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    Clinical Trial Results:
    A Phase I/II study to assess the safety and efficacy of pazopanib and MK-3475 in patients with advanced renal cell carcinoma

    Summary
    EudraCT number
    		 2013-003785-14
    Trial protocol
    		 GB  
    Global end of trial date
    17 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2020
    First version publication date
    11 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPZP034A2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02014636
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 GSK: 200249, Merck: KEYNOTE-018
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    17 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safety, tolerability, maximum tolerated regimen (MTR), and recommended Phase II dose (RP2D) of pazopanib in combination with MK-3475 in treatment naïve subjects with advanced renal cell carcinoma (RCC). Following an Urgent Safety Measure (USM) released on February 09, 2017, the phase II (Part 2) portion of this study did not commence. Hence, this is only a Phase 1 study.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Dec 2013
    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
    United Kingdom: 21
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    42
    EEA total number of subjects
    21
    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)
    28
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted in 6 centers across 2 countries (4 centers in the USA and 2 centers in the UK). In one of the 4 centers in the USA, no subjects were treated. 42 subjects were enrolled originally, however, in Cohort C, one subject did not receive treatment, as the patient was not clinically suitable to be treated, and withdrew consent.

    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
    		 Part 1: Cohort A
    Arm description
    		 10 subjects were enrolled and treated (6 subjects from the dose escalation period, and 4 subjects newly enrolled). All received treatment with pazopanib (800 mg oral once daily) + pembrolizumab (2 mg/kg iv Q3W)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    PZP034
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg once daily

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg iv Q3W

    Arm title
    		 Part 1: Cohort B
    Arm description
    		 10 new subjects were enrolled and treated with pazopanib (600 mg oral once daily) + pembrolizumab (2 mg/kg iv Q3W)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    PZP034
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg once daily

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Q3W

    Arm title
    		 Part 1: Cohort C
    Arm description
    		 Run-in period only: 9 pts. received pazopanib monotherapy starting dose of 800 mg oral daily for 9 weeks but did not continue after the run-in period. Run-in and post run-in periods: 12 pts. treated w/pazopanib in run-in, and post run-in pts. 6 pts. treated with combination therapy, 4 treated with pembrolizumab monotherapy, and 4 treated with pazopanib monotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    PZP034
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg daily for 9 weeks

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Q3W

    Number of subjects in period 1
    		Part 1: Cohort A Part 1: Cohort B Part 1: Cohort C
    Started
    10
    10
    22
    Completed
    3
    4
    6
    Not completed
    7
    6
    16
         Adverse event, serious fatal
    -
    1
    1
         Consent withdrawn by subject
    3
    2
    6
         Physician decision
    -
    3
    9
         Lost to follow-up
    4
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Cohort A
    Reporting group description
    		 10 subjects were enrolled and treated (6 subjects from the dose escalation period, and 4 subjects newly enrolled). All received treatment with pazopanib (800 mg oral once daily) + pembrolizumab (2 mg/kg iv Q3W)

    Reporting group title
    Part 1: Cohort B
    Reporting group description
    		 10 new subjects were enrolled and treated with pazopanib (600 mg oral once daily) + pembrolizumab (2 mg/kg iv Q3W)

    Reporting group title
    Part 1: Cohort C
    Reporting group description
    		 Run-in period only: 9 pts. received pazopanib monotherapy starting dose of 800 mg oral daily for 9 weeks but did not continue after the run-in period. Run-in and post run-in periods: 12 pts. treated w/pazopanib in run-in, and post run-in pts. 6 pts. treated with combination therapy, 4 treated with pembrolizumab monotherapy, and 4 treated with pazopanib monotherapy

    Reporting group values
    		 Part 1: Cohort A Part 1: Cohort B Part 1: Cohort C Total
    Number of subjects
    		 10 10 22 42
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 6 9 14 29
        From 65-84 years
    		 4 1 8 13
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 5 3 6 14
        Male
    		 5 7 16 28

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Cohort A
    Reporting group description
    		 10 subjects were enrolled and treated (6 subjects from the dose escalation period, and 4 subjects newly enrolled). All received treatment with pazopanib (800 mg oral once daily) + pembrolizumab (2 mg/kg iv Q3W)

    Reporting group title
    Part 1: Cohort B
    Reporting group description
    		 10 new subjects were enrolled and treated with pazopanib (600 mg oral once daily) + pembrolizumab (2 mg/kg iv Q3W)

    Reporting group title
    Part 1: Cohort C
    Reporting group description
    		 Run-in period only: 9 pts. received pazopanib monotherapy starting dose of 800 mg oral daily for 9 weeks but did not continue after the run-in period. Run-in and post run-in periods: 12 pts. treated w/pazopanib in run-in, and post run-in pts. 6 pts. treated with combination therapy, 4 treated with pembrolizumab monotherapy, and 4 treated with pazopanib monotherapy

    Primary: Summary of Adverse Events/Serious Adverse Events for Cohort A and B

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    End point title
    		 Summary of Adverse Events/Serious Adverse Events for Cohort A and B [1] [2]
    End point description
    Any sign or symptom that occurs during the study treatment plus the post treatment follow-up period
    End point type
    Primary
    End point timeframe
    From the start of study treatment (first dose) until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs
    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: Statistical analysis not performed for this primary endpoint.
    [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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B
    Number of subjects analysed
    10
    10
    Units: Number of Subjects
        Incidence of any AE
    6
    6
        Severity of Adverse Events by Grade 3/4
    9
    9
        Incidence of any SAE
    6
    6
    No statistical analyses for this end point

    Primary: Summary of Adverse Events/Serious Adverse Events for Cohort C

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    End point title
    		 Summary of Adverse Events/Serious Adverse Events for Cohort C [3] [4]
    End point description
    Any sign or symptom that occurs during the study treatment plus the post treatment follow-up period
    End point type
    Primary
    End point timeframe
    From the start of study treatment (first dose) until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs
    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: Statistical analysis not performed for this endpoint.
    [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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort C
    Number of subjects analysed
    21
    Units: Number of Subjects
        Incidence of any AE - Pazo + Pembro (N=6)
    6
        Incidence of any AE- Pembrolizumab (N=4)
    4
        Incidence of any AE- Pazopanib (N=11)
    11
        Severity of AEs Grade 3/4: Pazo + Pembro (N=6)
    6
        Severity of AEs by Grade 3/4:Pembrolizumab (N=4)
    2
        Severity of AEs Grade 3/4 :Pazo + Pembro (N=6)
    6
        Incidence of any SAE Pazo + Pembro (N=6
    3
        Incidence of any SAE Pembrolizumab (N=4)
    1
        Incidence of any SAE Pazopanib (N=11)
    3
    No statistical analyses for this end point

    Primary: Dose limiting toxicities (DLT) and maximum tolerated regimen (MTR)

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    End point title
    		 Dose limiting toxicities (DLT) and maximum tolerated regimen (MTR) [5]
    End point description
    MTR is defined as the highest dose of pazopanib in combination with the highest dose of MK 3475 at which no more than 1 of 6 subjects experiences a DLT after a minimum of 8 weeks of treatment. DLT is defined as a drug-related AE starting in the first 8 weeks of treatment
    End point type
    Primary
    End point timeframe
    8 weeks
    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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B Part 1: Cohort C
    Number of subjects analysed
    10
    10
    22
    Units: Number of Subjects
        Summary of Dose Limiting Toxicities
    2
    5
    1
    No statistical analyses for this end point

    Primary: Incidence of Anti-Drug Antibody Positivity (Mk-3475) for Cohorts A, B, C

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    End point title
    		 Incidence of Anti-Drug Antibody Positivity (Mk-3475) for Cohorts A, B, C [6]
    End point description
    Subjects were monitored for anti-MK 3475 antibodies throughout the study
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [6] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B Part 1: Cohort C
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: Number
    Notes
    [7] - Dataset has negative results for all analyzed subjects, hence no positive results.
    [8] - Dataset has negative results for all analyzed subjects, hence no positive results.
    [9] - Dataset has negative results for all analyzed subjects, hence no positive results.
    No statistical analyses for this end point

    Secondary: Summary of Pembrolizumab (MK-3475) PK Concentration-time data (Cmax and Ctrough) for Cohort A Dose Escalation

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    End point title
    		 Summary of Pembrolizumab (MK-3475) PK Concentration-time data (Cmax and Ctrough) for Cohort A Dose Escalation [10]
    End point description
    Analysis of plasma and serum concentrations in blood samples collected from subjects
    End point type
    Secondary
    End point timeframe
    MK-3475: Until 6 months after the last dose of MK-3475
    Notes
    [10] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A
    Number of subjects analysed
    5
    Units: ug/ML
    median (full range (min-max))
        Cmax- Cycle 1 (N=5)
    65.8 (53.4 to 71.4)
        Ctrough- Cycle 1 (N=5)
    999 (999 to 999)
        Cmax-Cycle 2 (N=5)
    69 (64.3 to 94.7)
        Ctrough- Cycle 2 (N=5)
    15.8 (0.00 to 18.1)
        Cmax- Cycle 4 (N=2)
    999 (999 to 999)
        Ctrough- Cycle 4 (N=2)
    38 (37.2 to 38.8)
        Cmax- Cycle 7 (N=4)
    999 (999 to 999)
        Ctrough- Cycle 7 (N=4)
    45.2 (28.4 to 57.2)
        Cmax-Cycle 13 (N=4)
    999 (999 to 999)
        Ctrough-Cycle 13 (N=4)
    49.9 (23.6 to 66.4)
        Cmax- Cycle 19 (N=4)
    999 (999 to 999)
        Ctrough- Cycle 19 (N=4)
    47.9 (33.2 to 61)
        Cmax- Cycle 25 (N=3)
    999 (999 to 999)
        Ctrough- Cycle 25 (N=3)
    45.8 (39.3 to 63.2)
        Cmax- Cycle 31 (N=4)
    999 (999 to 999)
        Ctrough- Cycle 31 (N=4)
    52.6 (38.8 to 76.8)
        Cmax- Cycle 37 (N=2)
    999 (999 to 999)
        Ctrough- Cycle 37 (N=2)
    50.5 (45.7 to 55.2)
    No statistical analyses for this end point

    Secondary: Summary of Pembrolizumab (MK-3475) PK Concentration-time Data (Cmax and Ctrough) for Cohort B

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    End point title
    		 Summary of Pembrolizumab (MK-3475) PK Concentration-time Data (Cmax and Ctrough) for Cohort B [11]
    End point description
    Analysis of plasma and serum concentrations for MK-3475 collected in subjects
    End point type
    Secondary
    End point timeframe
    MK-3475: until 6 months after the last dose of MK-3475
    Notes
    [11] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort B
    Number of subjects analysed
    6
    Units: ug/mL
    median (full range (min-max))
        Cmax -Cycle 1 (N=6)
    41.9 (33.4 to 52.4)
        Ctrough-Cycle 1 (N=6)
    999 (999 to 999)
        Cmax -Cycle 4 (N=3)
    67.6 (66.5 to 75.9)
        Ctrough-Cycle 4 (N=3)
    23.5 (19.3 to 26.4)
        Cmax -Cycle 7 (N=5)
    999 (999 to 999)
        Ctrough-Cycle 7 (N=5)
    25.4 (22.4 to 32.7)
        Cmax -Cycle 13 (N=5)
    999 (999 to 999)
        Ctrough-Cycle 13 (N=5)
    39.1 (33.1 to 43.5)
        Cmax -Cycle 19 (N=4)
    999 (999 to 999)
        Ctrough-Cycle 19 (N=4)
    44.4 (35.7 to 46.2)
        Cmax -Cycle 25 (N=3)
    999 (999 to 999)
        Ctrough-Cycle 25 (N=3)
    36.4 (35.4 to 39.8)
        Cmax-Cycle 31 (N=3)
    999 (999 to 999)
        Ctrough- Cycle (N=3)
    41 (38.6 to 44.7)
    No statistical analyses for this end point

    Secondary: Summary of Pazopanib Pharmacokinetic (PK) parameters for Cohort C (Run-in Period) in Expansion cohort

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    End point title
    		 Summary of Pazopanib Pharmacokinetic (PK) parameters for Cohort C (Run-in Period) in Expansion cohort [12]
    End point description
    Area under the plasma concentration-time curve from time 0 to 24 hrs (AUC[0-24], maximum observed concentration (Cmax), tmax, and concentration at 24 hours (C24) of pazopanib; Pre-dose (trough) concentration at the end of the dosing interval
    End point type
    Secondary
    End point timeframe
    For Pazopanib: before and after the 1st and 2nd dose of MK-3475.
    Notes
    [12] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort C
    Number of subjects analysed
    17
    Units: ng/ML, h, h*ng/ML,
    median (full range (min-max))
        AUC0-24h (h*ng/ML): Week 4
    999 (999 to 999)
        Cmax (ng/ML): Week 4
    48300 (10500 to 78900)
        Tmax (h) : Week 4
    3 (1.83 to 6.02)
        AUClast (h*ng/ML) Week 4
    846000 (185000 to 1520000)
        Ctrough (ng/ML) Week 4
    29900 (6250 to 54100)
    No statistical analyses for this end point

    Secondary: Summary of Pazopanib and Pazopanib+Pembrolizumab Pharmacokinetic (PK) parameters for Cohort C (Post Run-in Period) in Expansion cohort

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    End point title
    		 Summary of Pazopanib and Pazopanib+Pembrolizumab Pharmacokinetic (PK) parameters for Cohort C (Post Run-in Period) in Expansion cohort [13]
    End point description
    Area under the plasma concentration-time curve from time 0 to 24 hrs (AUC[0-24], maximum observed concentration Cmax, tmax, and concentration at 24 hours (C24) of pazopanib; Pre-dose (trough) concentration at the end of the dosing interval/AUClast
    End point type
    Secondary
    End point timeframe
    For Pazopanib: Before and after the 1st and 2nd dose of MK-3475. For MK-3475: Until 6 months after the last dose of MK-3475
    Notes
    [13] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort C
    Number of subjects analysed
    6
    Units: h*ng/mL, ng/mL, h
    median (full range (min-max))
        AUC0-24h (h*ng/mL) Pazopanib (Week 19, N=1)
    999 (999 to 999)
        Cmax (ng/mL) Pazopanib (Week 19, N=1)
    18600 (18600 to 18600)
        Tmax (h) Pazopanib (Week 19, N=1)
    0.967 (0.967 to 0.967)
        AUC0-24h (h*ng/mL) Pazo + Pembro (Week 10, N=6)
    999 (999 to 999)
        Cmax (ng/mL) Pazo + Pembro (Week 10, N=6)
    43000 (31300 to 65900)
        Tmax (h) Pazo + Pembro (Week 10, N=6)
    2 (1 to 4.03)
        AUC0-24h (h*ng/mL) Pazo + Pembro (Week 19, N=2)
    999 (999 to 999)
        Cmax (ng/mL) Pazo + Pembro (Week 19, N=2)
    40200 (37800 to 42700)
        Tmax (h) Pazo + Pembro (Week 19, N=2)
    2.5 (2 to 3)
        AUClast (h*ng/mL) Pazopanib (Week 19, N=1)
    281000 (281000 to 281000)
        Ctrough (ng/mL) Pazopanib (Week 19, N=1)
    8790 (8790 to 8790)
        AUClast (h*ng/mL) Pazo + Pembro (Week 10, N=6)
    880000 (163000 to 1300000)
        Ctrough (ng/mL) Pazo + Pembro (Week 10, N=6)
    32100 (24900 to 43200)
        AUClast (h*ng/mL) Pazo + Pembro (Week 19, N=2)
    747000 (682000 to 812000)
        Ctrough (ng/mL) Pazo + Pembro (Week 19, N=2)
    26600 (25800 to 27400)
    No statistical analyses for this end point

    Secondary: Summary of Investigator-Assessed Best Confirmed Response for Cohort A and B (RECIST 1.1 Criteria) Overall Response Rate (ORR)

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    End point title
    		 Summary of Investigator-Assessed Best Confirmed Response for Cohort A and B (RECIST 1.1 Criteria) Overall Response Rate (ORR) [14]
    End point description
    Overall response rate is defined as the percentage of subjects, who achieved either a confirmed complete response (CR) or partial response (PR) by RECIST v1.1 and modified RECIST
    End point type
    Secondary
    End point timeframe
    Average of 4 years
    Notes
    [14] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B
    Number of subjects analysed
    10
    10
    Units: Number
        Complete Response
    2
    1
        Partial response
    4
    1
        Stable disease
    4
    7
        Progressive disease
    0
    1
        Not evaluable
    0
    0
        ORR=Complete Response (CR) + Partial Response (PR)
    6
    6
    No statistical analyses for this end point

    Secondary: Summary of Investigator-Assessed Best Confirmed Response for Cohort A and B (RECIST 1.1 Criteria): Clinical Benefit Rate (CBR)

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    End point title
    		 Summary of Investigator-Assessed Best Confirmed Response for Cohort A and B (RECIST 1.1 Criteria): Clinical Benefit Rate (CBR) [15]
    End point description
    Clinical benefit rate is defined as a confirmed response of Complete Response (CR) or Partial Response (PR) or at least 6-months Stable Disease (SD) by RECIST v1.1 and modified RECIST.
    End point type
    Secondary
    End point timeframe
    Average of 4 years
    Notes
    [15] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B
    Number of subjects analysed
    10
    10
    Units: Number
        CBR: CR or PR with at least 6 months of SD
    6
    6
    No statistical analyses for this end point

    Secondary: Summary of Progression-free survival rate at 18 months (PFSR18) for Cohorts A and B (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria)

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    End point title
    		 Summary of Progression-free survival rate at 18 months (PFSR18) for Cohorts A and B (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria) [16]
    End point description
    Duration of response is defined for all subjects with confirmed Complete Response or Partial Response (as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first) by RECIST1.1 and modified RECIST 1.1 Criteria
    End point type
    Secondary
    End point timeframe
    18 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B
    Number of subjects analysed
    10
    10
    Units: Number
    median (full range (min-max))
        18 months PFS rate : RECIST 1.1 Criteria
    0.56 (0.22 to 0.96)
    0.88 (0.28 to 0.99)
        18 months PFS rate: modified RECIST 1.1 Criteria
    0.56 (0.22 to 0.96)
    0.88 (0.28 to 0.99)
    No statistical analyses for this end point

    Secondary: Summary of Progression-free survival rate at 18 months (PFSR18) for Cohort C (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria)

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    End point title
    		 Summary of Progression-free survival rate at 18 months (PFSR18) for Cohort C (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria) [17]
    End point description
    Duration of response is defined for all subjects with confirmed Complete Response or Partial Response (as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first) by RECIST1.1 and modified RECIST 1.1 Criteria
    End point type
    Secondary
    End point timeframe
    18 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort C
    Number of subjects analysed
    11
    Units: Number
    median (full range (min-max))
        Pazo + Pembro (N=6) RECIST 1.1 criteria
    0.20 (0.01 to 0.72)
        Pembrolizumab (N=4) RECIST 1.1 criteria
    0.50 (0.16 to 1.00)
        Pazopanib (N=11) RECIST 1.1 criteria
    1.00 (0.72 to 1.00)
        Pazo + Pembro (N=6) modified RECIST 1.1 criteria
    0.20 (0.01 to 0.72)
        Pembrolizumab (N=4)modified RECIST 1.1 criteria
    0.50 (0.16 to 1.00)
        Pazopanib (N=11) modified RECIST 1.1 criteria
    1.00 (0.72 to 1.00)
    No statistical analyses for this end point

    Secondary: Time to response in Months for Cohorts A and B (RECIST 1.1 Criteria)

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    End point title
    		 Time to response in Months for Cohorts A and B (RECIST 1.1 Criteria) [18]
    End point description
    Time to response is defined for all subjects with a confirmed Complete Response (CR) or Partial Response (PR) as per RECIST v1.1v as the time from randomization until the first documented evidence of CR or PR (whichever status is recorded first)
    End point type
    Secondary
    End point timeframe
    Average of 4 years
    Notes
    [18] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B
    Number of subjects analysed
    10
    10
    Units: Number
        median (full range (min-max))
    2.8 (2.6 to 2.8)
    2.7 (2.6 to 2.8)
    No statistical analyses for this end point

    Secondary: Time to Response in Months for Cohort C (RECIST 1.1 Criteria)

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    End point title
    		 Time to Response in Months for Cohort C (RECIST 1.1 Criteria) [19]
    End point description
    Time to response is defined for all subjects with a confirmed Complete Response (CR) or Partial Response (PR) as per RECIST v1.1v as the time from randomization until the first documented evidence of CR or PR (whichever status is recorded first)
    End point type
    Secondary
    End point timeframe
    Average of 4 years
    Notes
    [19] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort C
    Number of subjects analysed
    12
    Units: Number
    median (full range (min-max))
        Pazo + Pembro (n=2)
    1.6 (1.6 to 1.6)
        Pembrolizumab (n=1)
    1.6 (1.6 to 1.6)
        Pazopanib (n=0)
    0.0 (0.0 to 0.0)
    No statistical analyses for this end point

    Secondary: Duration of response in months for Cohorts A and B (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria)

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    End point title
    		 Duration of response in months for Cohorts A and B (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria) [20]
    End point description
    Duration of response is defined for all subjects with confirmed Complete Response (CR) or Partial Response (PR) as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first by RECIST v1.1 and modified RECIST
    End point type
    Secondary
    End point timeframe
    Average of 4 years
    Notes
    [20] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort A Part 1: Cohort B
    Number of subjects analysed
    6
    2
    Units: Number
        median (full range (min-max))
    20.6 (10.8 to 26.3)
    29.3 (19.6 to 38.9)
    No statistical analyses for this end point

    Secondary: Duration of Response in Months for Cohort C (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria)

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    End point title
    		 Duration of Response in Months for Cohort C (RECIST 1.1 Criteria/modified RECIST 1.1 Criteria) [21]
    End point description
    Duration of response is defined for all subjects with confirmed Complete Response (CR) or Partial Response (PR) as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first by RECIST v1.1 and modified RECIST
    End point type
    Secondary
    End point timeframe
    Average of 4 years
    Notes
    [21] - 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: Statistical analysis not performed for this endpoint.
    End point values
    		 Part 1: Cohort C
    Number of subjects analysed
    12
    Units: Number
    median (full range (min-max))
        Pazo + Pembro (n=2)
    19.5 (14.5 to 24.4)
        Pembrolizumab (n=1)
    28.4 (28.4 to 28.4)
        Pazopanib (n=0)
    0.0 (0.0 to 0.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to approximately maximum duration of 5 years, 2 months.
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Cohort A

    Reporting group title
    Cohort B
    Reporting group description
    		 Cohort B

    Reporting group title
    Cohort C
    Reporting group description
    		 Cohort C

    Serious adverse events
    		 Cohort A Cohort B Cohort C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 10 (60.00%)
    6 / 10 (60.00%)
    7 / 21 (33.33%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 10 (40.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Cohort B Cohort C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    21 / 21 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Hot flush
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Hypertension
         subjects affected / exposed
    3 / 10 (30.00%)
    8 / 10 (80.00%)
    10 / 21 (47.62%)
         occurrences all number
    4
    11
    14
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    4
    Fatigue
         subjects affected / exposed
    4 / 10 (40.00%)
    6 / 10 (60.00%)
    12 / 21 (57.14%)
         occurrences all number
    4
    8
    14
    Feeling jittery
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Ill-defined disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    6
    1
    2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    2
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    4
    3
    Temperature intolerance
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Pelvic discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    5 / 21 (23.81%)
         occurrences all number
    4
    4
    6
    Dysphonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    5 / 21 (23.81%)
         occurrences all number
    3
    2
    6
    Dyspnoea exertional
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Nasal congestion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1
    2
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    3
    Productive cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 10 (60.00%)
    7 / 10 (70.00%)
    10 / 21 (47.62%)
         occurrences all number
    10
    10
    13
    Amylase increased
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 10 (20.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    3
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 10 (70.00%)
    7 / 10 (70.00%)
    9 / 21 (42.86%)
         occurrences all number
    11
    11
    12
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
    9 / 21 (42.86%)
         occurrences all number
    3
    1
    9
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Lipase increased
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 10 (40.00%)
    5 / 21 (23.81%)
         occurrences all number
    13
    7
    5
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    2
    Dysgeusia
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    9 / 21 (42.86%)
         occurrences all number
    2
    3
    10
    Headache
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 10 (40.00%)
    5 / 21 (23.81%)
         occurrences all number
    6
    6
    5
    Lethargy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Neuropathy peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    3
    Sciatica
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus headache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Speech disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal cord compression
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Ocular discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Photopsia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    3
    2
    Constipation
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    4 / 21 (19.05%)
         occurrences all number
    2
    5
    4
    Diarrhoea
         subjects affected / exposed
    6 / 10 (60.00%)
    8 / 10 (80.00%)
    16 / 21 (76.19%)
         occurrences all number
    10
    11
    26
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 10 (40.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    4
    3
    Dyspepsia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Flatulence
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    3
    Haemorrhoids
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    6 / 10 (60.00%)
    3 / 10 (30.00%)
    12 / 21 (57.14%)
         occurrences all number
    7
    4
    17
    Oral pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Pancreatitis acute
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    4
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    5 / 10 (50.00%)
    1 / 10 (10.00%)
    9 / 21 (42.86%)
         occurrences all number
    8
    3
    9
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Alopecia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    3
    0
    Erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Hair colour changes
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 10 (40.00%)
    4 / 21 (19.05%)
         occurrences all number
    1
    4
    4
    Night sweats
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    0
    4
    Photosensitivity reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 10 (40.00%)
    3 / 21 (14.29%)
         occurrences all number
    5
    5
    4
    Pruritus generalised
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    2 / 10 (20.00%)
    5 / 10 (50.00%)
    3 / 21 (14.29%)
         occurrences all number
    2
    7
    3
    Rash macular
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    1
    Skin depigmentation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Skin hypopigmentation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Hypothyroidism
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
    3 / 21 (14.29%)
         occurrences all number
    3
    4
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 10 (40.00%)
    2 / 21 (9.52%)
         occurrences all number
    6
    6
    3
    Arthritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    2
    3
    Bone pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    2
    Limb discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    1
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    6
    2
    2
    Plantar fasciitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Diverticulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Sinusitis
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    8
    4
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    8 / 21 (38.10%)
         occurrences all number
    0
    3
    9
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Gout
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    3
    Hypercalcaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 10 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    4
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2018
    Final Protocol Amendment 6

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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