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    Clinical Trial Results:
    An Open-Label Phase Ib/II Study of Surufatinib in Combination with Tislelizumab in Subjects With Advanced Solid Tumors

    Summary
    EudraCT number
    		 2020-004163-12
    Trial protocol
    		 ES   FR  
    Global end of trial date
    27 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2025
    First version publication date
    18 Jul 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2020-012-GLOB1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04579757
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HUTCHMED Limited
    Sponsor organisation address
    Building 4, 720 Cailun Road China (Shanghai) Pilot Free Trade Zone, Shanghai, China, 201203
    Public contact
    Nicky Murray, HUTCHMED Limited, +44 7738 881999, nicolam@hutch-med.com
    Scientific contact
    William Schelman, HUTCHMED Limited, +1 9733064490, williams@hutch-med.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
    27 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Aug 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part 1: To evaluate the safety and tolerability of surufatinib, thereby determining the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of surufatinib in combination with tislelizumab. Part 2: To evaluate the objective response rate (ORR) as assessed by the investigator in patients with advanced solid tumors when treated with surufatinib in combination with tislelizumab according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, consensus and ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonization Good Clinical Practice guidelines, and applicable regulations and guidelines governing clinical study conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United States: 85
    Worldwide total number of subjects
    87
    EEA total number of subjects
    2
    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)
    47
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This phase 1b/2, 2-part, open-label study was conducted in patients with advanced solid tumors. The study consisted of a dose-escalation phase and a dose expansion phase. A total of 12 patients in dose-escalation phase and 75 patients in dose-expansion phase were enrolled in this study.

    Pre-assignment
    Screening details
    		 The study was terminated early based on the strategic re-evaluation of clinical development of surufatinib in the United States and Europe with no safety concerns. No patients were enrolled in Cohort E1 (alveolar soft part sarcoma) in the dose-expansion phase, hence this cohort is not presented in results.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab
    Arm description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 250 milligrams (mg) orally once daily (QD) in combination with tislelizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W) until progressive disease (PD), unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 250 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Arm description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort A: CRC
    Arm description
    		 Patients with microsatellite stable, locally advanced or metastatic colorectal cancer (CRC) that was previously treated with at least 3 prior lines of therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort B1: Thoracic NETs
    Arm description
    		 Patients with thoracic neuroendocrine tumor (NET) who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort B2: GEP NETs
    Arm description
    		 Patients with gastroenteropancreatic (GEP) NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort C: SCLC
    Arm description
    		 Patients with locally advanced or metastatic small-cell lung cancer (SCLC) that was previously progressed on first-line chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort D: GC
    Arm description
    		 Patients with microsatellite stable, programmed death-ligand 1 (PD-L1) ≥5%, locally advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction (gastric cancer [GC]), and were previously treated with at least 2 lines of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort E2: UPS
    Arm description
    		 Patients with undifferentiated pleomorphic sarcoma (UPS) who progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of standard therapy or were unsuitable for standard frontline cytotoxic chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Arm title
    		 Dose Expansion Phase: Cohort F: ATC
    Arm description
    		 Patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) and who had a B-Raf kinase V600E (BRAFV600E) mutation were previously treated with 1 line of systemic therapy (not including radiation therapy) with a BRAF-targeted therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Surufatinib
    Investigational medicinal product code
    HMPL-012
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Surufatinib 300 mg oral capsule was administered QD Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg IV infusion was administered over 60 minutes in Cycles 1 and 2 and over at least 30 minutes in subsequent cycles (cycle duration: 3 weeks) until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Number of subjects in period 1
    		Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Started
    6
    6
    15
    10
    20
    15
    3
    9
    3
    Completed
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Not completed
    6
    6
    15
    10
    19
    15
    3
    8
    3
         Consent withdrawn by subject
    1
    1
    -
    -
    2
    1
    -
    3
    -
         Physician decision
    -
    -
    -
    2
    1
    1
    1
    -
    -
         Start of new therapy
    -
    -
    -
    -
    2
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    2
    1
    1
    -
    -
    -
         Death
    4
    1
    14
    3
    2
    7
    -
    1
    3
         Study terminated by sponsor
    -
    -
    -
    -
    2
    -
    -
    2
    -
         Radiological or clinical PD
    1
    4
    1
    3
    9
    4
    2
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab
    Reporting group description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 250 milligrams (mg) orally once daily (QD) in combination with tislelizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W) until progressive disease (PD), unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Reporting group description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort A: CRC
    Reporting group description
    		 Patients with microsatellite stable, locally advanced or metastatic colorectal cancer (CRC) that was previously treated with at least 3 prior lines of therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort B1: Thoracic NETs
    Reporting group description
    		 Patients with thoracic neuroendocrine tumor (NET) who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort B2: GEP NETs
    Reporting group description
    		 Patients with gastroenteropancreatic (GEP) NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort C: SCLC
    Reporting group description
    		 Patients with locally advanced or metastatic small-cell lung cancer (SCLC) that was previously progressed on first-line chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort D: GC
    Reporting group description
    		 Patients with microsatellite stable, programmed death-ligand 1 (PD-L1) ≥5%, locally advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction (gastric cancer [GC]), and were previously treated with at least 2 lines of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort E2: UPS
    Reporting group description
    		 Patients with undifferentiated pleomorphic sarcoma (UPS) who progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of standard therapy or were unsuitable for standard frontline cytotoxic chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort F: ATC
    Reporting group description
    		 Patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) and who had a B-Raf kinase V600E (BRAFV600E) mutation were previously treated with 1 line of systemic therapy (not including radiation therapy) with a BRAF-targeted therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC Total
    Number of subjects
    		 6 6 15 10 20 15 3 9 3 87
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.5 ( 14.69 ) 68.2 ( 9.83 ) 53.5 ( 11.99 ) 58.6 ( 9.70 ) 63.2 ( 9.23 ) 58.1 ( 14.27 ) 60.7 ( 5.86 ) 59.9 ( 13.94 ) 63.0 ( 19.05 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 8 4 10 8 0 6 1 40
        Male
    		 5 4 7 6 10 7 3 3 2 47
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 2 1 0 1 0 4
        Not Hispanic or Latino
    		 5 6 15 9 18 13 3 8 2 79
        Unknown or Not Reported
    		 1 0 0 1 0 1 0 0 1 4
    Race
    Units: Subjects
        Asian
    		 0 0 0 1 0 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 0 0 0 0 0 1
        Black or African American
    		 0 1 4 0 3 1 0 0 0 9
        White
    		 3 3 10 8 17 12 3 9 3 68
        More than one race
    		 1 1 0 0 0 1 0 0 0 3
        Unknown or Not Reported
    		 1 1 1 1 0 1 0 0 0 5

    End points

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    End points reporting groups
    Reporting group title
    Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab
    Reporting group description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 250 milligrams (mg) orally once daily (QD) in combination with tislelizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W) until progressive disease (PD), unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Reporting group description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort A: CRC
    Reporting group description
    		 Patients with microsatellite stable, locally advanced or metastatic colorectal cancer (CRC) that was previously treated with at least 3 prior lines of therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort B1: Thoracic NETs
    Reporting group description
    		 Patients with thoracic neuroendocrine tumor (NET) who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort B2: GEP NETs
    Reporting group description
    		 Patients with gastroenteropancreatic (GEP) NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort C: SCLC
    Reporting group description
    		 Patients with locally advanced or metastatic small-cell lung cancer (SCLC) that was previously progressed on first-line chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort D: GC
    Reporting group description
    		 Patients with microsatellite stable, programmed death-ligand 1 (PD-L1) ≥5%, locally advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction (gastric cancer [GC]), and were previously treated with at least 2 lines of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort E2: UPS
    Reporting group description
    		 Patients with undifferentiated pleomorphic sarcoma (UPS) who progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of standard therapy or were unsuitable for standard frontline cytotoxic chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort F: ATC
    Reporting group description
    		 Patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) and who had a B-Raf kinase V600E (BRAFV600E) mutation were previously treated with 1 line of systemic therapy (not including radiation therapy) with a BRAF-targeted therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Primary: Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs)

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    End point title
    		 Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs) [1] [2]
    End point description
    Per National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) v5.0,DLT=any following AE:Nonhematologic toxicity:≥grade(G)3 nonhematologic toxicity,except:G3 fatigue lasting <7 days,G3 rash returning to baseline or ≤G1 within 7 days with treatment,G3 hypertension downgraded to ≤G1 within 7 days with therapy,G3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolving to ≤G1 within 7 days,≥G3 amylase/lipase elevation without symptoms of pancreatitis,G3 nausea/vomiting or diarrhea for <72 hours with care,≥G3 electrolyte abnormality lasting up to 72 hours and resolving with treatment.Hematologic toxicity:≥G3 febrile neutropenia,G4 neutropenia;G4 thrombocytopenia lasting >7 days,G3 thrombocytopenia with severe bleeding, G4 anemia. DLT-evaluable analysis set=all patients enrolled in dose escalation phase,evaluable for DLT assessment;received ≥85% of surufatinib and ≥67% of tislelizumab administration during DLT assessment or had a DLT.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to Day 21 of Cycle 1 (cycle duration: 3 weeks)
    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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only dose escalation phase arms were analyzed for this endpoint.
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Number of subjects analysed
    6
    6
    Units: patients
    1
    1
    No statistical analyses for this end point

    Primary: Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation

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    End point title
    		 Dose Escalation Phase: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation [3] [4]
    End point description
    An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment in humans, whether or not considered related to the treatment. An AE was considered “serious” if, in the view of either the investigator or sponsor, it resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, was a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study treatment and up to 30 days after the date of last study treatment administration. The safety analysis set (SAS) included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
    End point type
    Primary
    End point timeframe
    From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 9 months
    Notes
    [3] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only dose escalation phase arms were analyzed for this endpoint.
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Number of subjects analysed
    6
    6
    Units: patients
        Any TEAEs
    6
    6
        Any TESAEs
    5
    3
        Any TEAEs leading to surufatinib discontinuation
    3
    0
        Any TEAEs leading to tislelizumab discontinuation
    3
    0
    No statistical analyses for this end point

    Primary: Dose Expansion Phase: Objective Response Rate

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    End point title
    		 Dose Expansion Phase: Objective Response Rate [5] [6]
    End point description
    ORR was defined as the percentage of patients with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1. BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Here, +/- 9999 = values were not estimable as there were no patients with CR or PR in that disease cohort.
    End point type
    Primary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 37 months
    Notes
    [5] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only dose expansion phase arms were analyzed for this endpoint.
    End point values
    		 Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    15
    10
    20
    15
    3
    9
    3
    Units: percentage of patients
        number (confidence interval 95%)
    6.7 (0.2 to 31.9)
    0 (-9999 to 9999)
    15.0 (3.2 to 37.9)
    13.3 (1.7 to 40.5)
    33.3 (0.8 to 90.6)
    44.4 (13.7 to 78.8)
    0 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Dose Escalation Phase: Objective Response Rate

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    End point title
    		 Dose Escalation Phase: Objective Response Rate [7]
    End point description
    ORR was defined as the percentage of patients with a confirmed BOR of CR or PR as determined by the investigator using RECIST v1.1. BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Here, +/- 9999 = values were not estimable as there were no patients with CR or PR in that disease cohort.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only dose escalation phase arms were analyzed for this endpoint.
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Number of subjects analysed
    6
    6
    Units: percentage of patients
        number (confidence interval 95%)
    0 (-9999 to 9999)
    0 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS)

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from the start of study treatment until the first radiographic documentation of objective progression as assessed by the investigator using RECIST v1.1, or death from any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Here, 9999 = values were not estimable due to insufficient number of patients with events at study closure.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    6
    6
    15
    10
    20
    15
    3
    9
    3
    Units: months
        median (confidence interval 95%)
    1.5 (1.2 to 9999)
    6.0 (1.8 to 9999)
    4.7 (2.7 to 5.4)
    4.5 (0.3 to 9999)
    7.4 (3.1 to 20.0)
    1.4 (1.0 to 4.0)
    9.6 (5.6 to 9999)
    9999 (1.3 to 9999)
    2.8 (1.2 to 9999)
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR)

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR)
    End point description
    DCR was defined as percentage of patients with a BOR of CR, PR, or stable disease (SD) lasting for at least 7 weeks as determined by the investigator using RECIST v1.1. BOR was defined as best response recorded from start of study treatment until documented RECIST v1.1 progression or start date of new anticancer therapy, whichever came first. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum on study. SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Here, +/- 9999 = values were not estimable due to no patients with CR, PR, or SD for at least 7 weeks.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    6
    6
    15
    10
    20
    15
    3
    9
    3
    Units: percentage of patients
        number (confidence interval 95%)
    0 (-9999 to 9999)
    66.7 (22.3 to 95.7)
    66.7 (38.4 to 88.2)
    50.0 (18.7 to 81.3)
    70.0 (45.7 to 88.1)
    26.7 (7.8 to 55.1)
    66.7 (9.4 to 99.2)
    55.6 (21.2 to 86.3)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR)

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR)
    End point description
    CBR was defined as percentage of patients with BOR of CR, PR, or durable SD as determined by investigator using RECIST v1.1. Durable SD was SD for at least 6 months. BOR was defined as best response recorded from start of study treatment until documented RECIST v1.1 progression or start date of new anticancer therapy, whichever came first. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum on study. SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Here, +/- 9999 = values were not estimable due to no patients with CR, PR, or SD lasting for at least 6 months.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    6
    6
    15
    10
    20
    15
    3
    9
    3
    Units: percentage of patients
        number (confidence interval 95%)
    0 (-9999 to 9999)
    50.0 (11.8 to 88.2)
    20.0 (4.3 to 48.1)
    20.0 (2.5 to 55.6)
    40.0 (19.1 to 63.9)
    13.3 (1.7 to 40.5)
    33.3 (0.8 to 90.6)
    44.4 (13.7 to 78.8)
    0 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Duration of Response (DoR)

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Duration of Response (DoR)
    End point description
    DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, until PD or death, whichever came first. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Only those patients with PR or CR (responders) were included in the analysis. Here, +/- 9999 = values were not estimable due to insufficient number of patients with events at study closure.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    0 [8]
    0 [9]
    1
    0 [10]
    3
    2
    1
    4
    0 [11]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    9999 (9999 to 9999)
    ( to )
    9999 (15.0 to 9999)
    8.3 (5.8 to 9999)
    11.0 (-9999 to 9999)
    9999 (9999 to 9999)
    ( to )
    Notes
    [8] - There were no patients with PR or CR (responders) in this cohort.
    [9] - There were no patients with PR or CR (responders) in this cohort.
    [10] - There were no patients with PR or CR (responders) in this cohort.
    [11] - There were no patients with PR or CR (responders) in this cohort.
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Time to Response (TTR)

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Time to Response (TTR)
    End point description
    TTR was defined as the time from start of study treatment until the date of first documented objective response, either CR or PR (whichever status was recorded first), according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. Only those patients with PR or CR (responders) were included in the analysis. Here, +/- 9999 = values were not estimable due to insufficient number of patients with events at study closure.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    0 [12]
    0 [13]
    1
    0 [14]
    3
    2
    1
    4
    0 [15]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    2.7 (-9999 to 9999)
    ( to )
    3.9 (2.7 to 9999)
    3.5 (1.3 to 9999)
    2.7 (-9999 to 9999)
    1.4 (1.2 to 9999)
    ( to )
    Notes
    [12] - There were no patients with PR or CR (responders) in this cohort.
    [13] - There were no patients with PR or CR (responders) in this cohort.
    [14] - There were no patients with PR or CR (responders) in this cohort.
    [15] - There were no patients with PR or CR (responders) in this cohort.
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib
    End point description
    Blood samples were collected at the specified timepoints to determine plasma concentration of surufatinib. The pharmacokinetic (PK) analysis set included all patients with at least 1 quantifiable concentration of surufatinib or tislelizumab. Here, n = number of patients with data collected at specified timepoints. 9999 = values were not estimable as they were below the lower limit of quantification (LLOQ) of 1.00 nanograms per milliliter (ng/mL). 99999 = standard deviation (SD) was not estimable for 1 patient. 55555 = no patients were analyzed. C = Cycle and D = Day.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 1, 2, 5, 9, 17 and on Days 8 and 15 of Cycle 1; 2 to 4 hours (h) post-dose on Days 1 and 15 of Cycle 1 (cycle duration: 3 weeks)
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    6
    6
    15
    10
    19
    15
    3
    9
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1: Pre-dose (n=5,6,15,10,19,15,3,9,2)
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        C1D1: 2 to 4 h post-dose (n=6,6,15,10,19,15,3,9,2)
    293.03 ( 244.593 )
    576.00 ( 415.108 )
    426.62 ( 312.209 )
    276.36 ( 243.080 )
    294.13 ( 292.335 )
    406.97 ( 212.791 )
    506.27 ( 653.616 )
    275.64 ( 165.937 )
    782.50 ( 463.155 )
        C1D8: Pre-dose (n=4,6,12,5,14,9,2,6,1)
    77.00 ( 44.023 )
    189.93 ( 113.750 )
    170.33 ( 131.533 )
    100.12 ( 71.600 )
    92.26 ( 63.901 )
    122.80 ( 70.875 )
    109.10 ( 18.243 )
    97.70 ( 40.471 )
    709.00 ( 99999 )
        C1D15: Pre-dose (n=5,5,11,4,15,10,2,6,0)
    64.36 ( 15.246 )
    181.56 ( 125.156 )
    135.96 ( 83.673 )
    159.00 ( 139.802 )
    84.95 ( 70.121 )
    96.79 ( 43.933 )
    111.05 ( 19.728 )
    118.92 ( 75.457 )
    55555 ( 55555 )
        C1D15: 2 to 4 h post-dose (n=3,3,13,4,12,11,2,7,0)
    318.67 ( 146.770 )
    757.33 ( 498.399 )
    657.54 ( 369.146 )
    354.25 ( 52.519 )
    471.78 ( 330.598 )
    425.75 ( 235.698 )
    188.00 ( 41.012 )
    518.00 ( 302.182 )
    55555 ( 55555 )
        C2D1: Pre-dose (n=5,4,10,3,9,11,2,2,1)
    45.82 ( 27.567 )
    96.80 ( 38.895 )
    151.44 ( 99.521 )
    89.37 ( 53.475 )
    75.94 ( 53.028 )
    117.68 ( 79.721 )
    146.50 ( 26.163 )
    71.95 ( 9.405 )
    147.00 ( 99999 )
        C5D1: Pre-dose (n=0,2,3,1,4,2,0,0,0)
    55555 ( 55555 )
    55.25 ( 8.132 )
    141.20 ( 117.885 )
    41.00 ( 99999 )
    61.08 ( 22.279 )
    105.70 ( 54.164 )
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
        C9D1: Pre-dose (n=0,1,0,0,3,1,0,0,0)
    55555 ( 55555 )
    65.90 ( 99999 )
    55555 ( 55555 )
    55555 ( 55555 )
    87.20 ( 14.964 )
    41.70 ( 99999 )
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
        C17D1: Pre-dose (n=0,0,0,0,1,0,0,0,0)
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
    85.10 ( 99999 )
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab
    End point description
    Blood samples were collected at the specified timepoints to determine serum concentration of tislelizumab. The PK analysis set included all patients with at least 1 quantifiable concentration of surufatinib or tislelizumab. Here, n = number of patients with data collected at specified timepoints. 9999 = values were not estimable as they were below the LLOQ of 400 ng/mL. 99999 = SD was not estimable for 1 patient. 55555 = no patients were analyzed. C = Cycle and D = Day.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Day 1 of Cycles 1, 2, 5, 9, 17; end of infusion on Day 1 of Cycles 1 and 5; on Days 8 and 15 of Cycle 1 (cycle duration: 3 weeks)
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    6
    6
    15
    10
    19
    15
    3
    9
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1: Pre-infusion (n=6,6,15,9,19,15,3,9,2)
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        C1D1: End of infusion (n=6,6,15,10,19,15,3,9,2)
    44550.0 ( 7420.98 )
    62750.0 ( 17420.53 )
    57233.3 ( 8846.28 )
    70990.0 ( 41600.73 )
    61136.8 ( 15927.90 )
    66220.0 ( 17336.43 )
    67966.7 ( 45015.59 )
    55955.6 ( 15499.61 )
    42200.0 ( 12727.92 )
        C1D8 (n=6,6,13,8,18,12,3,8,2)
    16980.0 ( 6850.75 )
    26216.7 ( 7702.32 )
    26446.2 ( 6387.83 )
    29575.0 ( 5751.46 )
    32244.4 ( 7253.58 )
    35450.0 ( 8899.39 )
    38233.3 ( 35800.33 )
    25475.0 ( 6549.10 )
    16050.0 ( 1767.77 )
        C1D15 (n=6,6,12,7,16,12,2,8,2)
    14296.7 ( 5945.36 )
    17900.0 ( 5297.55 )
    17414.2 ( 4199.94 )
    20571.4 ( 2817.63 )
    24506.3 ( 6403.07 )
    23783.3 ( 4274.20 )
    43950.0 ( 40658.64 )
    19300.0 ( 4755.45 )
    10940.0 ( 2489.02 )
        C2D1: Pre-infusion (n=5,5,14,6,15,12,2,8,2)
    9564.0 ( 7871.14 )
    13804.0 ( 4782.16 )
    13858.6 ( 4730.49 )
    14033.3 ( 2436.12 )
    18020.0 ( 5688.23 )
    17725.0 ( 3860.55 )
    38000.0 ( 36910.97 )
    12161.3 ( 4443.93 )
    7640.0 ( 2729.43 )
        C5D1: Pre-infusion (n=0,3,8,1,8,4,1,3,1)
    55555 ( 55555 )
    24400.0 ( 14028.90 )
    36412.5 ( 34947.57 )
    46400.0 ( 99999 )
    41575.0 ( 10065.32 )
    31225.0 ( 12388.81 )
    20100.0 ( 99999 )
    19200.0 ( 3143.25 )
    22700.0 ( 99999 )
        C5D1: End of infusion (n=0,3,7,2,8,4,1,3,1)
    55555 ( 55555 )
    87166.7 ( 34425.04 )
    102500.0 ( 26662.02 )
    117500.0 ( 6363.96 )
    113475.0 ( 16286.34 )
    117550.0 ( 43800.65 )
    80800.0 ( 99999 )
    103033.3 ( 17737.06 )
    69000.0 ( 99999 )
        C9D1: Pre-infusion (n=0,2,1,1,5,2,0,2,0)
    55555 ( 55555 )
    22700.0 ( 4101.22 )
    44800.0 ( 99999 )
    50000.0 ( 99999 )
    45500.0 ( 5384.24 )
    41200.0 ( 24607.32 )
    55555 ( 55555 )
    41100.0 ( 16970.56 )
    55555 ( 55555 )
        C17D1: Pre-infusion (n=0,0,0,1,3,1,0,1,0)
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
    55555 ( 55555 )
    44766.7 ( 12196.86 )
    51900.0 ( 99999 )
    55555 ( 55555 )
    47300.0 ( 99999 )
    55555 ( 55555 )
    No statistical analyses for this end point

    Secondary: Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab

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    End point title
    		 Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab
    End point description
    Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline. The ADA analysis set included all patients who received at least 1 dose of tislelizumab and had a baseline and at least 1 post-baseline ADA result.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 9 months for dose escalation phase and approximately 33 months for dose expansion phase
    End point values
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    6
    5
    14
    8
    16
    13
    2
    9
    2
    Units: patients
        Treatment-Boosted ADA
    0
    0
    2
    0
    0
    0
    0
    0
    0
        Treatment-Induced ADA
    2
    2
    5
    3
    5
    1
    0
    5
    1
    No statistical analyses for this end point

    Secondary: Dose Expansion Phase (Cohorts A and F): Overall Survival (OS)

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    End point title
    		 Dose Expansion Phase (Cohorts A and F): Overall Survival (OS) [16]
    End point description
    OS was defined as the time from the start of study treatment until the date of death due to any cause. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab. As pre-specified in the protocol and statistical analysis plan (SAP), OS was assessed only in Cohort A (CRC) and Cohort F (ATC) of the dose expansion phase. Here, 9999 = value was not estimable due to insufficient number of patients with events at study closure.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment (Day 1) up to date of death due to any cause, up to approximately 42 months
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As pre-specified in the protocol and statistical analysis plan (SAP), this endpoint was analyzed only in Cohort A (CRC) and Cohort F (ATC) of the dose expansion phase.
    End point values
    		 Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    15
    3
    Units: months
        median (confidence interval 95%)
    7.1 (4.8 to 11.8)
    5.3 (2.8 to 9999)
    No statistical analyses for this end point

    Secondary: Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation

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    End point title
    		 Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events and TEAEs Leading to Treatment Discontinuation [17]
    End point description
    An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment in humans, whether or not considered related to the treatment. An AE was considered “serious” if, in the view of either the investigator or sponsor, it resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, was a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study treatment and up to 30 days after the date of last study treatment administration. The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 33 months
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only dose expansion phase arms were analyzed for this endpoint.
    End point values
    		 Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Number of subjects analysed
    15
    10
    20
    15
    3
    9
    3
    Units: patients
        Any TEAEs
    14
    10
    20
    15
    3
    9
    3
        Any TESAEs
    9
    5
    9
    8
    0
    4
    1
        Any TEAEs leading to surufatinib discontinuation
    3
    2
    5
    5
    0
    2
    0
        Any TEAEs leading to tislelizumab discontinuation
    6
    2
    6
    5
    0
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs: From first dose(Day 1) up to 30 days after last dose of study treatment, approximately 9 months for dose escalation and 33 months for dose expansion phase. Deaths: From signing of informed consent form up to end of follow up, approximately 42 months.
    Adverse event reporting additional description
    The SAS included all enrolled patients who received at least 1 dose of surufatinib or tislelizumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab
    Reporting group description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 250 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab
    Reporting group description
    		 Patients with advanced or metastatic solid tumors of any kind who had progressed on or were intolerant of standard therapies received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort A: CRC
    Reporting group description
    		 Patients with microsatellite stable, locally advanced or metastatic CRC that was previously treated with at least 3 prior lines of therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort B1: Thoracic NETs
    Reporting group description
    		 Patients with thoracic NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort B2: GEP NETs
    Reporting group description
    		 Patients with GEP NET who had progressive, locally advanced or metastatic, low-to-intermediate grade (Grade 1 or Grade 2), well-differentiated NETs that progressed on at least 1 line of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort C: SCLC
    Reporting group description
    		 Patients with locally advanced or metastatic SCLC that was previously progressed on first-line chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort D: GC
    Reporting group description
    		 Patients with microsatellite stable, PD-L1 ≥5%, locally advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GC), and were previously treated with at least 2 lines of standard therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort E2: UPS
    Reporting group description
    		 Patients with UPS who progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of standard therapy or were unsuitable for standard frontline cytotoxic chemotherapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Reporting group title
    Dose Expansion Phase: Cohort F: ATC
    Reporting group description
    		 Patients with locally advanced or metastatic ATC and who had a BRAFV600E mutation were previously treated with 1 line of systemic therapy (not including radiation therapy) with a BRAF-targeted therapy received surufatinib 300 mg orally QD in combination with tislelizumab 200 mg IV infusion Q3W until PD, unacceptable toxicity, withdrawal of consent, new anticancer therapy, lost to follow-up, or death.

    Serious adverse events
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    3 / 6 (50.00%)
    9 / 15 (60.00%)
    5 / 10 (50.00%)
    9 / 20 (45.00%)
    8 / 15 (53.33%)
    0 / 3 (0.00%)
    4 / 9 (44.44%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    4
    1
    14
    4
    2
    8
    0
    1
    3
         number of deaths resulting from adverse events
    2
    0
    1
    1
    1
    5
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic fistula
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose Escalation Phase: Surufatinib 250 mg + Tislelizumab Dose Escalation Phase: Surufatinib 300 mg + Tislelizumab Dose Expansion Phase: Cohort A: CRC Dose Expansion Phase: Cohort B1: Thoracic NETs Dose Expansion Phase: Cohort B2: GEP NETs Dose Expansion Phase: Cohort C: SCLC Dose Expansion Phase: Cohort D: GC Dose Expansion Phase: Cohort E2: UPS Dose Expansion Phase: Cohort F: ATC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    14 / 15 (93.33%)
    10 / 10 (100.00%)
    20 / 20 (100.00%)
    15 / 15 (100.00%)
    3 / 3 (100.00%)
    8 / 9 (88.89%)
    3 / 3 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    10 / 15 (66.67%)
    3 / 10 (30.00%)
    9 / 20 (45.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    4 / 9 (44.44%)
    2 / 3 (66.67%)
         occurrences all number
    0
    3
    23
    7
    37
    1
    4
    8
    4
    Flushing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    3
    0
    0
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vasculitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    6 / 15 (40.00%)
    5 / 10 (50.00%)
    11 / 20 (55.00%)
    7 / 15 (46.67%)
    3 / 3 (100.00%)
    4 / 9 (44.44%)
    1 / 3 (33.33%)
         occurrences all number
    3
    5
    9
    11
    14
    8
    4
    6
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    1 / 10 (10.00%)
    7 / 20 (35.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    2
    2
    12
    0
    1
    4
    0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 15 (13.33%)
    0 / 3 (0.00%)
    4 / 9 (44.44%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    3
    0
    1
    2
    0
    4
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    2
    3
    0
    0
    3
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 15 (13.33%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    1
    2
    2
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    1
    3
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    2
    Malaise
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Catheter site haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Facial pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Medical device site pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Xerosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Gynaecomastia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    3 / 10 (30.00%)
    5 / 20 (25.00%)
    3 / 15 (20.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    3
    7
    3
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    1 / 15 (6.67%)
    3 / 10 (30.00%)
    3 / 20 (15.00%)
    2 / 15 (13.33%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    1
    4
    3
    2
    0
    5
    0
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    3
    0
    0
    2
    0
    Dysphonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    2
    0
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Atelectasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    3 / 15 (20.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    2
    2
    5
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    1
    0
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Panic attack
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    3 / 10 (30.00%)
    13 / 20 (65.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    7
    11
    37
    3
    2
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    2 / 10 (20.00%)
    11 / 20 (55.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    3
    9
    26
    2
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    5 / 15 (33.33%)
    2 / 10 (20.00%)
    7 / 20 (35.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    7
    2
    24
    1
    0
    0
    2
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    4 / 15 (26.67%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
    1 / 15 (6.67%)
    2 / 3 (66.67%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    1
    4
    5
    7
    3
    1
    2
    2
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    2 / 10 (20.00%)
    6 / 20 (30.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    5
    5
    12
    3
    1
    0
    2
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    2 / 10 (20.00%)
    5 / 20 (25.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    2 / 3 (66.67%)
         occurrences all number
    0
    0
    2
    6
    16
    2
    0
    1
    3
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 15 (26.67%)
    4 / 10 (40.00%)
    4 / 20 (20.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    5
    4
    9
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 10 (10.00%)
    5 / 20 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    9
    0
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 10 (30.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    7
    6
    0
    0
    0
    0
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    14
    4
    1
    0
    0
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    5 / 20 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    7
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    10
    0
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    6
    0
    0
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    8
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    9
    0
    0
    0
    0
    Blood creatine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Troponin T increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    5
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    2
    0
    Incision site discharge
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Postoperative wound complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Wound dehiscence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Aortic valve disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    2 / 10 (20.00%)
    6 / 20 (30.00%)
    4 / 15 (26.67%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    2
    2
    7
    4
    0
    4
    0
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    6 / 20 (30.00%)
    2 / 15 (13.33%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    8
    2
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    0
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 15 (13.33%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Sinus headache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Spinal cord compression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    3 / 10 (30.00%)
    4 / 20 (20.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    1 / 3 (33.33%)
         occurrences all number
    2
    3
    1
    3
    11
    1
    0
    2
    1
    Coagulopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Ear pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    10 / 15 (66.67%)
    5 / 10 (50.00%)
    12 / 20 (60.00%)
    6 / 15 (40.00%)
    3 / 3 (100.00%)
    4 / 9 (44.44%)
    0 / 3 (0.00%)
         occurrences all number
    3
    3
    18
    10
    17
    12
    4
    7
    0
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    6 / 15 (40.00%)
    3 / 10 (30.00%)
    11 / 20 (55.00%)
    6 / 15 (40.00%)
    3 / 3 (100.00%)
    4 / 9 (44.44%)
    1 / 3 (33.33%)
         occurrences all number
    1
    4
    14
    15
    19
    8
    7
    16
    1
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    7 / 15 (46.67%)
    3 / 10 (30.00%)
    6 / 20 (30.00%)
    4 / 15 (26.67%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    13
    4
    10
    6
    0
    5
    0
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    3 / 15 (20.00%)
    4 / 10 (40.00%)
    4 / 20 (20.00%)
    5 / 15 (33.33%)
    2 / 3 (66.67%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    4
    8
    6
    5
    3
    2
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    3 / 15 (20.00%)
    1 / 3 (33.33%)
    3 / 9 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    1
    2
    4
    2
    2
    3
    1
    3
    2
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    2
    1
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    4
    1
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    3
    1
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 15 (20.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    0
    3
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Ileus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Odynophagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    3
    3
    0
    0
    0
    0
    Biliary obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hepatic artery thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    2
    3
    0
    2
    2
    1
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    2
    2
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 15 (13.33%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Cold sweat
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Immune-mediated dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    5 / 15 (33.33%)
    4 / 10 (40.00%)
    9 / 20 (45.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    6
    13
    5
    47
    0
    1
    10
    0
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    5 / 20 (25.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    5
    1
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hydronephrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Leukocyturia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Micturition disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Renal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Urine flow decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    2
    0
    2
    0
    0
    1
    1
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    3 / 10 (30.00%)
    8 / 20 (40.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    4
    24
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    1 / 10 (10.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    4
    1
    7
    0
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    8
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    2
    4
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Bursitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Muscle atrophy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    2
    3
    1
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 15 (26.67%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    6
    0
    1
    1
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    0
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    0
    0
    0
    Eye infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Abscess
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Bacteriuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Herpes simplex
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Kidney infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    9 / 15 (60.00%)
    4 / 10 (40.00%)
    11 / 20 (55.00%)
    3 / 15 (20.00%)
    3 / 3 (100.00%)
    3 / 9 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    3
    9
    10
    13
    3
    3
    4
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 15 (33.33%)
    2 / 10 (20.00%)
    5 / 20 (25.00%)
    2 / 15 (13.33%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    8
    2
    8
    2
    1
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 10 (20.00%)
    7 / 20 (35.00%)
    3 / 15 (20.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    2
    36
    7
    0
    2
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    4
    6
    7
    0
    0
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 15 (26.67%)
    1 / 10 (10.00%)
    4 / 20 (20.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    1
    6
    1
    0
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    4 / 15 (26.67%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    4
    2
    1
    4
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 15 (20.00%)
    2 / 10 (20.00%)
    5 / 20 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    8
    17
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    4
    0
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    3
    0
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    11
    0
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    0
    Food intolerance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2021
    The purpose of this amendment was to align the protocol across sponsor programs (inclusion/exclusion criteria) and to make administrative corrections to errors identified in the original protocol, v 1.
    10 Oct 2021
    The purpose of this amendment was to add a cohort in the dose expansion phase to further evaluate the efficacy and safety of surufatinib, to define the RP2D, to align the protocol across sponsor programs and to make administrative changes.
    16 Mar 2022
    The purpose of this amendment was to update the inclusion criteria, to provide guidance for diagnosis and management of infusion-related and hypersensitivity reactions and immune-related adverse events, to update the company name following a change, and to make administrative changes.
    30 Nov 2022
    The purpose of this amendment was to provide notification that further enrollment to all study cohorts was halted based upon the strategic evaluation of surufatinib in the United States and Europe with HUTCHMED as the study Sponsor. This change was not based on any concern for patient safety or efficacy relative to surufatinib treatment. Currently enrolled patients who were deriving clinical benefit from treatment with surufatinib could continue to participate in the study as per the protocol. There was no planned interruption in the supply of surufatinib to clinical trial sites with active patients.
    29 Nov 2023
    The purpose of this amendment was to provide notification of the termination of this study based on the strategic re-evaluation of the clinical development of surufatinib in the United States and Europe. This change was not based on any concern for patient safety or efficacy relative to surufatinib and/or tislelizumab treatment.

    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.
    The study was terminated based on the strategic re-evaluation of the clinical development of surufatinib in the United States and Europe with no safety concerns.
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