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    Clinical Trial Results:
    A Prospective, Randomized, Double-Blinded, Placebo-Controlled, Multinational, Multicenter, Parallel-group, Phase III Study to Evaluate the Efficacy and Safety of Apatinib Plus Best Supportive Care (BSC) Compared to Placebo Plus BSC in Patients With Advanced or Metastatic Gastric Cancer

    Summary
    EudraCT number
    		 2016-003984-20
    Trial protocol
    		 GB   DE   PL   FR   IT   RO  
    Global end of trial date
    23 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LSK-AM301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03042611
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Elevar Therapeutics, Inc
    Sponsor organisation address
    2755 E Cottonwood Pkwy #540, Salt Lake City, United States, 84121
    Public contact
    Elevar Clinical Trials, Elevar Therapeutics, Inc, 1 801 3037440, info-clinicalstudy@elevartherapeutics.com
    Scientific contact
    Elevar Clinical Trials, Elevar Therapeutics, Inc, 1 801 3037440, info-clinicalstudy@elevartherapeutics.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
    23 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of rivoceranib plus best supportive care (BSC) compared to placebo plus BSC in participants with advanced or metastatic gastric cancer (GC).
    Protection of trial subjects
    The study was conducted in accordance with the Good Clinical Practice (GCP) guideline developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The clinical trial was also conducted in compliance with Declaration of Helsinki, protocol, Standard specified in the Section 3 in the Article 14 and the Section 2 in the Article 80 in Pharmaceutical Law, Notification 28 from MHLW dated March 27th, 1997 “Ordinance on the criteria for the implementation of clinical trials of the drug (GCP)”.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2017
    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
    France: 19
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Japan: 59
    Country: Number of subjects enrolled
    Korea, Republic of: 214
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Taiwan: 37
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Ukraine: 27
    Worldwide total number of subjects
    460
    EEA total number of subjects
    78
    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)
    292
    From 65 to 84 years
    167
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized to receive either rivoceranib +best supportive care (BSC) or placebo +BSC for approximately 24 months. Participants who benefited from rivoceranib were permitted to continue rivoceranib during an extension period of the study, up to approximately 36 months.

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rivoceranib Plus Best Supportive Care (BSC)
    Arm description
    		 Participants received rivoceranib 700 milligrams (mg) orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivoceranib
    Investigational medicinal product code
    Other name
    Apatinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received rivoceranib 700 milligrams (mg) orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Arm title
    		 Placebo Plus BSC
    Arm description
    		 Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.
    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
    Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Number of subjects in period 1
    		Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Started
    308
    152
    Received at Least 1 Dose of Study Drug
    307
    151
    Completed
    52
    28
    Not completed
    256
    124
         Consent withdrawn by subject
    13
    4
         Physician decision
    7
    2
         Death
    232
    110
         Study Closed
    -
    1
         Lost to follow-up
    4
    7
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Extension Phase: Rivoceranib Plus BSC
    Arm description
    		 Participants received rivoceranib 700 mg orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivoceranib
    Investigational medicinal product code
    Other name
    Apatinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received rivoceranib 700 mg orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Arm title
    		 Extension Phase: Placebo Plus BSC
    Arm description
    		 Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.
    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
    Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Number of subjects in period 2
    		Extension Phase: Rivoceranib Plus BSC Extension Phase: Placebo Plus BSC
    Started
    52
    28
    Completed
    0
    0
    Not completed
    52
    28
         Death
    34
    16
         Study Closed
    17
    11
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rivoceranib Plus Best Supportive Care (BSC)
    Reporting group description
    		 Participants received rivoceranib 700 milligrams (mg) orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Reporting group title
    Placebo Plus BSC
    Reporting group description
    		 Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Reporting group values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC Total
    Number of subjects
    		 308 152 460
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.03 ± 11.11 59.96 ± 10.63 -
    Sex: Female, Male
    Units: participants
        Female
    		 67 40 107
        Male
    		 241 112 353
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 0 5
        Not Hispanic or Latino
    		 303 152 455
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 207 105 312
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 100 46 146
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Rivoceranib Plus Best Supportive Care (BSC)
    Reporting group description
    		 Participants received rivoceranib 700 milligrams (mg) orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Reporting group title
    Placebo Plus BSC
    Reporting group description
    		 Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.
    Reporting group title
    Extension Phase: Rivoceranib Plus BSC
    Reporting group description
    		 Participants received rivoceranib 700 mg orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Reporting group title
    Extension Phase: Placebo Plus BSC
    Reporting group description
    		 Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [1]
    End point description
    OS was defined as the time from randomization to death. Participants alive or lost to follow-up at the end of study (EOS) were censored. The Intent-to-treat (ITT) set for the OS final analysis consisted of data from all participants who were randomized, including participants who were still in OS follow-up at the time of primary analysis. In the ITT set, participants were included in the group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Day 1 (randomization) up to approximately 36 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summary statistics only
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    308
    152
    Units: Months
        median (confidence interval 95%)
    5.82 (5.26 to 6.47)
    5.13 (4.47 to 6.24)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    PFS was defined as the time from randomization to either documented radiological progression or death from any cause. Participants alive and free of progression at the EOS were censored. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    308
    152
    Units: Months
        median (confidence interval 95%)
    2.83 (2.07 to 3.52)
    1.77 (1.71 to 1.84)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) Per RECIST 1.1

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    End point title
    		 Objective Response Rate (ORR) Per RECIST 1.1
    End point description
    ORR was defined as the percentage of participants in the analysis population with the best overall response of Complete Response (CR: disappearance of all target lesions and reduction in short axis of any nodal target lesions to <10 millimeter [mm]) or a Partial Response (PR: ≥30% decrease in the sum of the longest diameters of the target lesions, taking as a reference the baseline sum diameters) per RECIST 1.1. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    308
    152
    Units: Percentage of Participants
        number (confidence interval 95%)
    6.5 (3.74 to 9.25)
    1.3 (0.16 to 4.67)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR was defined as the proportion of participants with a Best Overall Response of CR, PR, or stable disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum diameter while on study) per RECIST 1.1. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    308
    152
    Units: Percentage of Participants
        number (confidence interval 95%)
    40.3 (34.78 to 45.74)
    13.2 (7.78 to 18.53)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)

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    End point title
    		 Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30 is a cancer specific Questionnaire with 30 questions for assessing the health-related QOL of cancer participants. The questionnaire incorporates 5 functional scales, 4 symptom scales, a global QOL scale, and single items for the assessment of additional systems commonly reported by cancer participants. All items are scored on 4-point Likert scales, ranging from 1 (‘not at all’) to 4 (‘very much’), with the exception of 2 items in the global QOL scale which use modified 7-point linear analog scales. All scores and single-items were transformed to a scale of 0 to 100. For the functioning scales, a higher score indicated greater functioning and for the symptom scales, a higher score indicated a greater symptom burden. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized. Overall number of participants indicates total number of participants.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (EOT) (Up to 24 months)
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    207
    99
    Units: units on a scale
        arithmetic mean (standard deviation)
    -17.51 ± 22.72
    -18.01 ± 26.80
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Specific (EORTC QLQ-STO22) Score

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    End point title
    		 Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Specific (EORTC QLQ-STO22) Score
    End point description
    EORTC QLQ-STO22 is a 22-item gastric cancer-specific questionnaire-integrating system for assessing the health-related QOL of gastric cancer participants. Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100. For the functioning scales, a higher score indicates greater functioning and for the symptom scales, a higher score indicates a greater symptom burden. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized. Overall number of participants indicates total at baseline, number of participants analyzed indicates number of participants with evaluable data.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (Up to 24 months)
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    207
    99
    Units: units on a scale
    arithmetic mean (standard deviation)
        Body Image
    11.71 ± 29.95
    9.43 ± 35.01
        Dyspnea
    16.64 ± 26.34
    16.50 ± 24.91
        Pain
    12.72 ± 23.96
    13.75 ± 21.91
        Reflux Symptoms
    11.46 ± 24.80
    8.31 ± 21.73
        Eating Restrictions
    18.12 ± 26.45
    17.76 ± 22.89
        Anxiety
    13.69 ± 23.64
    10.55 ± 26.91
        Dry Mouth
    20.77 ± 33.22
    11.56 ± 29.15
        Taste
    15.30 ± 32.46
    14.48 ± 30.18
        Hair Loss
    -15.37 ± 33.71
    -18.69 ± 30.05
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol 5-Dimension 5-Level Visual Analogue Scale (EQ-5D-5L VAS) Score

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    End point title
    		 Change From Baseline in EuroQol 5-Dimension 5-Level Visual Analogue Scale (EQ-5D-5L VAS) Score
    End point description
    EQ-5D-5L Questionnaire consists of EQ-5D-5L descriptive system and the visual analogue scale (VAS). The descriptive system comprises the 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each dimension has 5 levels. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized. Overall number of participants indicates total number of participants with evaluable data.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (Up to 24 months)
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    207
    98
    Units: units on a scale
        arithmetic mean (standard deviation)
    -18.48 ± 19.11
    -15.36 ± 21.61
    No statistical analyses for this end point

    Secondary: Number of Participants per QOL Dimension Response as Measured by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire

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    End point title
    		 Number of Participants per QOL Dimension Response as Measured by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
    End point description
    EQ-5D-5L Questionnaire comprises the 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each dimension has 5 levels of response. The ITT set consisted of data from all participants who were randomized. In the ITT set, participants were included in the group to which they were randomized. Overall number of participants indicates total at baseline.
    End point type
    Secondary
    End point timeframe
    EOT (Month 24)
    End point values
    		 Rivoceranib Plus Best Supportive Care (BSC) Placebo Plus BSC
    Number of subjects analysed
    308
    152
    Units: Number
        Mobility: No problems
    46
    27
        Mobility: Slight problems
    60
    27
        Mobility: Moderate problems
    51
    23
        Mobility: Severe problems
    43
    17
        Mobility: Unable
    8
    6
        Mobility: Missing
    100
    52
        Self Care: No problems
    100
    54
        Self Care: Slight problems
    47
    22
        Self Care: Moderate problems
    40
    10
        Self Care: Severe problems
    14
    7
        Self Care: Unable
    7
    7
        Self Care: Missing
    100
    52
        Usual Activities: No problems
    36
    24
        Usual Activities: Slight problems
    61
    36
        Usual Activities: Moderate problems
    56
    18
        Usual Activities: Severe problems
    43
    13
        Usual Activities: Unable
    12
    9
        Usual Activities: Missing
    100
    52
        Pain/Discomfort: No pain or discomfort
    25
    13
        Pain/Discomfort: Slight pain or discomfort
    61
    36
        Pain/Discomfort: Moderate pain or discomfort
    67
    26
        Pain/Discomfort: Severe pain or discomfort
    47
    19
        Pain/Discomfort: Extreme pain or discomfort
    8
    6
        Pain/Discomfort: Missing
    100
    52
        Anxiety/Depression: Not anxious or depressed
    49
    26
        Anxiety/Depression: Slightly anxious or depressed
    60
    36
        Anxiety/Depression: Moderately anxious/depressed
    62
    25
        Anxiety/Depression: Severely anxious or depressed
    29
    8
        Anxiety/Depression: Extremely anxious or depressed
    8
    5
        Anxiety/Depression: Missing
    100
    52
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 36 months
    Adverse event reporting additional description
    The Safety set consisted of data from all participants in the ITT set who received at least 1 dose of rivoceranib or placebo. In the Safety set, participants were included in the group based on the treatment that was received. Safety data was analyzed by the Safety set which includes participants who were alive and on treatment or in OS follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo Plus BSC
    Reporting group description
    		 Participants received matching placebo to rivoceranib orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Reporting group title
    Rivoceranib Plus Best Supportive Care (BSC)
    Reporting group description
    		 Participants received rivoceranib 700 mg orally once per day during each cycle plus BSC. BSC is defined as palliative, non-cancer therapy. Each cycle duration was 28 days.

    Serious adverse events
    		 Placebo Plus BSC Rivoceranib Plus Best Supportive Care (BSC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 151 (43.71%)
    149 / 307 (48.53%)
         number of deaths (all causes)
    134
    283
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    3 / 151 (1.99%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Cancer pain
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastric cancer
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Central venous catheter removal
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 151 (5.30%)
    8 / 307 (2.61%)
         occurrences causally related to treatment / all
    0 / 18
    2 / 16
         deaths causally related to treatment / all
    0 / 9
    0 / 9
    Pyrexia
         subjects affected / exposed
    1 / 151 (0.66%)
    6 / 307 (1.95%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 7
    Pain
         subjects affected / exposed
    2 / 151 (1.32%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    2 / 151 (1.32%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Disease progression
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Death
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Localised oedema
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 151 (1.32%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Dyspnoea
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cough
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Delusion
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Lipase increased
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Amylase increased
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood creatinine increased
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Subdural haemorrhage
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Radiation mucositis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Spinal cord compression
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 151 (1.32%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 151 (1.99%)
    15 / 307 (4.89%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 31
         deaths causally related to treatment / all
    0 / 3
    0 / 16
    Ileus
         subjects affected / exposed
    4 / 151 (2.65%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 12
         deaths causally related to treatment / all
    0 / 8
    0 / 6
    Vomiting
         subjects affected / exposed
    2 / 151 (1.32%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 13
         deaths causally related to treatment / all
    0 / 2
    0 / 7
    Gastric haemorrhage
         subjects affected / exposed
    2 / 151 (1.32%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 6
    4 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Dysphagia
         subjects affected / exposed
    3 / 151 (1.99%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 151 (1.32%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 151 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Obstruction gastric
         subjects affected / exposed
    2 / 151 (1.32%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Small intestinal obstruction
         subjects affected / exposed
    2 / 151 (1.32%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Ascites
         subjects affected / exposed
    1 / 151 (0.66%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Diarrhoea
         subjects affected / exposed
    0 / 151 (0.00%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 8
    Pancreatitis
         subjects affected / exposed
    0 / 151 (0.00%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Abdominal pain upper
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Subileus
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Gastric perforation
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastric stenosis
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haematochezia
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Mechanical ileus
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Stomatitis
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Intestinal infarction
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute abdomen
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Abdominal distension
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestinal obstruction
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant dysphagia
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal pain
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal stenosis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis acute
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Volvulus
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    4 / 151 (2.65%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 4
         deaths causally related to treatment / all
    0 / 7
    0 / 2
    Bile duct obstruction
         subjects affected / exposed
    0 / 151 (0.00%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Hepatic failure
         subjects affected / exposed
    0 / 151 (0.00%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Jaundice cholestatic
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Biliary dilatation
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Hepatic function abnormal
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cholecystitis
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Bile duct stenosis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholangitis acute
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Liver disorder
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 151 (0.66%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Renal impairment
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nephropathy toxic
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal pain
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 151 (0.00%)
    8 / 307 (2.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 11
    Peritonitis
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Biliary sepsis
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Biliary tract infection
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Escherichia sepsis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urethritis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 151 (2.65%)
    8 / 307 (2.61%)
         occurrences causally related to treatment / all
    0 / 12
    5 / 17
         deaths causally related to treatment / all
    0 / 6
    0 / 11
    Hyponatraemia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Hypernatraemia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cachexia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Dehydration
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperuricaemia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypophagia
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Plus BSC Rivoceranib Plus Best Supportive Care (BSC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    140 / 151 (92.72%)
    299 / 307 (97.39%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 151 (7.28%)
    71 / 307 (23.13%)
         occurrences all number
    30
    274
    Weight decreased
         subjects affected / exposed
    12 / 151 (7.95%)
    69 / 307 (22.48%)
         occurrences all number
    30
    201
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 151 (5.96%)
    64 / 307 (20.85%)
         occurrences all number
    23
    190
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 151 (8.61%)
    43 / 307 (14.01%)
         occurrences all number
    33
    149
    Platelet count decreased
         subjects affected / exposed
    6 / 151 (3.97%)
    46 / 307 (14.98%)
         occurrences all number
    29
    127
    Blood bilirubin increased
         subjects affected / exposed
    8 / 151 (5.30%)
    37 / 307 (12.05%)
         occurrences all number
    17
    142
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 151 (3.31%)
    106 / 307 (34.53%)
         occurrences all number
    6
    303
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 151 (3.31%)
    41 / 307 (13.36%)
         occurrences all number
    8
    62
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    30 / 151 (19.87%)
    83 / 307 (27.04%)
         occurrences all number
    71
    190
    Fatigue
         subjects affected / exposed
    16 / 151 (10.60%)
    77 / 307 (25.08%)
         occurrences all number
    26
    145
    Pyrexia
         subjects affected / exposed
    17 / 151 (11.26%)
    36 / 307 (11.73%)
         occurrences all number
    44
    89
    Oedema peripheral
         subjects affected / exposed
    5 / 151 (3.31%)
    18 / 307 (5.86%)
         occurrences all number
    9
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    41 / 151 (27.15%)
    64 / 307 (20.85%)
         occurrences all number
    141
    333
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    30 / 151 (19.87%)
    78 / 307 (25.41%)
         occurrences all number
    65
    199
    Diarrhoea
         subjects affected / exposed
    22 / 151 (14.57%)
    92 / 307 (29.97%)
         occurrences all number
    36
    207
    Nausea
         subjects affected / exposed
    34 / 151 (22.52%)
    72 / 307 (23.45%)
         occurrences all number
    69
    147
    Stomatitis
         subjects affected / exposed
    5 / 151 (3.31%)
    69 / 307 (22.48%)
         occurrences all number
    7
    148
    Vomiting
         subjects affected / exposed
    21 / 151 (13.91%)
    53 / 307 (17.26%)
         occurrences all number
    46
    110
    Constipation
         subjects affected / exposed
    23 / 151 (15.23%)
    51 / 307 (16.61%)
         occurrences all number
    47
    123
    Abdominal pain upper
         subjects affected / exposed
    8 / 151 (5.30%)
    29 / 307 (9.45%)
         occurrences all number
    14
    61
    Dyspepsia
         subjects affected / exposed
    10 / 151 (6.62%)
    24 / 307 (7.82%)
         occurrences all number
    18
    51
    Ascites
         subjects affected / exposed
    13 / 151 (8.61%)
    15 / 307 (4.89%)
         occurrences all number
    31
    74
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    2 / 151 (1.32%)
    44 / 307 (14.33%)
         occurrences all number
    2
    59
    Dyspnoea
         subjects affected / exposed
    12 / 151 (7.95%)
    16 / 307 (5.21%)
         occurrences all number
    25
    31
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    6 / 151 (3.97%)
    81 / 307 (26.38%)
         occurrences all number
    6
    170
    Rash
         subjects affected / exposed
    4 / 151 (2.65%)
    19 / 307 (6.19%)
         occurrences all number
    6
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 151 (6.62%)
    18 / 307 (5.86%)
         occurrences all number
    20
    38
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    11 / 151 (7.28%)
    90 / 307 (29.32%)
         occurrences all number
    20
    308
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 151 (5.30%)
    17 / 307 (5.54%)
         occurrences all number
    22
    32
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 151 (29.80%)
    132 / 307 (43.00%)
         occurrences all number
    82
    287
    Hypoalbuminaemia
         subjects affected / exposed
    16 / 151 (10.60%)
    34 / 307 (11.07%)
         occurrences all number
    55
    156

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2016
    Protocol version under which patient enrollment to begin. Updated based on FDA, CHMP/EMA and PMDA comments and advice to adjust inclusion/exclusion and study evaluations and to clarify and require study activity that address these comments.
    03 Feb 2017
    Protocol version to clarify and make slight modifications to inclusion/exclusion criteria. Updated to include Japan specific PMDA requirements to global protocol version and to add more clear parameters for patients to qualify and consent to continued study treatment after disease progression.
    07 Feb 2018
    Change of inclusion criteria to allow for later line study treatment in some study regions where recent approval of therapy or standardization of therapy in later line has occurred. This is to maintain the target study population to be subjects who failed approved standard therapies.
    16 Nov 2018
    Created open-label extension period for patients taking apatinib after unblinding study results during final analysis. Extended trial period estimation. Clarified ECG data collection. Integrated previous country specific protocol versions.

    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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    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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