan@med.unc.edu
    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 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare progression-free survival (PFS) between the two treatment arms (PFS: time from randomization until progression or death).
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations SI 190 of 2004 as amend and European Directive 2001/20/EC. The study was approved by the HPRA and Cork Teaching Hospitals Clinical Research Ethics Committee.
    Background therapy
    		 N/A
    Evidence for comparator
    		 Active Comparator: Regorafenib + FOLFIRI (ARM A) Placebo Comparator: Placebo + FOLFIRI (ARM B) The trial is designed to compare the Progression Free Survival of ARM A versus ARM B in patients with metastatic colorectal carcinoma (mCRC) previously treated with a FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) regimen.
    Actual start date of recruitment
    01 Mar 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
    United States: 127
    Country: Number of subjects enrolled
    Ireland: 54
    Worldwide total number of subjects
    181
    EEA total number of subjects
    54
    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)
    131
    From 65 to 84 years
    48
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 224 participants were consented to the study from 39 institutions in the United States and Ireland from 4July2011 - 8October2015.

    Pre-assignment
    Screening details
    		 The target population will be previously treated patients with Metastatic Colorectal Cancer who have had one prior oxaliplatin-containing regimen which failed. They must meet all of the inclusion criteria and none of the exclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 224 [1]
    Number of subjects completed
    		 181

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligible: 30
    Reason: Number of subjects
    		 Consent withdrawn by subject: 7
    Reason: Number of subjects
    		 Study Closure: 3
    Reason: Number of subjects
    		 Financial Reasons: 2
    Reason: Number of subjects
    		 No reason given for non participation: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 224 participant were consented, however did not take part in the study for a number of reasons including ineligibility, withdrawn, study closure, financial reasons. 181 patients were enrolled and went onto treatment
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    At the end of the screening period, eligible patients were randomly assigned in a 2:1 ratio to regorafenib + FOLFIRI or placebo + FOLFIRI in a double-blind fashion such that the Investigator, Sponsor, nor the patient knew which agent was administered. The randomization number was assigned by the UNC Cancer Network (UNCCN) or its designate. Regorafenib and placebo were be identical in appearance in order to preserve blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 regorafenib 160 mg + FOLFIRI
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY 73-4506
    Other name
    Stivarga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On Days 4-10 and 18-24 of each cycle, the patient should be instructed to take regorafenib PO once daily in the morning (close to the same time each day) with approximately 8 ounces of water after a low-fat (<30% fat) breakfast

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    FOLFIRI : (Irinotecan,180 mg/m2 IV over 90 minutes; Leucovorin 200-400c mg/m2 IV over 2 hours; 5-Fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours;) Day 1 and Day 15 of each 28 day cycle Both irinotecan and leucovorin should be administered prior to fluorouracil (5-FU)

    Arm title
    		 Arm B
    Arm description
    		 Placebo + FOLFIRI
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, 160 mg, PO oral administration, Days 4-10 and Days 18-24 of 28 day cycle

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    FOLFIRI : (Irinotecan,180 mg/m2 IV over 90 minutes; Leucovorin 200-400c mg/m2 IV over 2 hours; 5-Fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours;) Day 1 and Day 15 of each 28 day cycle Both irinotecan and leucovorin should be administered prior to fluorouracil (5-FU)

    Number of subjects in period 1
    		Arm A Arm B
    Started
    120
    61
    Completed
    0
    0
    Not completed
    120
    61
         Physician decision
    4
    2
         Symptomatic Progression/deterioration
    3
    2
         Treatment Delay > 4 weeks
    4
    5
         Adverse Event
    -
    2
         Adverse event, non-fatal
    20
    -
         Death
    -
    1
         Other complicating disease
    -
    1
         Surgery
    2
    1
         Ineligibility
    -
    1
         Other complicating Disease
    2
    -
         Disease Progression
    64
    40
         Withdrawal by subject
    21
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 regorafenib 160 mg + FOLFIRI

    Reporting group title
    Arm B
    Reporting group description
    		 Placebo + FOLFIRI

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 120 61 181
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 88 43 131
        From 65-84 years
    		 30 18 48
        85 years and over
    		 2 0 2
    Age continuous
    Units: years
        median (full range (min-max))
    		 62 (30 to 94) 62 (30 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 52 29 81
        Male
    		 68 32 100
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0
        Black or African American
    		 20 11 31
        White
    		 99 48 147
        More than one race
    		 0 0 0
        Unknown or not reported
    		 1 2 3
    Region of Enrollment
    Units: Subjects
        Ireland
    		 84 43 127
        United States
    		 36 18 54
    ECOG Performance Status
    Measure Description: A scale by the Eastern Cooperative Oncology Group (ECOG) from 0-5 to describe patient's selfcare ability and activity level. 0.Fully active 1.Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature 2.Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours 3.Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 4.Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 5.Dead
    Units: Subjects
        0 - Fully Active
    		 52 23 75
        1. (see description)
    		 68 38 106
    Stage at Diagnosis
    Measure Description: Stages I, II, III indicate that cancer is present, and the higher the number the larger the cancer tumor and the more it has spread into nearby tissues. Stage IV indicates that cancer has spread to distant parts of the body.
    Units: Subjects
        Stage I
    		 3 0 3
        Stage II
    		 4 4 8
        Stage III
    		 24 11 35
        Stage IV
    		 86 46 132
        Unknown
    		 3 0 3
    Prior Biological Agent
    Units: Subjects
        None
    		 33 16 49
        Bevacizumab
    		 76 41 117
        EGFR Inhibitor
    		 11 4 15
    Locally Reported RAS
    Measure Description: The 3 Ras genes in humans (HRas, KRas, and NRas) are the most common oncogenes in human cancer; some therapies are more effective with nonmutated wildtype genes.
    Units: Subjects
        Wildtype
    		 49 18 67
        Mutated
    		 54 37 91
        Unknown
    		 17 6 23
    Locally Reported BRAF
    Measure Description: Many mutations of the BRAF gene are associated with cancer. Some drugs are designed to work with mutated forms of the gene.
    Units: Subjects
        Wildtype
    		 22 12 34
        Mutated
    		 10 2 12
        Unknown
    		 88 47 135

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 regorafenib 160 mg + FOLFIRI

    Reporting group title
    Arm B
    Reporting group description
    		 Placebo + FOLFIRI

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    To compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for metastatic colorectal cancer. PFS is defined as the time from randomization until metastatic colorectal cancer (mCRC) progression or death as a result of any cause. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    End point type
    Primary
    End point timeframe
    5.5 years
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    120
    61
    Units: Months
        median (confidence interval 95%)
    6.1 (5.5 to 7.3)
    5.3 (4.1 to 6.0)
    Statistical analysis title
    		 Improvement in PFS in Arm A vs Arm B
    Statistical analysis description
    Unstratified log-rank test was used to test for differences between treatment arms in the time-to-event analyses
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.01
    Variability estimate
    Standard deviation
    Dispersion value
    1.01

    Secondary: Overall Response (OR) Rate

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    End point title
    		 Overall Response (OR) Rate
    End point description
    To compare overall response (OR) rates (OR= CR + PR) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    102 [1]
    58 [2]
    Units: Participants
    number (not applicable)
        Complete Response (CR)
    0
    0
        Partial Response (PR)
    35
    12
        Other
    67
    46
    Notes
    [1] - Only evaluable subjects (those who had RECIST measurements after baseline) were included in analysis
    [2] - Only evaluable subjects (those who had RECIST measurements after baseline) were included in analysis
    No statistical analyses for this end point

    Secondary: Disease Control (DC) Rate

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    End point title
    		 Disease Control (DC) Rate
    End point description
    To compare Disease Control (DC) Rate (DC= CR + PR + SD) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions and Stable Disease (SD) ), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    102 [3]
    58 [4]
    Units: Participants
    number (not applicable)
        Disease Control Total (CR+PR+SD)
    84
    43
        Progression
    18
    15
    Notes
    [3] - Only evaluable subjects (those who had RECIST measurements after baseline)were included in analysis
    [4] - Only evaluable subjects (those who had RECIST measurements after baseline)were included in analysis
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    To compare overall survival (OS) between ARM A and ARM B. OS is defined as the time from randomization until death as a result of any cause.
    End point type
    Secondary
    End point timeframe
    5.5 years
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    120
    61
    Units: Months
    median (full range (min-max))
        Overall Survival (OS)
    13.8 (10.5 to 14.8)
    11.7 (9.0 to 15.9)
    No statistical analyses for this end point

    Secondary: Drug Metabolism

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    End point title
    		 Drug Metabolism
    End point description
    To compare the pharmacokinetic (PK) profile of FOLFIRI between a subset of patients receiving regorafenib (ARM A) and patients receiving placebo (Arm B). The Area Under the Curve (AUC) levels of the irinotecan metabolite SN-38 were compared
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    11 [5]
    11 [6]
    Units: AUC/dose=(ng/mL*h)/(mg/m^2)
    median (inter-quartile range (Q1-Q3))
        Cycle 1
    0.68 (0.49 to 0.89)
    0.63 (0.47 to 0.91)
        Cycle 2
    0.59 (0.24 to 0.85)
    0.72 (0.47 to 0.91)
    Notes
    [5] - This objective was designed to only look at a small subset of participants (11 on each arm)
    [6] - This objective was designed to only look at a small subset of participants (11 on each arm)
    No statistical analyses for this end point

    Secondary: Percentage of Patients with Severe Adverse Events

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    End point title
    		 Percentage of Patients with Severe Adverse Events
    End point description
    Toxicity Assessments were made according to NCI CTCAE v. 4.0 . Severe events (grades 3-4) that occurred in a higher percentage of regorafenib treated participants as compared to placebo are reported below.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    120
    61
    Units: percentage of participants
    number (not applicable)
        neutropenia
    41
    30
        diarrhea
    15
    5
        hypophosphatemia
    14
    0
        hypertension
    8
    2
        elevated lipase
    8
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs must be recorded in the SAE console within Oncore™ for that patient within 24 hours of learning of its occurrence.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 regorafenib 160 mg + FOLFIRI

    Reporting group title
    Arm B
    Reporting group description
    		 Placebo + FOLFIRI

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    60 / 120 (50.00%)
    20 / 61 (32.79%)
         number of deaths (all causes)
    112
    59
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death NOS
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Fatigue
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    9 / 120 (7.50%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    7 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like Symptoms
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (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 / 120 (0.83%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pressure in head
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rigors
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Lung Infection
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Headache
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psycosis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asparate aminotransferase increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deteriorating LFTs
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Elevated INR
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GGT Increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    22 / 120 (18.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         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
    Alkaline Aminotransferase Increased
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Stoma Site Bleeding
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severely elevated lipase level
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain- cardiac
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradicardia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (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
    Anaemia
         subjects affected / exposed
    2 / 120 (1.67%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal varices hemorrhage
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    6 / 120 (5.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomal Ulcer
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    9 / 120 (7.50%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic Hemorrhage
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic perforation
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    10 / 120 (8.33%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    9 / 11
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 120 (2.50%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movements involuntary
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal hemorrhage
         subjects affected / exposed
    4 / 120 (3.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive Jaundice
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         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 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalized muscle weakness
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness lower limb
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Pain
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right hip abscess
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (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
    Abdominal infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal Infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cecal Infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 120 (5.83%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    6 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection of unknown source
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, specify
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    3 / 120 (2.50%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 120 (4.17%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    6 / 8
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminemia
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 120 (100.00%)
    61 / 61 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 120 (19.17%)
    9 / 61 (14.75%)
         occurrences all number
    83
    15
    Hypotension
         subjects affected / exposed
    10 / 120 (8.33%)
    3 / 61 (4.92%)
         occurrences all number
    17
    3
    Thromboembolic event
         subjects affected / exposed
    10 / 120 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    11
    1
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    5 / 120 (4.17%)
    4 / 61 (6.56%)
         occurrences all number
    6
    4
    Fatigue
         subjects affected / exposed
    76 / 120 (63.33%)
    33 / 61 (54.10%)
         occurrences all number
    200
    47
    Fever
         subjects affected / exposed
    18 / 120 (15.00%)
    3 / 61 (4.92%)
         occurrences all number
    28
    3
    Flu like symptoms
         subjects affected / exposed
    7 / 120 (5.83%)
    1 / 61 (1.64%)
         occurrences all number
    7
    1
    Pain
         subjects affected / exposed
    26 / 120 (21.67%)
    4 / 61 (6.56%)
         occurrences all number
    48
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 120 (12.50%)
    4 / 61 (6.56%)
         occurrences all number
    29
    5
    Dyspnea
         subjects affected / exposed
    22 / 120 (18.33%)
    7 / 61 (11.48%)
         occurrences all number
    33
    11
    Epistaxis
         subjects affected / exposed
    9 / 120 (7.50%)
    2 / 61 (3.28%)
         occurrences all number
    9
    3
    Hoarseness
         subjects affected / exposed
    15 / 120 (12.50%)
    0 / 61 (0.00%)
         occurrences all number
    20
    0
    Sore throat
         subjects affected / exposed
    11 / 120 (9.17%)
    11 / 61 (18.03%)
         occurrences all number
    12
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 61 (1.64%)
         occurrences all number
    7
    2
    Depression
         subjects affected / exposed
    9 / 120 (7.50%)
    5 / 61 (8.20%)
         occurrences all number
    11
    6
    Insomnia
         subjects affected / exposed
    13 / 120 (10.83%)
    3 / 61 (4.92%)
         occurrences all number
    15
    4
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    7 / 120 (5.83%)
    3 / 61 (4.92%)
         occurrences all number
    11
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    30 / 120 (25.00%)
    9 / 61 (14.75%)
         occurrences all number
    74
    13
    Alkaline phosphatase increased
         subjects affected / exposed
    35 / 120 (29.17%)
    14 / 61 (22.95%)
         occurrences all number
    59
    21
    Aspartate aminotransferase increased
         subjects affected / exposed
    28 / 120 (23.33%)
    10 / 61 (16.39%)
         occurrences all number
    57
    17
    Blood bilirubin increased
         subjects affected / exposed
    22 / 120 (18.33%)
    4 / 61 (6.56%)
         occurrences all number
    47
    5
    Creatinine increased
         subjects affected / exposed
    6 / 120 (5.00%)
    5 / 61 (8.20%)
         occurrences all number
    24
    14
    INR increased
         subjects affected / exposed
    6 / 120 (5.00%)
    5 / 61 (8.20%)
         occurrences all number
    10
    8
    Lipase increased
         subjects affected / exposed
    21 / 120 (17.50%)
    13 / 61 (21.31%)
         occurrences all number
    45
    32
    Lymphocyte count decreased
         subjects affected / exposed
    15 / 120 (12.50%)
    11 / 61 (18.03%)
         occurrences all number
    48
    26
    Neutrophil count decreased
         subjects affected / exposed
    69 / 120 (57.50%)
    36 / 61 (59.02%)
         occurrences all number
    189
    86
    Platelet count decreased
         subjects affected / exposed
    34 / 120 (28.33%)
    9 / 61 (14.75%)
         occurrences all number
    97
    11
    Serum amylase increased
         subjects affected / exposed
    16 / 120 (13.33%)
    8 / 61 (13.11%)
         occurrences all number
    23
    19
    Weight loss
         subjects affected / exposed
    27 / 120 (22.50%)
    5 / 61 (8.20%)
         occurrences all number
    45
    5
    White blood cell decreased
         subjects affected / exposed
    35 / 120 (29.17%)
    23 / 61 (37.70%)
         occurrences all number
    121
    75
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    6 / 120 (5.00%)
    2 / 61 (3.28%)
         occurrences all number
    12
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 120 (7.50%)
    1 / 61 (1.64%)
         occurrences all number
    15
    1
    Headache
         subjects affected / exposed
    24 / 120 (20.00%)
    6 / 61 (9.84%)
         occurrences all number
    27
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    28 / 120 (23.33%)
    8 / 61 (13.11%)
         occurrences all number
    40
    12
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    67 / 120 (55.83%)
    38 / 61 (62.30%)
         occurrences all number
    159
    86
    Febrile neutropenia
         subjects affected / exposed
    7 / 120 (5.83%)
    1 / 61 (1.64%)
         occurrences all number
    10
    3
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    41 / 120 (34.17%)
    9 / 61 (14.75%)
         occurrences all number
    77
    10
    Constipation
         subjects affected / exposed
    41 / 120 (34.17%)
    17 / 61 (27.87%)
         occurrences all number
    67
    24
    Diarrhoea
         subjects affected / exposed
    63 / 120 (52.50%)
    28 / 61 (45.90%)
         occurrences all number
    212
    51
    Dysgeusia
         subjects affected / exposed
    6 / 120 (5.00%)
    2 / 61 (3.28%)
         occurrences all number
    8
    3
    Dyspepsia
         subjects affected / exposed
    9 / 120 (7.50%)
    1 / 61 (1.64%)
         occurrences all number
    11
    1
    Dysphagia
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 61 (1.64%)
         occurrences all number
    6
    1
    Hemorrhoids
         subjects affected / exposed
    10 / 120 (8.33%)
    2 / 61 (3.28%)
         occurrences all number
    14
    2
    Mucositis oral
         subjects affected / exposed
    65 / 120 (54.17%)
    20 / 61 (32.79%)
         occurrences all number
    146
    34
    Nausea
         subjects affected / exposed
    60 / 120 (50.00%)
    34 / 61 (55.74%)
         occurrences all number
    124
    53
    Oral pain
         subjects affected / exposed
    8 / 120 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    12
    0
    Rectal pain
         subjects affected / exposed
    10 / 120 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    14
    1
    Vomiting
         subjects affected / exposed
    40 / 120 (33.33%)
    10 / 61 (16.39%)
         occurrences all number
    68
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    30 / 120 (25.00%)
    15 / 61 (24.59%)
         occurrences all number
    34
    17
    Dry skin
         subjects affected / exposed
    15 / 120 (12.50%)
    5 / 61 (8.20%)
         occurrences all number
    20
    6
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    35 / 120 (29.17%)
    6 / 61 (9.84%)
         occurrences all number
    80
    14
    Rash maculo-papular
         subjects affected / exposed
    18 / 120 (15.00%)
    5 / 61 (8.20%)
         occurrences all number
    28
    6
    Rash acneiform
         subjects affected / exposed
    12 / 120 (10.00%)
    2 / 61 (3.28%)
         occurrences all number
    30
    2
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    9 / 120 (7.50%)
    3 / 61 (4.92%)
         occurrences all number
    11
    5
    Proteinuria
         subjects affected / exposed
    18 / 120 (15.00%)
    14 / 61 (22.95%)
         occurrences all number
    51
    25
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    8 / 120 (6.67%)
    1 / 61 (1.64%)
         occurrences all number
    9
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    12 / 120 (10.00%)
    4 / 61 (6.56%)
         occurrences all number
    17
    4
    Bone pain
         subjects affected / exposed
    6 / 120 (5.00%)
    0 / 61 (0.00%)
         occurrences all number
    7
    0
    Pain in extremity
         subjects affected / exposed
    8 / 120 (6.67%)
    3 / 61 (4.92%)
         occurrences all number
    16
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 120 (9.17%)
    3 / 61 (4.92%)
         occurrences all number
    19
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    43 / 120 (35.83%)
    7 / 61 (11.48%)
         occurrences all number
    70
    7
    Dehydration
         subjects affected / exposed
    15 / 120 (12.50%)
    5 / 61 (8.20%)
         occurrences all number
    23
    5
    Hyperglycemia
         subjects affected / exposed
    17 / 120 (14.17%)
    16 / 61 (26.23%)
         occurrences all number
    41
    44
    Hypertriglyceridemia
         subjects affected / exposed
    25 / 120 (20.83%)
    19 / 61 (31.15%)
         occurrences all number
    72
    42
    Hypoalbuminemia
         subjects affected / exposed
    37 / 120 (30.83%)
    14 / 61 (22.95%)
         occurrences all number
    93
    28
    Hyperuricemia
         subjects affected / exposed
    5 / 120 (4.17%)
    7 / 61 (11.48%)
         occurrences all number
    10
    13
    Hypocalcemia
         subjects affected / exposed
    29 / 120 (24.17%)
    10 / 61 (16.39%)
         occurrences all number
    57
    12
    Hypokalemia
         subjects affected / exposed
    40 / 120 (33.33%)
    19 / 61 (31.15%)
         occurrences all number
    82
    33
    Hypomagnesemia
         subjects affected / exposed
    16 / 120 (13.33%)
    9 / 61 (14.75%)
         occurrences all number
    28
    15
    Hyponatremia
         subjects affected / exposed
    20 / 120 (16.67%)
    13 / 61 (21.31%)
         occurrences all number
    33
    20
    Hypophosphatemia
         subjects affected / exposed
    38 / 120 (31.67%)
    6 / 61 (9.84%)
         occurrences all number
    109
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Apr 2012
    Protocol V3: First protocol approved in EU. Updates from Protocol Amendment 2 included editorial and admin changes as well as Therapy changes
    23 May 2012
    Protocol Amendment 4: Protocol Amendment 4 has Updated safety information on regorafenib from Investigator Brochure, Version 7.0 and revised dose modification instructions for changes in liver function tests attributed to Regorafenib and for FOLFIRI toxicities
    03 Apr 2013
    Protocol Amendment 5: has updated regorafenib dose modification instructions, monitoring for liver toxicity and potential drug interactions in line with the Sept 2012 prescribing information published for regorafenib which is now licenced in the US under the trade name Stivarga®.
    11 Sep 2013
    Protocol Amendment 6: Inclusion criterion 3.1.5 amended from “progression during or within 3 months following administration of a standard regimen…” to “progression during or within 6 months following administration of a standard regimen…” Other updates detailed in cover page of protocol update
    29 Sep 2014
    Protocol Amendment 7: The main purpose of this Global protocol amendment is to revise the study to meet MHRA requirements in the UK. LCCC 1029 - ICORG 12-07 Protocol Amendment 7, 10th June 2014 - Clarified in objective 2.2.4 that pharmacokinetic sub-study will be limited to UNC and other selected sites. - Section 3.1.10 requires contraception to be used for 6 months (not 3 months) post chemotherapy, and advice on counseling for sperm preservation added to ensure patients informed. - Added exclusion criteria 3.2.31 (Any chronic inflammatory bowel disease and/or chronic bowl obstruction) and 3.2.32 (Unwilling to avoid vaccinations with live vaccine and concomitant use of attenuated live vaccines) - Section 4.2 (Emergency Unblinding) was revised “Unblinding” to emphasize that the study Investigator may also receive unblinded patient information after disease progression to inform subsequent treatment decisions. - Section 5.1.5: added “Prolonged exposure to sunlight is not advisable because of risk to photosensitivity during the administration of regorafenib” - Each of the generic drugs now as the following statement in the Drug information section (section 5.0) In addition, the SPC (or SmPC) is a Summary of Product Characteristics document for licensed marketed products as licensed in the UK. The Investigators can use whichever generic irinotecan product they choose per local practice for the purposes of this study. - Each of the generic drugs has additional information related to contraception and pregnancy from a representative SmPC (Section 5.0) - Section 7.8.3 (European SAE and SUSAR reporting requirements) was added. - Appendix I (a list of protocol abbreviations) was added to the end of the protocol document.
    09 Mar 2015
    Protocol Amendment 8: The main purpose of this Global protocol amendment is to revise the target accrual of this study. This is as a result of a decision by UNC (international sponsor) in consultation with manufacturer of the IMP regorafenib (Bayer) to close study once total accrual of 180 (versus 240) is reached. This will still allow 90% power to detect 60% improvement in median PFS when regorafenib is added to FOLFIRI. As a consequence of this decision the study will no longer be opening at sites in the United Kingdom.
    09 Jun 2016
    Protocol Amendment 9: Updates made further to new safety information becoming available. Protocol: • Section 4.6: Concomitant Medications/Treatments: Clarified that regorafenib has no effect on digoxin pharmacokinetics, and can be given with drugs that are p-glycoprotein substrates. • Section 4.6.2: Prohibited Drugs: updated information regarding CYP3A4 inhibitors and inducers. • Section 4.6.3: Drugs to be used with Caution: updated guidance for medications that have a narrow therapeutic index. • Section 11.2: Appendix B List of Prohibited Drugs: updated list with new drugs.

    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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