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    Clinical Trial Results:
    A Phase II, Multicenter, Open Label Study of Bintrafusp Alfa (M7824) Monotherapy in Participants With Advanced, Unresectable Cervical Cancer With Disease Progression During or After Platinum-Containing Chemotherapy

    Summary
    EudraCT number
    		 2019-003583-40
    Trial protocol
    		 FR   ES   HU   BE  
    Global end of trial date
    14 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Nov 2023
    First version publication date
    03 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MS200647_0017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04246489
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Healthcare KGaA, Darmstadt, Germany
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.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 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to evaluate clinical efficacy and safety of bintrafusp alfa in subjects with advanced, unresectable cervical cancer with disease progression during or after platinum-containing chemotherapy.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Mar 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 23
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    China: 23
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Russian Federation: 4
    Worldwide total number of subjects
    146
    EEA total number of subjects
    37
    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)
    123
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 203 subjects were screened, of which 146 subjects received bintrafusp alfa monotherapy.

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

    Arms
    Arm title
    		 Bintrafusp Alfa
    Arm description
    		 Subjects received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bintrafusp alfa
    Investigational medicinal product code
    Other name
    M7824
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, death, unacceptable toxicity and study withdrawal.

    Number of subjects in period 1
    		Bintrafusp Alfa
    Started
    146
    Completed
    146

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bintrafusp Alfa
    Reporting group description
    		 Subjects received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death.

    Reporting group values
    		 Bintrafusp Alfa Total
    Number of subjects
    		 146 146
    Age categorical
    Units: subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 123 123
        From 65-84 years
    		 23 23
        85 years and over
    		 0 0
    Sex: Female, Male
    Units: subjects
        Female
    		 146 146
        Male
    		 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 11 11
        Not Hispanic or Latino
    		 132 132
        Unknown or Not Reported
    		 3 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 90 90
        Native Hawaiian or Other Pacific Islander
    		 1 1
        Black or African American
    		 1 1
        White
    		 37 37
        More than one race
    		 0 0
        Unknown or Not Reported
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Bintrafusp Alfa
    Reporting group description
    		 Subjects received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death.

    Primary: Number of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)

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    End point title
    		 Number of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) [1]
    End point description
    Confirmed objective response was defined as the number of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by IRC. Full Analysis Set (FAS) included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Primary
    End point timeframe
    Time from first treatment to up to data cutoff up to 688 days
    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 and comparison analysis were performed in single arm for this endpoint.
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146
    Units: subjects
    32
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)

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    End point title
    		 Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)
    End point description
    DOR was defined for subjects with confirmed response, as the time from first documentation of confirmed objective response (Complete Response [CR] or Partial Response [PR]) according to RECIST 1.1 to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. Results were calculated based on Kaplan-Meier estimates. FAS included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Secondary
    End point timeframe
    Time from first documentation of a confirmed objective response up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146 [2]
    Units: months
        median (confidence interval 95%)
    99999 (7.4 to 99999)
    Notes
    [2] - The median was not reached and the upper limit was not estimated. 99999 represents no observation.
    No statistical analyses for this end point

    Secondary: Durable Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)

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    End point title
    		 Durable Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)
    End point description
    Durable Response was defined as the number of subjects with confirmed objective response (CR or PR) according to RECIST 1.1, determined by IRC with duration of at least 6 months. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. FAS included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Secondary
    End point timeframe
    Time from first treatment up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146
    Units: subjects
    19
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs, Including Adverse Event of Special Interests (AESIs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs, Including Adverse Event of Special Interests (AESIs)
    End point description
    Adverse Event (AE) was defined any untoward medical occurrence in a subjects administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention. AESIs included Infusion-related reactions, Immune-related AEs, Transforming growth factor- beta (TGF-ß) inhibition mediated skin AE, bleeding and anemia. Safety analysis set included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Secondary
    End point timeframe
    Time from first treatment up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146
    Units: subjects
        TEAE's
    145
        Treatment Related TEAEs
    106
        AESI: Infusion-related reaction
    5
        AESI: Immune-related AE
    49
        AESI: TGF-beta inhibition mediated skin AE
    7
        AESI: Anemia
    82
        AESI: Bleeding events
    81
    No statistical analyses for this end point

    Secondary: Number of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator

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    End point title
    		 Number of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator
    End point description
    Confirmed objective response was defined as the number of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by Investigator. FAS included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Secondary
    End point timeframe
    Time from first treatment up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146
    Units: subjects
    25
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC)

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    End point title
    		 Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC)
    End point description
    PFS was defined as the time from first administration of study intervention until date of the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Kaplan-Meier estimates was used to calculate PFS. FAS included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Secondary
    End point timeframe
    Time from first administration of study drug until the first documentation of PD or death, assessed up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146
    Units: months
        median (confidence interval 95%)
    1.9 (1.8 to 2.2)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from first administration of study intervention to the date of death due to any cause. The OS was analyzed by using the Kaplan-Meier method. FAS included all subjects who were administered at least one dose of bintrafusp alfa.
    End point type
    Secondary
    End point timeframe
    Time from first administration of study drug up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    146
    Units: months
        median (confidence interval 95%)
    13.7 (10.6 to 17.1)
    No statistical analyses for this end point

    Secondary: Serum Pre-Dose Concentrations (Ctrough) of Bintrafusp Alfa

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    End point title
    		 Serum Pre-Dose Concentrations (Ctrough) of Bintrafusp Alfa
    End point description
    Ctrough was defined as the concentration observed immediately before next dosing (corresponding to pre-dose or trough concentration for multiple dosing). Pharmacokinetic (PK) analysis set included all subjects who completed at least one dose of bintrafusp alfa and who provided at least one sample with a measurable concentration of bintrafusp alfa. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "number analyzed(n)" signifies those subjects who were evaluable at specified time points for this endpoint.
    End point type
    Secondary
    End point timeframe
    At Day 15, Day 29, Day 43, Day 85, Day 127, Day 169, Day 253, Day 337, Day 421, Day 505 and Day 589
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    143
    Units: microgram per milliliter (mcg/mL)
    geometric mean (geometric coefficient of variation)
        Day 15(n=125)
    73.7 ( 55.3 )
        Day 29(n=103)
    107 ( 48.7 )
        Day 43(n=84)
    108 ( 53 )
        Day 85(n=47)
    115 ( 44.9 )
        Day 127(n=35)
    107 ( 69 )
        Day 169(n=25)
    137 ( 41 )
        Day 253(n=12)
    101 ( 45.8 )
        Day 337(n=11)
    120 ( 50.9 )
        Day 421(n=5)
    103 ( 56.4 )
        Day 505(n=4)
    220 ( 22.4 )
        Day 589(n=3)
    154 ( 10.4 )
    No statistical analyses for this end point

    Secondary: Serum Concentration at End of Infusion (CEOI) of Bintrafusp Alfa

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    End point title
    		 Serum Concentration at End of Infusion (CEOI) of Bintrafusp Alfa
    End point description
    Serum Concentration at End of Infusion (CEOI) of bintrafusp alfa is reported. PK analysis set included all subjects who completed at least one dose of Bintrafusp Alfa and who provided at least one sample with a measurable concentration of Bintrafusp Alfa. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "number analyzed(n)" signifies those subjects who were evaluable at specified time points for this endpoint.
    End point type
    Secondary
    End point timeframe
    At Day 1 and Day 29
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    143
    Units: mcg/mL
    geometric mean (geometric coefficient of variation)
        Day 1(n=142)
    469 ( 21.9 )
        Day 29(n=102)
    546 ( 24.1 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Antidrug Antibodies (ADA)

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    End point title
    		 Number of Subjects With Positive Antidrug Antibodies (ADA)
    End point description
    Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of subjects with positive ADA were reported. Immunogenicity analysis set included all subjects who received at least one dose of bintrafusp alfa and who had at least one valid result of ADA.
    End point type
    Secondary
    End point timeframe
    Time from first treatment up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    142
    Units: subjects
    33
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) According to Programmed Death Ligand 1 (PD-L1) Expression

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) According to Programmed Death Ligand 1 (PD-L1) Expression
    End point description
    Confirmed objective response was defined as the percentage of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Subjects with PD-L1 positive tumors (Combined positive score (CPS) >=1) and PD-L1 negative tumors (CPS<1). FAS included all subjects who were administered at least one dose of bintrafusp alfa. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "number analyzed(n)" signifies those subjects who were evaluable at specified categories for this endpoint.
    End point type
    Secondary
    End point timeframe
    Time from first treatment up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    141
    Units: percentage of subjects
    number (confidence interval 95%)
        PD-L1 positive tumors (CPS>=1)(n=86)
    25.6 (16.8 to 36.1)
        PD-L1 negative tumors (CPS <1)(n=55)
    18.2 (9.1 to 30.9)
    No statistical analyses for this end point

    Secondary: PFS According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) According to Programmed Death Ligand 1 (PD-L1) Expression

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    End point title
    		 PFS According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) According to Programmed Death Ligand 1 (PD-L1) Expression
    End point description
    PFS was defined as the time from first administration of study intervention until the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was determined according to RECIST v1.1 and as adjudicated by IRC through PD-L1 Subgroup. Subjects with PD-L1 positive tumors (Combined positive score (CPS) >=1) and PD-L1 negative tumors (CPS<1). FAS included all subjects who were administered at least one dose of bintrafusp alfa. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "number analyzed(n)" signifies those subjects who were evaluable at specified categories for this endpoint.
    End point type
    Secondary
    End point timeframe
    Time from first administration of study drug until the first documentation of PD or death, assessed up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    141
    Units: months
    median (confidence interval 95%)
        PD-L1 positive tumors (CPS>=1)(n=86)
    1.9 (1.8 to 4.3)
        PD-L1 negative tumors (CPS<1)(n=55)
    1.9 (1.7 to 2.0)
    No statistical analyses for this end point

    Secondary: OS as Assessed According to Programmed Death Ligand 1 (PD-L1) Expression

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    End point title
    		 OS as Assessed According to Programmed Death Ligand 1 (PD-L1) Expression
    End point description
    OS was defined as the time from first administration of study intervention to the date of death due to any cause. The OS was analyzed by using the Kaplan-Meier method. Participants with PD-L1 positive tumors (Combined positive score (CPS) >=1) and PD-L1 negative tumors (CPS<1). FAS included all subjects who were administered at least one dose of bintrafusp alfa. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "number analyzed(n)" signifies those subjects who were evaluable at specified categories for this endpoint.
    End point type
    Secondary
    End point timeframe
    Time from first administration of study drug up to 688 days
    End point values
    		 Bintrafusp Alfa
    Number of subjects analysed
    141 [3]
    Units: months
    median (confidence interval 95%)
        PD-L1positive tumors(CPS>=1)(n=86)
    17.5 (12.5 to 99999)
        PD-L1negative tumors(CPS<1)(n=55)
    8.7 (5.8 to 11.8)
    Notes
    [3] - Due to small number of events Upper limit was not derived. 99999 represents no observation.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time from first treatment up to 688 days
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Bintrafusp Alfa
    Reporting group description
    		 Subjects received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death.

    Serious adverse events
    		 Bintrafusp Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    94 / 146 (64.38%)
         number of deaths (all causes)
    76
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    12 / 146 (8.22%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 146 (2.74%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intermenstrual bleeding
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 146 (2.74%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Cystitis radiation
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stoma obstruction
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuritis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy in malignant disease
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    14 / 146 (9.59%)
         occurrences causally related to treatment / all
    4 / 14
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 146 (2.74%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant gastrointestinal obstruction
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive defaecation
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Immune-mediated dermatitis
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 146 (2.05%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    15 / 146 (10.27%)
         occurrences causally related to treatment / all
    6 / 15
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    3 / 146 (2.05%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ureteral polyp
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune-mediated thyroiditis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal fistula infection
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic arthritis streptococcal
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bintrafusp Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 146 (99.32%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    23 / 146 (15.75%)
         occurrences all number
    23
    Fatigue
         subjects affected / exposed
    14 / 146 (9.59%)
         occurrences all number
    14
    Pyrexia
         subjects affected / exposed
    25 / 146 (17.12%)
         occurrences all number
    25
    Oedema peripheral
         subjects affected / exposed
    12 / 146 (8.22%)
         occurrences all number
    12
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    11 / 146 (7.53%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 146 (8.90%)
         occurrences all number
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 146 (7.53%)
         occurrences all number
    11
    Investigations
    Weight decreased
         subjects affected / exposed
    8 / 146 (5.48%)
         occurrences all number
    8
    Lipase increased
         subjects affected / exposed
    10 / 146 (6.85%)
         occurrences all number
    10
    Blood creatinine increased
         subjects affected / exposed
    9 / 146 (6.16%)
         occurrences all number
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 146 (13.01%)
         occurrences all number
    19
    Amylase increased
         subjects affected / exposed
    8 / 146 (5.48%)
         occurrences all number
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    20 / 146 (13.70%)
         occurrences all number
    20
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 146 (6.85%)
         occurrences all number
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 146 (7.53%)
         occurrences all number
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    80 / 146 (54.79%)
         occurrences all number
    80
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    20 / 146 (13.70%)
         occurrences all number
    20
    Stomatitis
         subjects affected / exposed
    10 / 146 (6.85%)
         occurrences all number
    10
    Nausea
         subjects affected / exposed
    30 / 146 (20.55%)
         occurrences all number
    30
    Diarrhoea
         subjects affected / exposed
    12 / 146 (8.22%)
         occurrences all number
    12
    Constipation
         subjects affected / exposed
    22 / 146 (15.07%)
         occurrences all number
    22
    Abdominal pain
         subjects affected / exposed
    12 / 146 (8.22%)
         occurrences all number
    12
    Gingival bleeding
         subjects affected / exposed
    17 / 146 (11.64%)
         occurrences all number
    17
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    17 / 146 (11.64%)
         occurrences all number
    17
    Rash
         subjects affected / exposed
    24 / 146 (16.44%)
         occurrences all number
    24
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    26 / 146 (17.81%)
         occurrences all number
    26
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    10 / 146 (6.85%)
         occurrences all number
    10
    Hypothyroidism
         subjects affected / exposed
    17 / 146 (11.64%)
         occurrences all number
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 146 (5.48%)
         occurrences all number
    8
    Back pain
         subjects affected / exposed
    10 / 146 (6.85%)
         occurrences all number
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    14 / 146 (9.59%)
         occurrences all number
    14
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    15 / 146 (10.27%)
         occurrences all number
    15
    Hypokalaemia
         subjects affected / exposed
    12 / 146 (8.22%)
         occurrences all number
    12
    Hyponatraemia
         subjects affected / exposed
    8 / 146 (5.48%)
         occurrences all number
    8
    Decreased appetite
         subjects affected / exposed
    24 / 146 (16.44%)
         occurrences all number
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2020
    The protocol is being amended to incorporate the main changes to specify and enroll a more homogeneous population (inclusion criterion #2), add contingency plan for the possibility of continued enrollment in China to meet local requirements (if needed), and to reflect the change in patient interview approach to exit interviews only, therewith incorporating regulatory feedback obtained.
    22 Jun 2021
    The primary purpose of this amendment is to update the risk classification. In addition, the primary analysis time point has been moved from 8 months to 12 months after the accrual of the last global subject.

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

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

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