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    Clinical Trial Results:
    A Phase 2, Open Label Study to Evaluate Safety and Clinical Activity of Avelumab (Bavencio) in Combination With Axitinib (Inlyta) in Patients With Advanced or Metastatic Previously Treated Non-Small Cell Lung Cancer or Treatment naïve cisplatin-ineligible urothelial cancer.

    Summary
    EudraCT number
    		 2017-004345-24
    Trial protocol
    		 HU   ES   PL  
    Global end of trial date
    09 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B9991027
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03472560
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 AVE/ AXI COMBO UC: Other Study ID, AVE/AXI COMBO UC/NSCLC: Other Study ID
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    14 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the Objective Response Rate (ORR) based on Investigator assessment, per Response Evaluation Criteria in Solid Tumors V1.1 (RECIST v1.1) of avelumab in combination with axitinib in subjects with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) who have received at least one prior platinum-containing therapy and in treatment naïve subjects with advanced or metastatic Urothelial Cancer (UC), who are ineligible for cisplatin-containing chemotherapy for their advanced disease.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 56 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    61
    EEA total number of subjects
    20
    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)
    26
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects diagnosed with advanced or metastatic non- small cell lung cancer (NSCLC) and received at least 1 prior platinum-containing therapy or subjects with advanced or metastatic urothelial cancer (UC) and were treatment naive and ineligible for cisplatin-containing chemotherapy for their advanced disease were enrolled.

    Pre-assignment
    Screening details
    		 A total of 104 subjects were screened, out of which 43 subjects failed screening and 61 subjects were enrolled into the study.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NSCLC Avelumab + Axitinib
    Arm description
    		 Subjects with NSCLC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Axitinib 5 mg
    Investigational medicinal product code
    AG-013736
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subject received Axitinib 5 mg twice daily orally

    Investigational medicinal product name
    Avelumab 800mg
    Investigational medicinal product code
    MSB0010718C
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Avelumab 800 mg intravenously every two weeks of each 28-day cycle

    Arm title
    		 UC Avelumab + Axitinib
    Arm description
    		 Subjects with UC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab 800mg
    Investigational medicinal product code
    MSB0010718C
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Avelumab 800 mg intravenously every two weeks of each 28-day cycle

    Investigational medicinal product name
    Axitinib 5 mg
    Investigational medicinal product code
    AG-013736
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subject received Axitinib 5 mg twice daily orally

    Number of subjects in period 1
    		NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Started
    41
    20
    Completed
    0
    0
    Not completed
    41
    20
         Adverse event, serious fatal
    7
    4
         Physician decision
    1
    -
         Consent withdrawn by subject
    4
    -
         Global deterioration of health status
    -
    4
         Adverse event, non-fatal
    5
    3
         Subject transfer to continuation protocol
    -
    1
         Progressive disease
    24
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NSCLC Avelumab + Axitinib
    Reporting group description
    		 Subjects with NSCLC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.

    Reporting group title
    UC Avelumab + Axitinib
    Reporting group description
    		 Subjects with UC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.

    Reporting group values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib Total
    Number of subjects
    		 41 20 61
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 22 4 26
        From 65-84 years
    		 19 16 35
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.0 ( 8.93 ) 70.7 ( 8.66 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 11 8 19
        Male
    		 30 12 42
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 21 1 22
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 20 17 37
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 2 3
        Not Hispanic or Latino
    		 40 17 57
        Unknown or Not Reported
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    NSCLC Avelumab + Axitinib
    Reporting group description
    		 Subjects with NSCLC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.

    Reporting group title
    UC Avelumab + Axitinib
    Reporting group description
    		 Subjects with UC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.

    Primary: Percentage of Subjects With Confirmed Objective Response- Objective Response Rate (ORR)

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response- Objective Response Rate (ORR) [1]
    End point description
    ORR: Percentage of subjects with confirmed Complete Response (CR)/Partial Response (PR) based on investigator’s assessment as per Response Evaluation Criteria in Solid Tumours (RECIST v1.1). CR and PR were confirmed by repeat assessments performed no less than 4 weeks after criteria for response first met. CR:complete disappearance of all target(T) lesions, non-target(NT) disease, with exception of nodal disease. All nodes,T and NT, must decrease to normal(short axis less than [<]10 millimeter [mm]). No new lesions. PR: greater than or equal to (>=)30% decrease under baseline of sum of diameters of all T lesions. Short axis was used in sum for T nodes, while longest diameter was used in sum for all other T lesions. No unequivocal progression of NT disease. No new lesions. Stable disease=not qualifying for CR, PR, progressive disease. Full Analysis Set=subjects who received at least one dose of avelumab and axitinib. Subjects were classified according to the study treatment received.
    End point type
    Primary
    End point timeframe
    Baseline up to 56 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    20
    Units: Percentage of subjects
        number (confidence interval 95%)
    31.7 (18.1 to 48.1)
    10.0 (1.2 to 31.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Hematology Test Results of Maximum National Cancer Institute; Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade During the On-Treatment Period

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    End point title
    		 Percentage of Subjects With Hematology Test Results of Maximum National Cancer Institute; Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade During the On-Treatment Period
    End point description
    The following hematology parameters were assessed: anemia, hemoglobin increased, international normalized ratio (INR) increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE version 4.03 (grade 3= severe and grade 4= life-threatening). Categories with non-zero values are presented. Safety analysis set included all subjects who received at least one dose of study drug (avelumab or axitinib). Subjects were classified according to the study treatment received. Here 'Overall Number of Subjects Analyzed' signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    18
    Units: Percentage of subjects
    number (not applicable)
        Lymphocyte count decreased (Grade >=3)
    12.2
    5.6
        Neutrophil count decreased (Grade >=3)
    2.4
    0
        Platelet count decreased (Grade >=3)
    0
    5.6
        White blood cell decreased (Grade >=3)
    2.4
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) During the On-Treatment Period

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    End point title
    		 Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) During the On-Treatment Period
    End point description
    An Adverse Event (AE) was any untoward medical occurrence attributed to study drug in a subject who received avelumab or axitinib. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period (the time from the first dose of study treatment through minimum 30 days post last dose of study treatment or start day of new anti-cancer treatment -1 day). Safety analysis set included all subjects who received at least one dose of study drug (avelumab or axitinib). Subjects were classified according to the study treatment received.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    20
    Units: Percentage of subjects
        number (not applicable)
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Chemistry Test Results of Maximum CTCAE Grade During the On-Treatment Period

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    End point title
    		 Percentage of Subjects With Chemistry Test Results of Maximum CTCAE Grade During the On-Treatment Period
    End point description
    The following chemistry parameters were assessed: alanine aminotransferase(ALT) increased, alkaline phosphatase(ALP) increased, aspartate aminotransferase(AST) increased, blood bilirubin increased, cholesterol high, creatine phosphokinase (CPK) increased, creatinine increased, gamma-glutamyl transferase (GGT) increased, hypercalcaemia, hyperglycaemia, hyperkalaemia, hypermagnesemia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypocalcaemia, hypoglycaemia, hypokalaemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased and serum amylase increased. Laboratory abnormalities were graded according CTCAE version 4.03; Grade(G) 3= severe, G4= life-threatening and G5= death related. Categories with non-zero values are presented. Safety analysis set. Subjects were classified according to the study treatment received. Overall Number of Subjects Analyzed =subjects evaluable for this outcome measure. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    18
    Units: Percentage of subjects
    number (not applicable)
        ALT increased Grade 3 (n=41,18)
    7.3
    5.6
        ALP increased Grade 3 (n=41,18)
    2.4
    11.1
        AST increased Grade 3 (n=41,18)
    2.4
    5.6
        Blood bilirubin increased Grade 3 (n=41,18)
    2.4
    0
        Creatinine increased Grade 3 (n=41,18)
    2.4
    5.6
        GGT increased Grade 3 (n=40,16)
    7.5
    18.8
        Hyperglycemia Grade 3 (n=41,18)
    4.9
    5.6
        Hyperglycemia Grade 4 (n=41,18)
    2.4
    0
        Hyperkalemia Grade 3 (n=41,18)
    7.3
    0
        Hypermagnesemia Grade 3 (n=41,18)
    2.4
    0
        Hypermagnesemia Grade 4 (n=41,18)
    0
    5.6
        Hypoalbuminemia Grade 3 (n=41,18)
    0
    5.6
        Hypocalcemia Grade 3 (n=41,18)
    4.9
    5.6
        Hypoglycemia Grade 4 (n=41,18)
    2.4
    0
        Hypokalemia Grade 3 (n=41,18)
    4.9
    0
        Hypomagnesemia Grade 3 (n=41,18)
    2.4
    0
        Hypomagnesemia Grade 4 (n=41,18)
    2.4
    0
        Hyponatremia Grade 3 (n=41,18)
    9.8
    16.7
        Hyponatremia Grade 4 (n=41,18)
    2.4
    0
        Hypophosphatemia Grade 3 (n=41,18)
    4.9
    5.6
        Lipase increased Grade 3 (n=39,16)
    10.3
    6.3
        Lipase increased Grade 4 (n=39,16)
    2.6
    6.3
        Serum amylase increase Grade 3 (n=40,16)
    2.5
    12.5
    No statistical analyses for this end point

    Secondary: Time to Tumor Response (TTR) in Subjects With Confirmed CR or PR

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    End point title
    		 Time to Tumor Response (TTR) in Subjects With Confirmed CR or PR
    End point description
    TTR was defined as the time from the first dose of study treatment to the first documentation of objective tumor response documented in subjects with confirmed objective response (CR or PR). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Analysis was performed using Kaplan-Meier method. Full Analysis Set was used. Subjects were classified according to the study treatment received. Here, ‘Overall Number of subjects Analyzed = subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From date of start of treatment until date of first documentation of objective tumor response (maximum up to 56 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    13
    2
    Units: Months
        median (confidence interval 95%)
    1.9 (1.8 to 5.3)
    2.8 (1.3 to 3.7)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from first dose of study treatment (ie, start date) to the date of progression of disease (PD) by RECIST v 1.1 or death due to any cause, whichever occurred first. PFS data was censored on the date of the last adequate tumor assessment for subjects without an event (PD or death), for subjects who started new anti-cancer treatment prior to an event, or for subjects with an event after two or more missing tumor assessments. PD as per RECIST v1.1 for target lesions was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. For non-target lesions PD was defined as unequivocal progression of pre-existing lesions. Analysis was performed using Kaplan-Meier method. Full Analysis Set was used. Subjects were classified according to the study treatment received.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 24 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    20
    Units: Months
        median (confidence interval 95%)
    5.5 (2.5 to 7.0)
    2.3 (1.8 to 5.6)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Subjects last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. Full Analysis Set included all subjects who received at least one dose of avelumab and axitinib. Subjects were classified according to the study treatment actually received.
    End point type
    Secondary
    End point timeframe
    From date of start of study treatment until date of death or censoring date (maximum up to 56 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    20
    Units: Months
        median (confidence interval 95%)
    15.4 (8.0 to 26.9)
    16.8 (2.3 to 35.4)
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Avelumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Avelumab
    End point description
    The Pharmacokinetic (PK) parameter analysis set is a subset of the safety analysis set and included all subjects who have at least one of the PK parameters of interest for avelumab or axitinib. Here, 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour post-dose on Cycle 1 Day 1, Day 15 and Cycle 2 Day 1
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    35
    15
    Units: Nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1: Day 1 (n=35,12)
    235.0 ( 26 )
    206.3 ( 27 )
        Cycle 1: Day 15 (n=32,15)
    264.0 ( 34 )
    163.9 ( 211 )
        Cycle 2: Day 1 (n=29,15)
    283.2 ( 24 )
    260.4 ( 25 )
    No statistical analyses for this end point

    Secondary: Duration of Response in Subjects With Confirmed CR or PR

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    End point title
    		 Duration of Response in Subjects With Confirmed CR or PR
    End point description
    Duration of response (DOR) was defined as time from first documentation of objective tumor response to first documentation of objective tumor progression or to death due to any cause, whichever occurred first in subjects with confirmed objective response (CR or PR). CR=complete disappearance of all target (T) lesions and non-target (NT) disease, with the exception of nodal disease. All nodes, both T and NT, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Analysis was performed using Kaplan-Meier method. Full analysis set was used. Subjects were classified according to the study treatment received. Overall Number of subjects Analyzed = subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From date of first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first (maximum up to 56 months)
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    13
    2
    Units: Months
        median (confidence interval 95%)
    7.5 (3.7 to 15.5)
    17.4 (5.6 to 29.2)
    No statistical analyses for this end point

    Secondary: Cmax of Axitinib

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    End point title
    		 Cmax of Axitinib
    End point description
    PK parameter analysis set is a subset of the safety analysis set and included all subjects who have at least one of the PK parameters of interest for avelumab or axitinib. Here, 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 2 hour post-dose on Cycle 1 Day 15, Cycle 2 Day 1 and 15
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    16
    5
    Units: Nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1: Day 15 (n=12,5)
    17.29 ( 198 )
    14.64 ( 448 )
        Cycle 2: Day 1 (n=16,3)
    16.46 ( 91 )
    5.206 ( 448 )
        Cycle 2: Day 15 (n=10,4)
    10.64 ( 223 )
    2.868 ( 24 )
    No statistical analyses for this end point

    Secondary: Pre-dose Observed Serum Concentration (Ctrough) of Avelumab

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    End point title
    		 Pre-dose Observed Serum Concentration (Ctrough) of Avelumab
    End point description
    PK parameter analysis set is a subset of the safety analysis set and included all subjects who have at least one of the PK parameters of interest for avelumab or axitinib. Here, 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Cycle 1 Day 1, 15, Cycle 2 Day 1, Cycle 3 Day 15, Cycle 6 Day 15, Cycle 9 Day 15, and Cycle 12 Day 15
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    39
    19
    Units: Nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1: Day 1 (n=38,19)
    0 ( 0 )
    0 ( 0 )
        Cycle 1: Day 15 (n=39,18)
    19.46 ( 80 )
    18.84 ( 101 )
        Cycle 2: Day 1 (n=32,17)
    20.96 ( 119 )
    19.62 ( 91 )
        Cycle 3: Day 15 (n=21,9)
    28.22 ( 55 )
    39.29 ( 36 )
        Cycle 6: Day 15 (n=17,6)
    29.68 ( 52 )
    43.30 ( 57 )
        Cycle 9: Day 15 (n=12,3)
    32.84 ( 29 )
    42.41 ( 47 )
        Cycle 12: Day 15 (n=6,3)
    36.71 ( 50 )
    39.01 ( 20 )
    No statistical analyses for this end point

    Secondary: Ctrough of Axitinib

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    End point title
    		 Ctrough of Axitinib
    End point description
    PK parameter analysis set is a subset of the safety analysis set and included all subjects who have at least one of the PK parameters of interest for avelumab or axitinib. Here, 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Cycle 1 Day 15, Cycle 2 Day 1 and 15
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    29
    14
    Units: Nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1: Day 15 (n=29,12)
    7.923 ( 127 )
    4.613 ( 231 )
        Cycle 2: Day 1 (n=28,14)
    8.871 ( 123 )
    5.247 ( 172 )
        Cycle 2: Day 15 (n=23,12)
    6.455 ( 129 )
    3.944 ( 172 )
    No statistical analyses for this end point

    Secondary: T-cell Receptor (TCR) Sequencing to Identify Fraction Productive of Cells, Simpson Clonality, Total T Cells

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    End point title
    		 T-cell Receptor (TCR) Sequencing to Identify Fraction Productive of Cells, Simpson Clonality, Total T Cells
    End point description
    The immune response was measured by total TCR sequencing in peripheral blood. It is used to determine the fraction productive of cells, simpson clonality and total number of T Cells for the characterization of immune repertoires. Fraction productive of cells is defined as the number of T cells within the total nucleated cell count (T cells and non-T cells). Simpson clonality is calculated for a sample as the square root of Simpson’s diversity index for all productive rearrangements. Values for clonality range from 0 to 1. Values near 1 represent samples with one or a few predominant rearrangements (monoclonal or oligoclonal samples) dominating the observed repertoire. Clonality values near 0 represent more polyclonal samples. Biomarker analysis set was used. Here 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    15
    10
    Units: Number
    arithmetic mean (standard deviation)
        Fraction Productive of Cells
    0.2 ( 0.17 )
    0.1 ( 0.08 )
        Simpson Clonality
    0.1 ( 0.04 )
    0.1 ( 0.03 )
        Total T Cells
    1623.7 ( 1971.39 )
    1168.4 ( 1450.51 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Programmed Death-Ligand 1 (PD-L1) Status

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    End point title
    		 Number of Subjects With Programmed Death-Ligand 1 (PD-L1) Status
    End point description
    PD-L1 status was defined as positive when PD-L1 staining of any intensity was observed in >= 1% of the tumor cells. PD-L1 status was defined as negative when PD-L1 staining of any intensity was observed in < 1% of the tumor cells. Biomarker analysis set is a subset of the safety analysis set and included subjects who had at least one baseline biomarker assessment. Analysis sets was defined separately for blood-based and tumor tissue-based biomarkers. Here 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    32
    16
    Units: Subjects
        PD-L1 positive
    8
    5
        PD-L1 negative
    24
    11
    No statistical analyses for this end point

    Secondary: Tumour Mutational Burden (TMB) in Tumor Tissue

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    End point title
    		 Tumour Mutational Burden (TMB) in Tumor Tissue
    End point description
    Mutational load within tumor tissue was defined as number per megabase of the genome, coding, base substitution, and indel mutations present in the sample. Mutational load was determined in whole blood samples using next generation deoxyribonucleic acid (DNA) sequencing followed by computational analysis. Biomarker analysis set is a subset of the safety analysis set and included subjects who had at least one baseline biomarker assessment. Analysis sets was defined separately for blood-based and tumor tissue-based biomarkers. Here 'Overall Number of subjects Analyzed' signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    24
    15
    Units: Mutations per megabase
        arithmetic mean (standard deviation)
    2.8 ( 2.97 )
    3.7 ( 4.53 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-drug Antibody (ADA) and Neutralizing Antibodies (nAb) Against Avelumab

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    End point title
    		 Number of Subjects With Positive Anti-drug Antibody (ADA) and Neutralizing Antibodies (nAb) Against Avelumab
    End point description
    ADA and nAb positive was defined as presence of at least one positive ADA and nAb sample, respectively. NAb analysis was planned to be conducted for ADA positive samples. Immunogenicity analysis set is a subset of the safety analysis set and included subjects who had at least one ADA assessment collected for avelumab. Here, ‘Number Analyzed’ signifies number of subjects evaluable for the specified rows. Here, 99999 indicates due to low observed rate of the treatment-induced immunogenicity responses, none of the ADA positive samples was tested for the NAb assay.
    End point type
    Secondary
    End point timeframe
    2 hours pre-dose on Cycle 1 Day 1,15, Cycle 2 Day 1; Day 15 of Cycle 3, 6, 9, 12, end of treatment and 30 days after last dose of study treatment
    End point values
    		 NSCLC Avelumab + Axitinib UC Avelumab + Axitinib
    Number of subjects analysed
    41
    20
    Units: Subjects
        ADA ever-Positive (n=41,20)
    7
    0
        nAb ever-Positive (n=0,0)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)
    Adverse event reporting additional description
    Same event may appear as both non-SAE and SAE but are distinct events. An event may be categorised as serious in 1 subject and non-serious in another, or a subject may have experienced both SAE and non-SAE.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    UC Avelumab + Axitinib
    Reporting group description
    		 Subjects with UC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.

    Reporting group title
    NSCLC Avelumab + Axitinib
    Reporting group description
    		 Subjects with NSCLC received avelumab 800 mg intravenous dose every two weeks, (Day 1 and 15) of each 28-day cycle in combination with axitinib 5 mg twice daily dose on a continuous dosing schedule.

    Serious adverse events
    		 UC Avelumab + Axitinib NSCLC Avelumab + Axitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 20 (55.00%)
    21 / 41 (51.22%)
         number of deaths (all causes)
    11
    27
         number of deaths resulting from adverse events
    1
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 20 (15.00%)
    4 / 41 (9.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pyrexia
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Liver function test increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac dysfunction
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatobiliary disorders
    Hepatobiliary disease
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infectious pleural effusion
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 UC Avelumab + Axitinib NSCLC Avelumab + Axitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 20 (85.00%)
    41 / 41 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Hypertensive crisis
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    4
    Hypertension
         subjects affected / exposed
    4 / 20 (20.00%)
    17 / 41 (41.46%)
         occurrences all number
    7
    32
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 20 (25.00%)
    9 / 41 (21.95%)
         occurrences all number
    8
    17
    General physical health deterioration
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    2 / 20 (10.00%)
    4 / 41 (9.76%)
         occurrences all number
    2
    4
    Asthenia
         subjects affected / exposed
    5 / 20 (25.00%)
    7 / 41 (17.07%)
         occurrences all number
    6
    7
    Chills
         subjects affected / exposed
    1 / 20 (5.00%)
    7 / 41 (17.07%)
         occurrences all number
    1
    8
    Pyrexia
         subjects affected / exposed
    0 / 20 (0.00%)
    6 / 41 (14.63%)
         occurrences all number
    0
    8
    Oedema peripheral
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Pain
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Dysphonia
         subjects affected / exposed
    3 / 20 (15.00%)
    6 / 41 (14.63%)
         occurrences all number
    5
    6
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    5 / 41 (12.20%)
         occurrences all number
    3
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Anxiety
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Blood corticotrophin increased
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    5
    Blood bilirubin increased
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 41 (2.44%)
         occurrences all number
    5
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 20 (20.00%)
    8 / 41 (19.51%)
         occurrences all number
    6
    15
    Amylase increased
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 41 (7.32%)
         occurrences all number
    5
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 20 (15.00%)
    9 / 41 (21.95%)
         occurrences all number
    4
    15
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    Weight decreased
         subjects affected / exposed
    6 / 20 (30.00%)
    9 / 41 (21.95%)
         occurrences all number
    7
    17
    Lipase increased
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 41 (7.32%)
         occurrences all number
    7
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 20 (20.00%)
    3 / 41 (7.32%)
         occurrences all number
    6
    5
    C-reactive protein increased
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    6
    Blood triglycerides increased
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 20 (0.00%)
    6 / 41 (14.63%)
         occurrences all number
    0
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 41 (9.76%)
         occurrences all number
    1
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 20 (15.00%)
    4 / 41 (9.76%)
         occurrences all number
    4
    7
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    4
    Dysphagia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    4 / 20 (20.00%)
    8 / 41 (19.51%)
         occurrences all number
    6
    8
    Stomatitis
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 41 (9.76%)
         occurrences all number
    2
    5
    Diarrhoea
         subjects affected / exposed
    3 / 20 (15.00%)
    12 / 41 (29.27%)
         occurrences all number
    7
    43
    Constipation
         subjects affected / exposed
    2 / 20 (10.00%)
    7 / 41 (17.07%)
         occurrences all number
    2
    7
    Abdominal pain upper
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 41 (9.76%)
         occurrences all number
    1
    5
    Abdominal pain
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    2 / 20 (10.00%)
    4 / 41 (9.76%)
         occurrences all number
    3
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    7 / 41 (17.07%)
         occurrences all number
    1
    10
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 20 (10.00%)
    6 / 41 (14.63%)
         occurrences all number
    11
    15
    Dry skin
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 20 (10.00%)
    4 / 41 (9.76%)
         occurrences all number
    4
    31
    Haematuria
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 20 (5.00%)
    5 / 41 (12.20%)
         occurrences all number
    1
    6
    Hypothyroidism
         subjects affected / exposed
    1 / 20 (5.00%)
    13 / 41 (31.71%)
         occurrences all number
    1
    15
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 41 (4.88%)
         occurrences all number
    3
    4
    Arthralgia
         subjects affected / exposed
    3 / 20 (15.00%)
    6 / 41 (14.63%)
         occurrences all number
    6
    9
    Myalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    4
    Pain in extremity
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 41 (7.32%)
         occurrences all number
    4
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 41 (2.44%)
         occurrences all number
    9
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 41 (2.44%)
         occurrences all number
    9
    1
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 41 (0.00%)
         occurrences all number
    8
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 20 (10.00%)
    4 / 41 (9.76%)
         occurrences all number
    4
    5
    Hypermagnesaemia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    6
    Decreased appetite
         subjects affected / exposed
    5 / 20 (25.00%)
    14 / 41 (34.15%)
         occurrences all number
    6
    23

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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