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    Clinical Trial Results:
    An Open-Label, Multi-Centre, Global Study to Evaluate Long Term Safety and Efficacy in Patients Who are Receiving or Who Previously Received Durvalumab in Other Protocols (WAVE)

    Summary
    EudraCT number
    		 2019-001402-20
    Trial protocol
    		 NL   FR   DE   HU   PL   ES   GR   BE   BG   IT   RO  
    Global end of trial date
    30 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2025
    First version publication date
    10 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D910FC00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04078152
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Karlebyhusentren, B674 Astraallen, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca AB, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca AB, +1 877-240-9479, information.center@astrazeneca.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
    31 Oct 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To monitor long-term safety of durvalumab (all cohorts)
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Sep 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 37 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    Türkiye: 2
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Viet Nam: 1
    Worldwide total number of subjects
    163
    EEA total number of subjects
    43
    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)
    74
    From 65 to 84 years
    86
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase IV, open-label study was conducted at 112 investigational sites across 31 countries in participants who were receiving durvalumab monotherapy and/or those who previously received durvalumab as a monotherapy or in combination with any other approved or investigational anticancer agent in previously enrolled parent study.

    Pre-assignment
    Screening details
    		 A total of 163 participants were enrolled in this study.

    Period 1
    Period 1 title
    Overall Study (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
    		 Cohort 1: Durvalumab Continuation
    Arm description
    		 Cohort 1 included participants who had received durvalumab monotherapy or durvalumab combination therapy under the parent clinical study (including those who underwent retreatment per the parent study) who had not clinically progressed and who were eligible to continue durvalumab treatment after completing dosing of all other anticancer agents, including other investigational agents. Participants received durvalumab monotherapy 1500 milligrams (mg) via intravenous (IV) infusion every 4 weeks on Day 1 of each cycle until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab was supplied as a 500 mg vial solution for infusion after dilution, and it was administered as 1500 mg IV every 4 weeks until protocol-specified discontinuation criteria was met.

    Arm title
    		 Cohort 2: Durvalumab Restart
    Arm description
    		 Cohort 2 included participants who had completed durvalumab monotherapy or combination therapy with any other approved or investigational anticancer agents in a parent study, without confirmed PD during the period of treatment, and who were potentially eligible for retreatment with durvalumab. Participants received durvalumab monotherapy 1500 mg via IV infusion every 4 weeks on Day 1 of each cycle until confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab was supplied as a 500 mg vial solution for infusion after dilution, and it was administered as 1500 mg IV every 4 weeks until protocol-specified discontinuation criteria was met.

    Arm title
    		 Cohort 3: No Restart of Durvalumab
    Arm description
    		 Cohort 3 included participants previously treated with durvalumab monotherapy or in combination with any other approved or investigational anticancer agents who were no longer receiving durvalumab and were not eligible to receive retreatment. Participants did not receive any study drug.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Cohort 1: Durvalumab Continuation Cohort 2: Durvalumab Restart Cohort 3: No Restart of Durvalumab
    Started
    100
    25
    38
    Treated in WAVE/90 days within enrolment
    100
    7
    2
    Completed
    0
    0
    0
    Not completed
    100
    25
    38
         Consent withdrawn by subject
    5
    -
    1
         Adverse event, non-fatal
    1
    -
    -
         Death
    10
    2
    12
         Development of study specific withdrawal criteria
    1
    1
    -
         Unspecified
    83
    22
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Durvalumab Continuation
    Reporting group description
    		 Cohort 1 included participants who had received durvalumab monotherapy or durvalumab combination therapy under the parent clinical study (including those who underwent retreatment per the parent study) who had not clinically progressed and who were eligible to continue durvalumab treatment after completing dosing of all other anticancer agents, including other investigational agents. Participants received durvalumab monotherapy 1500 milligrams (mg) via intravenous (IV) infusion every 4 weeks on Day 1 of each cycle until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 2: Durvalumab Restart
    Reporting group description
    		 Cohort 2 included participants who had completed durvalumab monotherapy or combination therapy with any other approved or investigational anticancer agents in a parent study, without confirmed PD during the period of treatment, and who were potentially eligible for retreatment with durvalumab. Participants received durvalumab monotherapy 1500 mg via IV infusion every 4 weeks on Day 1 of each cycle until confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 3: No Restart of Durvalumab
    Reporting group description
    		 Cohort 3 included participants previously treated with durvalumab monotherapy or in combination with any other approved or investigational anticancer agents who were no longer receiving durvalumab and were not eligible to receive retreatment. Participants did not receive any study drug.

    Reporting group values
    		 Cohort 1: Durvalumab Continuation Cohort 2: Durvalumab Restart Cohort 3: No Restart of Durvalumab Total
    Number of subjects
    		 100 25 38 163
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.5 ( 10.31 ) 66.4 ( 9.30 ) 66.1 ( 9.95 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 18 7 16 41
        Male
    		 82 18 22 122
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 75 16 21 112
        Black or African American
    		 0 1 1 2
        Asian
    		 25 8 16 49
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 9 0 0 9
        Not Hispanic or Latino
    		 91 23 37 151
        Missing
    		 0 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Durvalumab Continuation
    Reporting group description
    		 Cohort 1 included participants who had received durvalumab monotherapy or durvalumab combination therapy under the parent clinical study (including those who underwent retreatment per the parent study) who had not clinically progressed and who were eligible to continue durvalumab treatment after completing dosing of all other anticancer agents, including other investigational agents. Participants received durvalumab monotherapy 1500 milligrams (mg) via intravenous (IV) infusion every 4 weeks on Day 1 of each cycle until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 2: Durvalumab Restart
    Reporting group description
    		 Cohort 2 included participants who had completed durvalumab monotherapy or combination therapy with any other approved or investigational anticancer agents in a parent study, without confirmed PD during the period of treatment, and who were potentially eligible for retreatment with durvalumab. Participants received durvalumab monotherapy 1500 mg via IV infusion every 4 weeks on Day 1 of each cycle until confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 3: No Restart of Durvalumab
    Reporting group description
    		 Cohort 3 included participants previously treated with durvalumab monotherapy or in combination with any other approved or investigational anticancer agents who were no longer receiving durvalumab and were not eligible to receive retreatment. Participants did not receive any study drug.

    Primary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE: Development of any untoward medical occurrence (other than progression of malignancy under evaluation) in participant or clinical study participant administered a medicinal product which did not necessarily have a causal relationship with this treatment. SAE:AE occurring during any study phase fulfilling 1 or more of following: resulted in death; was immediately life-threatening; required in-patient hospitalization/prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; was a congenital abnormality or birth defect; was an important medical event that jeopardized participant/required medical treatment to prevent 1 of the outcomes listed above. The Safety analysis set included those participants who received at least 1 dose of durvalumab in this study or enrolled in this study within 90 days of last dose of durvalumab or durvalumab combination in the respective parent clinical study. Data from this study only, not parent study.
    End point type
    Primary
    End point timeframe
    From the time of signing the informed consent form until the follow-up period is completed (90 days after the last dose of durvalumab); approximately 37 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: As the endpoint is descriptive in nature, no statistical analysis is presented,
    End point values
    		 Cohort 1: Durvalumab Continuation Cohort 2: Durvalumab Restart Cohort 3: No Restart of Durvalumab
    Number of subjects analysed
    100
    7
    2
    Units: participants
        Any AEs
    85
    1
    0
        Any SAEs
    23
    0
    0
    No statistical analyses for this end point

    Secondary: Cohort 2: Duration of Response (DOR)

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    End point title
    		 Cohort 2: Duration of Response (DOR) [2]
    End point description
    The DOR was defined as the time from first documented CR or PR to time of first documented disease progression or death in the absence of disease progression. Tumor assessments were performed according to RECIST v1.1. The Response evaluable analysis set included those participants who underwent retreatment with durvalumab in Cohort 2. 99999 signifies 'Not Applicable'. As no participant in the response evaluable analysis set was assessed to have had either CR or PR, the DOR analysis was not applicable.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as determined by the Investigator (at least every 12 weeks) until withdrawal of consent, progression or death; approximately 30 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is presented,
    End point values
    		 Cohort 2: Durvalumab Restart
    Number of subjects analysed
    2
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants who Were Alive

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    End point title
    		 Number of Participants who Were Alive
    End point description
    Number of participants who were alive are reported in this outcome measure. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. The Full analysis set included all participants enrolled in the study, regardless of the treatment received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 37 months
    End point values
    		 Cohort 1: Durvalumab Continuation Cohort 2: Durvalumab Restart Cohort 3: No Restart of Durvalumab
    Number of subjects analysed
    100
    25
    38
    Units: participants
    90
    23
    26
    No statistical analyses for this end point

    Secondary: Cohort 2: Overall Response Rate (ORR)

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    End point title
    		 Cohort 2: Overall Response Rate (ORR) [3]
    End point description
    The ORR was defined as the percentage of participants with a confirmed investigator-assessed response of either complete response (CR) or partial response (PR) from the date of re-initiation of treatment with durvalumab monotherapy. Tumor assessments were performed according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions (TLs) since baseline and reduction in short axis diameter to <10 millimeters (mm) for any pathological lymph nodes selected as TLs. PR was defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameter. The Response evaluable analysis set included those participants who underwent retreatment with durvalumab in Cohort 2.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as determined by the Investigator (at least every 12 weeks) until withdrawal of consent, progression or death; approximately 30 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As the endpoint is descriAs the endpoint is descriptive in nature, no statistical analysis is presented,ptive in nature, no statistical analysis is presented,
    End point values
    		 Cohort 2: Durvalumab Restart
    Number of subjects analysed
    2
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 84)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of signing the informed consent form until the follow-up period is completed (90 days after the last dose of durvalumab); approximately 37 months
    Adverse event reporting additional description
    The Safety analysis set included those participants who received at least 1 dose of durvalumab on this study or enrolled on this study within 90 days of the last dose of durvalumab or durvalumab combination on the respective parent clinical study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Cohort 1 included participants who had received durvalumab monotherapy or durvalumab combination therapy under the parent clinical study (including those who underwent retreatment per the parent study) who had not clinically progressed and who were eligible to continue durvalumab treatment after completing dosing of all other anticancer agents, including other investigational agents. Participants received durvalumab monotherapy 1500 mg via IV infusion every 4 weeks on Day 1 of each cycle until confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Cohort 3 included participants previously treated with durvalumab monotherapy or in combination with any other approved or investigational anticancer agents who were no longer receiving durvalumab and were not eligible to receive retreatment. Participants did not receive any study drug.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cohort 2 included participants who had completed durvalumab monotherapy or combination therapy with any other approved or investigational anticancer agents in a parent study, without confirmed PD during the period of treatment, and who were potentially eligible for retreatment with durvalumab. Participants received durvalumab monotherapy 1500 mg via IV infusion every 4 weeks on Day 1 of each cycle until confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Serious adverse events
    		 Cohort 1 Cohort 3 Cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 100 (23.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    10
    1
    0
         number of deaths resulting from adverse events
    4
    0
    0
    Investigations
    Lipase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pemphigoid
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 Cohort 3 Cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 100 (72.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 100 (7.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 100 (11.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    17
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    12
    0
    0
    Lipase increased
         subjects affected / exposed
    7 / 100 (7.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    14
    0
    0
    Amylase increased
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    11
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 100 (11.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    11
    0
    0
    Asthenia
         subjects affected / exposed
    9 / 100 (9.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Pyrexia
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    12
    0
    0
    Neutropenia
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    15
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    8
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    10
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    10
    0
    0
    Rash
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    17 / 100 (17.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    17
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 100 (9.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    11
    0
    0
    Back pain
         subjects affected / exposed
    9 / 100 (9.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    11
    0
    0
    Myalgia
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    Pain in extremity
         subjects affected / exposed
    8 / 100 (8.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    10
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    17 / 100 (17.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    19
    0
    0
    Pneumonia
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    Escherichia infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2019
    An inclusion criterion was added and editorial changes were made in the exclusion criteria. Redundant reference was removed. Appendices were updated.
    25 Sep 2019
    Clarification was provided for study assessments and subsequent anticancer therapy after treatment discontinuation. Details for study assessments and exclusion criteria were updated. Time period for prohibition of live (attenuated) vaccines and information for rescue medications was updated. Updates were made in applicable regulations.
    12 Apr 2022
    Revised that the last patient visit will be completed in quarter 4 of 2022. Updated the sample size limit. Clarification provided for efficacy and safety analysis and concomitant medications. Updates were made in study completion activities. Participant management details after study completion were added.

    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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