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    Clinical Trial Results:
    A Phase III, Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With and following Chemoradiotherapy Compared to Chemoradiotherapy Alone for Treatment in Women With Locally Advanced Cervical Cancer (CALLA)

    Summary
    EudraCT number
    		 2018-002872-42
    Trial protocol
    		 HU   PL  
    Global end of trial date
    03 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jul 2024
    First version publication date
    19 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D9100C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03830866
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Clinical Study Information Center
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.com
    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
    03 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jul 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of durvalumab + SoC CCRT compared with placebo + SoC CCRT in terms of PFS as assessed by investigator tumor assessments and histopathologic confirmation of local tumor progression.
    Protection of trial subjects
    Patients given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2019
    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
    Japan: 58
    Country: Number of subjects enrolled
    Hungary: 49
    Country: Number of subjects enrolled
    Korea, Republic of: 41
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Mexico: 114
    Country: Number of subjects enrolled
    China: 105
    Country: Number of subjects enrolled
    Peru: 104
    Country: Number of subjects enrolled
    Brazil: 78
    Country: Number of subjects enrolled
    Chile: 45
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    Taiwan: 37
    Country: Number of subjects enrolled
    India: 31
    Country: Number of subjects enrolled
    Philippines: 23
    Country: Number of subjects enrolled
    South Africa: 2
    Worldwide total number of subjects
    770
    EEA total number of subjects
    69
    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)
    686
    From 65 to 84 years
    84
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Consenting subjects were assessed to ensure they met eligibility criteria.

    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
    		 Investigator, Monitor, Carer, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Durvalumab + SoC CCRT
    Arm description
    		 Durvalumab 1500mg IV infusion every 4 weeks plus Standard of Care (SoC) concurrent chemoradiotherapy (CCRT) (chemotherapy for 5 weeks plus external beam radiotherapy and brachytherapy)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    MEDI4736
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1500 mg IV q4w

    Investigational medicinal product name
    Standard of Care (SOC)
    Investigational medicinal product code
    Carboplatin
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (Sourced locally by site)

    Investigational medicinal product name
    Standard of Care (SOC)
    Investigational medicinal product code
    Cisplatin
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (Sourced locally by site)

    Arm title
    		 Placebo + SoC CCRT
    Arm description
    		 Placebo IV infusion every 4 weeks plus Standard of Care (SoC) concurrent chemoradiotherapy (CCRT) (chemotherapy for 5 weeks plus external beam radiotherapy and brachytherapy)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline solution
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosing to match durvalumab

    Investigational medicinal product name
    Standard of Care (SOC)
    Investigational medicinal product code
    Carboplatin
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (Sourced locally by site)

    Investigational medicinal product name
    Standard of Care (SOC)
    Investigational medicinal product code
    Cisplatin
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (Sourced locally by site)

    Number of subjects in period 1
    		Durvalumab + SoC CCRT Placebo + SoC CCRT
    Started
    385
    385
    Completed
    268
    249
    Not completed
    117
    136
         Adverse event, serious fatal
    90
    111
         Consent withdrawn by subject
    19
    16
         Not eligible due to additional cancer diagnosis
    -
    1
         Unknown
    1
    1
         Lost to follow-up
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Durvalumab + SoC CCRT
    Reporting group description
    		 Durvalumab 1500mg IV infusion every 4 weeks plus Standard of Care (SoC) concurrent chemoradiotherapy (CCRT) (chemotherapy for 5 weeks plus external beam radiotherapy and brachytherapy)

    Reporting group title
    Placebo + SoC CCRT
    Reporting group description
    		 Placebo IV infusion every 4 weeks plus Standard of Care (SoC) concurrent chemoradiotherapy (CCRT) (chemotherapy for 5 weeks plus external beam radiotherapy and brachytherapy)

    Reporting group values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT Total
    Number of subjects
    		 385 385 770
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 341 345 686
        From 65-84 years
    		 44 40 84
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 49.6 ( 11.74 ) 48.8 ( 11.67 ) -
    Sex: Female, Male
    Units:
        Female
    		 385 385 770
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 130 125 255
        Black or African American
    		 10 12 22
        Asian
    		 152 148 300
        American Indian or Alaska Native
    		 47 56 103
        Other
    		 46 44 90

    End points

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    End points reporting groups
    Reporting group title
    Durvalumab + SoC CCRT
    Reporting group description
    		 Durvalumab 1500mg IV infusion every 4 weeks plus Standard of Care (SoC) concurrent chemoradiotherapy (CCRT) (chemotherapy for 5 weeks plus external beam radiotherapy and brachytherapy)

    Reporting group title
    Placebo + SoC CCRT
    Reporting group description
    		 Placebo IV infusion every 4 weeks plus Standard of Care (SoC) concurrent chemoradiotherapy (CCRT) (chemotherapy for 5 weeks plus external beam radiotherapy and brachytherapy)

    Primary: Progression-free survival (PFS) based on the investigator assessment according to RECIST 1.1 or histopathologic confirmation of local tumour progression

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    End point title
    		 Progression-free survival (PFS) based on the investigator assessment according to RECIST 1.1 or histopathologic confirmation of local tumour progression
    End point description
    PFS defined as time from date of randomisation until date of tumour progression or death by any cause, regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression
    End point type
    Primary
    End point timeframe
    Tumor assessments start 20 weeks after randomisation then every 12 weeks up to 164 weeks, then every 24 weeks until date of RECIST1.1 defined radiological progression. Assessed up to date of DCO (20-Jan-2022) to a maximum of 32.6 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Months
        median (confidence interval 95%)
    999999999 (999999999 to 999999999)
    999999999 (999999999 to 999999999)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Durvalumab + SoC CCRT v Placebo + SoC CCRT
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.174
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.08

    Secondary: Overall Survival (count)

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    End point title
    		 Overall Survival (count)
    End point description
    Number of Participants with Overall Survival (OS) where OS was defined as the time from the date of randomisation until death by any cause
    End point type
    Secondary
    End point timeframe
    Time from date of randomisation until date of death by any cause, assessed up to the data cut-off date (3rd July 2023), assessed up to a maximum of 51.7 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Participants
        Died
    91
    112
        Censored includes w/d consent & lost to follow up
    294
    273
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) based on the investigator assessment according to RECIST 1.1 or histopathologic confirmation of local tumour progression, PD-L1 Expression >= 1%

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    End point title
    		 Progression-free survival (PFS) based on the investigator assessment according to RECIST 1.1 or histopathologic confirmation of local tumour progression, PD-L1 Expression >= 1%
    End point description
    PFS defined as time from date of randomisation until date of tumour progression or death by any cause, regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression
    End point type
    Secondary
    End point timeframe
    Tumor assessments start 20 weeks after randomisation then every 12 weeks up to 164 weeks, then every 24 weeks until date of RECIST1.1 defined radiological progression. Assessed up to date of DCO (20-Jan-2022) to a maximum of 32.6 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Months
        median (confidence interval 95%)
    999999999 (999999999 to 999999999)
    999999999 (26.9 to 999999999)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Durvalumab + SoC CCRT v Placebo + SoC CCRT
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.203
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.1

    Secondary: Overall Survival (duration)

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    End point title
    		 Overall Survival (duration)
    End point description
    Time from the date of randomisation until death by any cause
    End point type
    Secondary
    End point timeframe
    Time from date of randomisation until date of death by any cause, assessed up to the data cut-off date (3rd July 2023), assessed up to a maximum of 51.7 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Months
        median (confidence interval 95%)
    999999999 (999999999 to 999999999)
    999999999 (999999999 to 999999999)
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Durvalumab + SoC CCRT v Placebo + SoC CCRT
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.091
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.04

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Percentage of evaluable patients with an Investigator-assessed visit response of complete response (CR) or partial response (PR). CR defined as disappearance of all target and non-target lesions and no new lesions. PR defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion
    End point type
    Secondary
    End point timeframe
    Tumor assessments start 20 weeks after randomisation then every 12 weeks up to 164 weeks, then every 24 weeks until date of RECIST1.1 defined radiological progression. Assessed up to date of DCO (20-Jan-2022) to a maximum of 32.6 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Percentage of Participants
        number (not applicable)
    82.6
    80.5
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Durvalumab + SoC CCRT v Placebo + SoC CCRT
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.465
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.794
         upper limit
    		 1.657

    Secondary: Complete Response Rate

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    End point title
    		 Complete Response Rate
    End point description
    Percentage of evaluable patients with an overall visit response of Complete Response (disappearance of all target and non-target lesions)
    End point type
    Secondary
    End point timeframe
    Tumor assessments start 20 weeks after randomisation then every 12 weeks up to 164 weeks, then every 24 weeks until date of RECIST1.1 defined radiological progression. Assessed up to date of DCO (20-Jan-2022) to a maximum of 32.6 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Percentage of Participants
        number (not applicable)
    42.9
    40.3
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Durvalumab + SoC CCRT v Placebo + SoC CCRT
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.469
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.833
         upper limit
    		 1.487

    Secondary: Duration of Response (DoR) in patients with Complete Response (CR)

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    End point title
    		 Duration of Response (DoR) in patients with Complete Response (CR)
    End point description
    Time from date of first documented CR until date of documented progression or death in the absence of progression. For patients who did not progress their DoR was their Progression-free survival censoring time
    End point type
    Secondary
    End point timeframe
    Tumor assessments start 20 weeks after randomisation then every 12 weeks up to 164 weeks, then every 24 weeks until date of RECIST1.1 defined radiological progression. Assessed up to date of DCO (20-Jan-2022) to a maximum of 32.6 months
    End point values
    		 Durvalumab + SoC CCRT Placebo + SoC CCRT
    Number of subjects analysed
    385
    385
    Units: Months
        median (inter-quartile range (Q1-Q3))
    999999999 (999999999 to 999999999)
    999999999 (999999999 to 999999999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent throughout the treatment period (median duration of 656 & 532 days for durvalumab & placebo respectively) up to & including 90-day safety follow-up period after the last dose of study treatment, up to a maximum of 53 months.
    Adverse event reporting additional description
    There were 385 subjects randomised to each of Durva + SoC CCRT and Placebo + SoC CCRT respectively (Full Analysis Set), however 1 of the subjects allocated to Placebo + SoC CCRT did not receive treatment, resulting in 384 in the Safety Analysis Set. Causally related AEs are those that are possibly related to Durvalumab/Placebo only.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Placebo + SoC CCRT
    Reporting group description
    		 Description (Arm-group)

    Reporting group title
    Durva + SoC CCRT
    Reporting group description
    		 Description (Arm-group)

    Serious adverse events
    		 Placebo + SoC CCRT Durva + SoC CCRT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 384 (23.44%)
    113 / 385 (29.35%)
         number of deaths (all causes)
    112
    91
         number of deaths resulting from adverse events
    5
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory pseudotumour
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cancer
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Venous thrombosis limb
         subjects affected / exposed
    2 / 384 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accelerated hypertension
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         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
    Oedema peripheral
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 384 (0.26%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix haemorrhage uterine
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    5 / 384 (1.30%)
    7 / 385 (1.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Vaginal fistula
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         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 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    2 / 384 (0.52%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    4 / 384 (1.04%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram q wave abnormal
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Full blood count decreased
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 384 (0.78%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation proctitis
         subjects affected / exposed
    2 / 384 (0.52%)
    6 / 385 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine perforation
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
         subjects affected / exposed
    1 / 384 (0.26%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    4 / 384 (1.04%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    20 / 384 (5.21%)
    20 / 385 (5.19%)
         occurrences causally related to treatment / all
    0 / 20
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    1 / 384 (0.26%)
    5 / 385 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    2 / 384 (0.52%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 384 (0.52%)
    6 / 385 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal disorder
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 384 (0.26%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 384 (0.52%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 384 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 384 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 384 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal ulcer
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Telangiectasia
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exfoliative rash
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 384 (0.78%)
    6 / 385 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric fistula
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 384 (0.00%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 384 (0.26%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urogenital fistula
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorder
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 384 (0.26%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis c
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    11 / 384 (2.86%)
    16 / 385 (4.16%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ureteritis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 384 (0.26%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Salpingitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal abscess
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 384 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 384 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 384 (1.04%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pelvic infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound abscess
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 384 (1.04%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + SoC CCRT Durva + SoC CCRT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    368 / 384 (95.83%)
    373 / 385 (96.88%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    21 / 384 (5.47%)
    28 / 385 (7.27%)
         occurrences all number
    24
    31
    Hypertension
         subjects affected / exposed
    24 / 384 (6.25%)
    16 / 385 (4.16%)
         occurrences all number
    31
    25
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    32 / 384 (8.33%)
    35 / 385 (9.09%)
         occurrences all number
    37
    51
    Asthenia
         subjects affected / exposed
    35 / 384 (9.11%)
    34 / 385 (8.83%)
         occurrences all number
    43
    45
    Fatigue
         subjects affected / exposed
    70 / 384 (18.23%)
    52 / 385 (13.51%)
         occurrences all number
    79
    55
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    37 / 384 (9.64%)
    40 / 385 (10.39%)
         occurrences all number
    41
    48
    Vaginal discharge
         subjects affected / exposed
    28 / 384 (7.29%)
    30 / 385 (7.79%)
         occurrences all number
    31
    37
    Vaginal haemorrhage
         subjects affected / exposed
    29 / 384 (7.55%)
    24 / 385 (6.23%)
         occurrences all number
    33
    28
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    33 / 384 (8.59%)
    41 / 385 (10.65%)
         occurrences all number
    34
    47
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    23 / 384 (5.99%)
    31 / 385 (8.05%)
         occurrences all number
    30
    48
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    28 / 384 (7.29%)
    30 / 385 (7.79%)
         occurrences all number
    37
    41
    Aspartate aminotransferase increased
         subjects affected / exposed
    30 / 384 (7.81%)
    34 / 385 (8.83%)
         occurrences all number
    38
    56
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 384 (3.39%)
    21 / 385 (5.45%)
         occurrences all number
    17
    30
    Platelet count decreased
         subjects affected / exposed
    62 / 384 (16.15%)
    48 / 385 (12.47%)
         occurrences all number
    107
    81
    Neutrophil count decreased
         subjects affected / exposed
    85 / 384 (22.14%)
    74 / 385 (19.22%)
         occurrences all number
    221
    216
    Lymphocyte count decreased
         subjects affected / exposed
    34 / 384 (8.85%)
    18 / 385 (4.68%)
         occurrences all number
    47
    29
    Weight decreased
         subjects affected / exposed
    42 / 384 (10.94%)
    43 / 385 (11.17%)
         occurrences all number
    53
    46
    White blood cell count decreased
         subjects affected / exposed
    85 / 384 (22.14%)
    71 / 385 (18.44%)
         occurrences all number
    340
    296
    Alanine aminotransferase increased
         subjects affected / exposed
    37 / 384 (9.64%)
    43 / 385 (11.17%)
         occurrences all number
    48
    64
    Injury, poisoning and procedural complications
    Gastroenteritis radiation
         subjects affected / exposed
    10 / 384 (2.60%)
    20 / 385 (5.19%)
         occurrences all number
    10
    21
    Radiation skin injury
         subjects affected / exposed
    27 / 384 (7.03%)
    17 / 385 (4.42%)
         occurrences all number
    27
    18
    Radiation proctitis
         subjects affected / exposed
    26 / 384 (6.77%)
    25 / 385 (6.49%)
         occurrences all number
    26
    27
    Nervous system disorders
    Headache
         subjects affected / exposed
    43 / 384 (11.20%)
    42 / 385 (10.91%)
         occurrences all number
    51
    55
    Dizziness
         subjects affected / exposed
    20 / 384 (5.21%)
    19 / 385 (4.94%)
         occurrences all number
    25
    24
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    28 / 384 (7.29%)
    38 / 385 (9.87%)
         occurrences all number
    38
    46
    Lymphopenia
         subjects affected / exposed
    29 / 384 (7.55%)
    39 / 385 (10.13%)
         occurrences all number
    51
    59
    Leukopenia
         subjects affected / exposed
    58 / 384 (15.10%)
    59 / 385 (15.32%)
         occurrences all number
    120
    100
    Anaemia
         subjects affected / exposed
    200 / 384 (52.08%)
    209 / 385 (54.29%)
         occurrences all number
    322
    315
    Neutropenia
         subjects affected / exposed
    55 / 384 (14.32%)
    74 / 385 (19.22%)
         occurrences all number
    100
    120
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    11 / 384 (2.86%)
    20 / 385 (5.19%)
         occurrences all number
    13
    21
    Abdominal pain
         subjects affected / exposed
    54 / 384 (14.06%)
    50 / 385 (12.99%)
         occurrences all number
    68
    71
    Abdominal pain upper
         subjects affected / exposed
    20 / 384 (5.21%)
    30 / 385 (7.79%)
         occurrences all number
    23
    31
    Constipation
         subjects affected / exposed
    87 / 384 (22.66%)
    97 / 385 (25.19%)
         occurrences all number
    106
    119
    Diarrhoea
         subjects affected / exposed
    190 / 384 (49.48%)
    177 / 385 (45.97%)
         occurrences all number
    289
    257
    Haemorrhoids
         subjects affected / exposed
    23 / 384 (5.99%)
    14 / 385 (3.64%)
         occurrences all number
    24
    14
    Nausea
         subjects affected / exposed
    202 / 384 (52.60%)
    213 / 385 (55.32%)
         occurrences all number
    293
    289
    Vomiting
         subjects affected / exposed
    107 / 384 (27.86%)
    105 / 385 (27.27%)
         occurrences all number
    202
    194
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    70 / 384 (18.23%)
    61 / 385 (15.84%)
         occurrences all number
    80
    74
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    12 / 384 (3.13%)
    26 / 385 (6.75%)
         occurrences all number
    13
    27
    Hypothyroidism
         subjects affected / exposed
    21 / 384 (5.47%)
    60 / 385 (15.58%)
         occurrences all number
    21
    68
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    14 / 384 (3.65%)
    26 / 385 (6.75%)
         occurrences all number
    18
    29
    Back pain
         subjects affected / exposed
    43 / 384 (11.20%)
    40 / 385 (10.39%)
         occurrences all number
    45
    47
    Arthralgia
         subjects affected / exposed
    42 / 384 (10.94%)
    44 / 385 (11.43%)
         occurrences all number
    49
    51
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    4 / 384 (1.04%)
    22 / 385 (5.71%)
         occurrences all number
    5
    24
    Cystitis
         subjects affected / exposed
    19 / 384 (4.95%)
    25 / 385 (6.49%)
         occurrences all number
    21
    28
    Covid-19
         subjects affected / exposed
    40 / 384 (10.42%)
    29 / 385 (7.53%)
         occurrences all number
    46
    29
    Urinary tract infection
         subjects affected / exposed
    92 / 384 (23.96%)
    90 / 385 (23.38%)
         occurrences all number
    124
    123
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 384 (3.65%)
    26 / 385 (6.75%)
         occurrences all number
    19
    27
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    64 / 384 (16.67%)
    89 / 385 (23.12%)
         occurrences all number
    74
    103
    Hyperglycaemia
         subjects affected / exposed
    19 / 384 (4.95%)
    26 / 385 (6.75%)
         occurrences all number
    23
    28
    Hyponatraemia
         subjects affected / exposed
    23 / 384 (5.99%)
    29 / 385 (7.53%)
         occurrences all number
    29
    40
    Hypomagnesaemia
         subjects affected / exposed
    38 / 384 (9.90%)
    40 / 385 (10.39%)
         occurrences all number
    61
    52
    Hypokalaemia
         subjects affected / exposed
    46 / 384 (11.98%)
    44 / 385 (11.43%)
         occurrences all number
    74
    63
    Hypoalbuminaemia
         subjects affected / exposed
    25 / 384 (6.51%)
    24 / 385 (6.23%)
         occurrences all number
    34
    32

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2018
    Version 1.0. Initial creation
    09 Sep 2019
    Version 2. PFS analysis at 3 years moved from exploratory objective to secondary objective. Clarified that duration of response in patients with a complete response endpoint is measured from the date of first detection of CR as determined at the 20-week assessment.
    29 May 2020
    Version 3. Removal of Carboplatin. To ensure appropriate balance between patients treated with cisplatin and carboplatin as the radiosensitizer across regions in the ongoing study, no further use of carboplatin as the radiosensitizer will be allowed in this study.
    11 Mar 2021
    Version 4. Removal of interim analyses for PFS and removal of first two interim analyses for OS.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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