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    Clinical Trial Results:
    A Phase II, Open-Label, Multi-Centre, International Safety Study of Durvalumab Following Sequential Chemotherapy and Radiation Therapy in Patients with Stage III, Unresectable Non-Small Cell Lung Cancer (PACIFIC 6)

    Summary
    EudraCT number
    		 2018-002220-16
    Trial protocol
    		 GB   FR   ES   DE   IT  
    Global end of trial date
    21 Apr 2023

    Results information
    Results version number
    		 v1
    This version publication date
    05 May 2024
    First version publication date
    05 May 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    D4194C00006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03693300
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +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
    16 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability profile of durvalumab (MEDI4736) as defined by Grade 3 and Grade 4 Treatment-related adverse events (TRAEs) within 6 months from the initiation of durvalumab (MEDI4736) treatment.
    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 (ICH) Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics. Written informed consent was obtained before the patient was enrolled in the study, along with the date the written consent was obtained.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Apr 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Spain: 30
    Worldwide total number of subjects
    117
    EEA total number of subjects
    103
    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)
    40
    From 65 to 84 years
    76
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 16 April 2019 to 21 April 2023 at 25 sites in the United States of America (USA), France, Germany, Italy, Spain, and the United Kingdom.

    Pre-assignment
    Screening details
    		 Patients who met all the inclusion and none of the exclusion criteria were included in the study. The screening period was from Day -28 to Day -1. Informed consent form was signed prior to screening procedures.

    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
    		 Durvalumab ECOG PS 0 or 1
    Arm description
    		 Patients received 1500 mg Durvalumab monotherapy via Intravenous (IV) infusion every 4 weeks (q4w).
    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, Intravenous drip use
    Dosage and administration details
    Durvalumab 1500 mg was administered via IV infusion every 4 weeks.

    Arm title
    		 Durvalumab ECOG PS 2
    Arm description
    		 Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.
    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, Intravenous drip use
    Dosage and administration details
    Durvalumab 1500 mg was administered via IV infusion every 4 weeks.

    Number of subjects in period 1
    		Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Started
    114
    3
    Completed
    56
    1
    Not completed
    58
    2
         Adverse event, serious fatal
    50
    2
         Consent withdrawn by subject
    6
    -
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Durvalumab ECOG PS 0 or 1
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via Intravenous (IV) infusion every 4 weeks (q4w).

    Reporting group title
    Durvalumab ECOG PS 2
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Reporting group values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2 Total
    Number of subjects
    		 114 3 117
    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)
    		 39 1 40
        From 65-84 years
    		 74 2 76
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.0 ( 8.46 ) 65.0 ( 12.00 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 43 1 44
        Male
    		 71 2 73
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 101 3 104
        Unknown
    		 13 0 13
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 103 3 106
        Unknown or Not Reported
    		 10 0 10

    End points

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    End points reporting groups
    Reporting group title
    Durvalumab ECOG PS 0 or 1
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via Intravenous (IV) infusion every 4 weeks (q4w).

    Reporting group title
    Durvalumab ECOG PS 2
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Subject analysis set title
    Durvalumab ECOG PS 0 or 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Subject analysis set title
    Durvalumab ECOG PS 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Primary: Number of patients with Grade 3 and Grade 4 Treatment-related adverse events (TRAEs)

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    End point title
    		 Number of patients with Grade 3 and Grade 4 Treatment-related adverse events (TRAEs)
    End point description
    Safety and tolerability of Durvalumab as defined by Grade 3 and Grade 4 TRAEs following IV infusion administration was assessed. The Subject Analysis set was added to report statistical analysis, and this is the only option available in order to accommodate reporting of statistical data for same cohorts. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full). Category A: Any possibly related AEs of CTCAE Grade 3 or Grade 4 Category B: Any possibly related AEs of Grade 3 or Grade 4 with onset date within 6 months of the first dose
    End point type
    Primary
    End point timeframe
    Up to 6 months
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    114
    3
    Units: Participants
        Category A
    7
    0
    7
    0
        Category B
    5
    0
    5
    0
    Statistical analysis title
    		 Proportion and 95% CI for incidence of PRAEs
    Statistical analysis description
    Any possibly related adverse events of CTCAE Grade 3 or Grade 4. 95% CI were based on the Clopper-Pearson method.
    Comparison groups
    Durvalumab ECOG PS 0 or 1 v Durvalumab ECOG PS 0 or 1
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Proportion (%)
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 12.24
    Notes
    [1] - 114 patients were evaluated in this analysis
    Statistical analysis title
    		 Proportion and 95% CI for incidence of PRAEs
    Statistical analysis description
    Any possibly related adverse events of CTCAE Grade 3 or Grade 4. 95% CI were based on the Clopper-Pearson method.
    Comparison groups
    Durvalumab ECOG PS 2 v Durvalumab ECOG PS 2
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Proportion (%)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 70.76
    Notes
    [2] - 3 patients were evaluated in this analysis
    Statistical analysis title
    		 Proportion and 95% CI for incidence of PRAEs
    Statistical analysis description
    Any possibly related AEs of Grade 3 or Grade 4 with onset date within 6 months of the first dose. 95% CI were based on the Clopper-Pearson method.
    Comparison groups
    Durvalumab ECOG PS 0 or 1 v Durvalumab ECOG PS 0 or 1
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Proportion (%)
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.44
         upper limit
    		 9.94
    Notes
    [3] - 114 patients were evaluated in this analysis
    Statistical analysis title
    		 Proportion and 95% CI for incidence of PRAEs
    Statistical analysis description
    Any possibly related AEs of Grade 3 or Grade 4 with onset date within 6 months of the first dose. 95% CI were based on the Clopper-Pearson method.
    Comparison groups
    Durvalumab ECOG PS 2 v Durvalumab ECOG PS 2
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Proportion (%)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 70.76
    Notes
    [4] - 6 patients were evaluated in this analysis

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    The efficacy of Durvalumab (MEDI4736) treatment in terms of PFS. PFS was defined as the time from the first date of treatment until the date of objective disease progression based on Investigator’s assessment according to RECIST 1.1 or death (by any cause in the absence of progression) regardless of whether the patient withdraws from IP or receives another anticancer therapy prior to progression. Here, arbitrary value 9999.9999 represent not calculated due to low number of events as well as low sample size. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full).
    End point type
    Secondary
    End point timeframe
    From the first date of treatment until the date of objective disease progression or death (approximately upto 27 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    Units: Months
        median (confidence interval 95%)
    13.1 (7.36 to 19.91)
    3.7 (1.81 to 9999.9999)
    No statistical analyses for this end point

    Secondary: Percentage of patients progression-free at 12 months

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    End point title
    		 Percentage of patients progression-free at 12 months
    End point description
    The percentage of patients treated with Durvalumab who are progression-free was estimated. PFS12 according to RECIST 1.1 as assessed by the Investigator. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full).
    End point type
    Secondary
    End point timeframe
    From the first date of treatment until the date of objective disease progression or death (upto 12 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    Units: Percentage of patient
        number (confidence interval 95%)
    51.1 (41.29 to 60.02)
    33.3 (0.90 to 77.41)
    No statistical analyses for this end point

    Secondary: Percentage of patients alive

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    End point title
    		 Percentage of patients alive
    End point description
    Percentage of patients alive at 12 months, 24 months, and 36 months were estimated. Here, arbitrary value 9999.9999 represent not calculated due to low number of events as well as low sample size. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full).
    End point type
    Secondary
    End point timeframe
    From the first date of treatment until the date of objective disease progression or death (12 months, and 24 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    Units: Percentage of patient
    number (confidence interval 95%)
        Survival at 12 months
    83.9 (75.73 to 89.57)
    66.7 (5.41 to 94.52)
        Survival at 24 months
    68.2 (58.54 to 76.00)
    33.3 (0.90 to 77.41)
        Survival at 36 months
    57.2 (46.94 to 66.20)
    9999.9999 (9999.9999 to 9999.9999)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    The efficacy of Durvalumab (MEDI4736) treatment in terms of OS were assessed. OS was defined as the time from the first date of treatment until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. Here, arbitrary value 9999.9999 represent not calculated due to low number of events as well as low sample size. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full).
    End point type
    Secondary
    End point timeframe
    From the first date of treatment until death due to any cause (approximately upto 27 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    Units: Months
        median (confidence interval 95%)
    39.0 (30.59 to 9999.9999)
    12.3 (4.96 to 9999.9999)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Objective response is complete response (CR), or partial response (PR) confirmed by a follow-up visit at least 4 weeks after. Both visits contributing to response should have occurred before any further anti-cancer therapy, in order for the patient to be considered a responder. Responses that occurred after the start of subsequent anti-cancer therapy were not included in the numerator. Response excluded unconfirmed response. Participants with unconfirmed responses include those whose CR, or PR don't have a confirmed response. These responses occur at any time during the study, recur after anti-cancer therapy, and these participants were missing for a follow-up visit 4 weeks after. Here, arbitrary value 9999.9999 represent not applicable. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full).
    End point type
    Secondary
    End point timeframe
    From 8 weeks ±1 week after investigational product (IP) treatment initiation and continue every 8 weeks (q8w) ±1 week through 52 weeks and every 12 weeks (q12w) ±1 week until disease progression (approximately upto 27 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    Units: Participants
        Number of patients with response
    24
    0
        Number of patients with unconfirmed response
    5
    0
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) from onset of response

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    End point title
    		 Duration of Response (DOR) from onset of response
    End point description
    The efficacy of Durvalumab (MEDI4736) treatment in terms of DoR were assessed. DoR was defined as the time from the date of first documented response per RECIST1.1 until the first date of documented progression per RECIST1.1 or death in the absence of disease progression. If a patient did not progress following a response, then the patients’ DoR was censored at the PFS censoring time. Here, arbitrary value 9999.9999 represent not applicable - Not calculated due to insufficient number of events. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full). The patients with objective response were evaluated.
    End point type
    Secondary
    End point timeframe
    From 8 weeks ±1 week after IP treatment initiation and continue q8w ±1 week through 52 weeks and q12w ±1 week until disease progression (approximately upto 27 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    24
    0 [5]
    Units: Weeks
        median (confidence interval 95%)
    9999.9999 (9999.9999 to 9999.9999)
    ( to )
    Notes
    [5] - Not calculated due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Lung cancer mortality

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    End point title
    		 Lung cancer mortality
    End point description
    The efficacy of durvalumab (MEDI4736) treatment in terms of lung cancer mortality was assessed. Lung Cancer Mortality was defined as the time from the date of treatment start until death due to lung cancer. Any patient not known to have died due to lung cancer will be censored based on the last recorded date on which the patient was known to be alive or died due to reason other than lung cancer. Here, arbitrary value 9999.9999 represent not applicable - Not calculated due to insufficient number of events. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full). Patients who had died due to causes related to non-small cell lung cancer were evaluated.
    End point type
    Secondary
    End point timeframe
    From date of treatment start until death due to lung cancer (approximately upto 27 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    40
    1
    Units: Months
        median (confidence interval 95%)
    41.8 (36.50 to 9999.9999)
    9999.9999 (4.96 to 9999.9999)
    No statistical analyses for this end point

    Secondary: Number of participants with Adverse events (AEs), Serious adverse events (SAEs), Adverse event of special interests (AESIs), and Immune-mediated adverse event (imAEs)

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    End point title
    		 Number of participants with Adverse events (AEs), Serious adverse events (SAEs), Adverse event of special interests (AESIs), and Immune-mediated adverse event (imAEs)
    End point description
    The safety and tolerability profile of Durvalumab(MEDI4736) treatment, including all AEs were assessed. The safety analysis set consisted of all patients who received at least one dose of IP (partial or in full). This include treatment emergent AEs only, ie. AEs occurred during screening period are NOT included.
    End point type
    Secondary
    End point timeframe
    Until the final visit (upto 27 months)
    End point values
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2
    Number of subjects analysed
    114
    3
    Units: Participants
        Any AE
    108
    3
        Any AE possibly related to treatment (PRT)
    87
    3
        Any AE of CTCAE Grade 3 or Grade 4
    32
    0
        Any AE of CTCAE Grade 3 or Grade 4 PRT
    7
    0
        Any AE with outcome of death
    3
    0
        Any AE with outcome of death PRT
    1
    0
        Any SAE (including events with outcome of death)
    32
    0
        Any SAE (inc. events with outcome of death) PRT
    7
    0
        Any AE leading to discontinuation of treatment
    32
    0
        Any AE leading to DOT PRT
    19
    0
        Any AE leading to treatment interruption
    52
    1
        Any AE leading to treatment interruption, PRT
    24
    1
        Any AESI/AEPI (inc. events with outcome of death)
    86
    3
        Any AESI/AEPI (events with outcome of death), PRT
    73
    2
        Any imAE
    48
    2
        Any imAE, PRT
    43
    2
        Any imAE as assessed by Investigator
    64
    1
        Any imAE as assessed by Investigator, PRT
    64
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Upto 27 months
    Adverse event reporting additional description
    One patient was alive at the data cut-off date but was recorded as death on the end of study form because the patient died one day after the data cut-off date. Therefore, this patient was counted in the death category in participant flow table.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Durvalumab ECOG PS 0 or 1
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Reporting group title
    Durvalumab ECOG PS 2
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Reporting group title
    Durvalumab Total
    Reporting group description
    		 Patients received 1500 mg Durvalumab monotherapy via IV infusion q4w.

    Serious adverse events
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2 Durvalumab Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 114 (28.07%)
    0 / 3 (0.00%)
    23 / 117 (19.66%)
         number of deaths (all causes)
    49
    2
    51
         number of deaths resulting from adverse events
    3
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    2 / 114 (1.75%)
    0 / 3 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 114 (1.75%)
    0 / 3 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 114 (1.75%)
    0 / 3 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Lung disorder
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pulmonary sepsis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pneumonia legionella
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 3 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Durvalumab ECOG PS 0 or 1 Durvalumab ECOG PS 2 Durvalumab Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 114 (92.98%)
    3 / 3 (100.00%)
    109 / 117 (93.16%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 114 (6.14%)
    1 / 3 (33.33%)
    8 / 117 (6.84%)
         occurrences all number
    8
    2
    10
    Deep vein thrombosis
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Hypotension
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    24 / 114 (21.05%)
    0 / 3 (0.00%)
    24 / 117 (20.51%)
         occurrences all number
    35
    0
    35
    Pyrexia
         subjects affected / exposed
    22 / 114 (19.30%)
    0 / 3 (0.00%)
    22 / 117 (18.80%)
         occurrences all number
    25
    0
    25
    Non-cardiac chest pain
         subjects affected / exposed
    15 / 114 (13.16%)
    1 / 3 (33.33%)
    16 / 117 (13.68%)
         occurrences all number
    18
    1
    19
    Oedema peripheral
         subjects affected / exposed
    10 / 114 (8.77%)
    0 / 3 (0.00%)
    10 / 117 (8.55%)
         occurrences all number
    10
    0
    10
    Asthenia
         subjects affected / exposed
    29 / 114 (25.44%)
    2 / 3 (66.67%)
    31 / 117 (26.50%)
         occurrences all number
    40
    2
    42
    Chest discomfort
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Chills
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Chest pain
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 3 (33.33%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    27 / 114 (23.68%)
    2 / 3 (66.67%)
    29 / 117 (24.79%)
         occurrences all number
    39
    3
    42
    Pneumonitis
         subjects affected / exposed
    16 / 114 (14.04%)
    1 / 3 (33.33%)
    17 / 117 (14.53%)
         occurrences all number
    20
    1
    21
    Productive cough
         subjects affected / exposed
    10 / 114 (8.77%)
    0 / 3 (0.00%)
    10 / 117 (8.55%)
         occurrences all number
    11
    0
    11
    Cough
         subjects affected / exposed
    43 / 114 (37.72%)
    2 / 3 (66.67%)
    45 / 117 (38.46%)
         occurrences all number
    49
    3
    52
    Haemoptysis
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    8
    0
    8
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 3 (33.33%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Lung disorder
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Pleuritic pain
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Pneumothorax
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 114 (6.14%)
    0 / 3 (0.00%)
    7 / 117 (5.98%)
         occurrences all number
    7
    0
    7
    Depressed mood
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Anxiety
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    6
    0
    6
    Depression
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    8 / 114 (7.02%)
    0 / 3 (0.00%)
    8 / 117 (6.84%)
         occurrences all number
    13
    0
    13
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 114 (6.14%)
    0 / 3 (0.00%)
    7 / 117 (5.98%)
         occurrences all number
    9
    0
    9
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    7
    0
    7
    Weight decreased
         subjects affected / exposed
    8 / 114 (7.02%)
    0 / 3 (0.00%)
    8 / 117 (6.84%)
         occurrences all number
    8
    0
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Lipase increased
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    4
    0
    4
    Blood glucose increased
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Platelet count decreased
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    4
    0
    4
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    9 / 114 (7.89%)
    0 / 3 (0.00%)
    9 / 117 (7.69%)
         occurrences all number
    9
    0
    9
    Headache
         subjects affected / exposed
    17 / 114 (14.91%)
    1 / 3 (33.33%)
    18 / 117 (15.38%)
         occurrences all number
    18
    1
    19
    Dizziness
         subjects affected / exposed
    7 / 114 (6.14%)
    0 / 3 (0.00%)
    7 / 117 (5.98%)
         occurrences all number
    13
    0
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    8
    0
    8
    Lymphadenopathy
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 3 (33.33%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    1
    Lymphopenia
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    8
    0
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    5
    0
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    23 / 114 (20.18%)
    0 / 3 (0.00%)
    23 / 117 (19.66%)
         occurrences all number
    24
    0
    24
    Diarrhoea
         subjects affected / exposed
    24 / 114 (21.05%)
    0 / 3 (0.00%)
    24 / 117 (20.51%)
         occurrences all number
    33
    0
    33
    Nausea
         subjects affected / exposed
    17 / 114 (14.91%)
    0 / 3 (0.00%)
    17 / 117 (14.53%)
         occurrences all number
    21
    0
    21
    Vomiting
         subjects affected / exposed
    9 / 114 (7.89%)
    0 / 3 (0.00%)
    9 / 117 (7.69%)
         occurrences all number
    9
    0
    9
    Dry mouth
         subjects affected / exposed
    7 / 114 (6.14%)
    0 / 3 (0.00%)
    7 / 117 (5.98%)
         occurrences all number
    7
    0
    7
    Abdominal pain
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences all number
    5
    0
    5
    Abdominal pain upper
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    6
    0
    6
    Dyspepsia
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences all number
    5
    0
    5
    Noninfective gingivitis
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 3 (33.33%)
    1 / 117 (0.85%)
         occurrences all number
    0
    1
    1
    Dysphagia
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    4
    0
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 114 (11.40%)
    1 / 3 (33.33%)
    14 / 117 (11.97%)
         occurrences all number
    17
    1
    18
    Pruritus
         subjects affected / exposed
    19 / 114 (16.67%)
    2 / 3 (66.67%)
    21 / 117 (17.95%)
         occurrences all number
    21
    3
    24
    Dry skin
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Erythema
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Psoriasis
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    5
    0
    5
    Night sweats
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Rash pruritic
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 3 (33.33%)
    2 / 117 (1.71%)
         occurrences all number
    1
    1
    2
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    12 / 114 (10.53%)
    0 / 3 (0.00%)
    12 / 117 (10.26%)
         occurrences all number
    12
    0
    12
    Hypothyroidism
         subjects affected / exposed
    15 / 114 (13.16%)
    1 / 3 (33.33%)
    16 / 117 (13.68%)
         occurrences all number
    15
    1
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 114 (19.30%)
    1 / 3 (33.33%)
    23 / 117 (19.66%)
         occurrences all number
    28
    2
    30
    Back pain
         subjects affected / exposed
    17 / 114 (14.91%)
    0 / 3 (0.00%)
    17 / 117 (14.53%)
         occurrences all number
    17
    0
    17
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    5
    0
    5
    Musculoskeletal pain
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences all number
    5
    0
    5
    Myalgia
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences all number
    5
    0
    5
    Neck pain
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    4
    0
    4
    Pain in extremity
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    4
    0
    4
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 114 (7.02%)
    0 / 3 (0.00%)
    8 / 117 (6.84%)
         occurrences all number
    8
    0
    8
    Nasopharyngitis
         subjects affected / exposed
    10 / 114 (8.77%)
    0 / 3 (0.00%)
    10 / 117 (8.55%)
         occurrences all number
    12
    0
    12
    Conjunctivitis
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    6
    0
    6
    Urinary tract infection
         subjects affected / exposed
    5 / 114 (4.39%)
    0 / 3 (0.00%)
    5 / 117 (4.27%)
         occurrences all number
    5
    0
    5
    COVID-19
         subjects affected / exposed
    7 / 114 (6.14%)
    0 / 3 (0.00%)
    7 / 117 (5.98%)
         occurrences all number
    7
    0
    7
    Oral candidiasis
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Rhinitis
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    7 / 114 (6.14%)
    1 / 3 (33.33%)
    8 / 117 (6.84%)
         occurrences all number
    8
    1
    9
    Decreased appetite
         subjects affected / exposed
    14 / 114 (12.28%)
    1 / 3 (33.33%)
    15 / 117 (12.82%)
         occurrences all number
    14
    2
    16
    Hypomagnesaemia
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 3 (0.00%)
    6 / 117 (5.13%)
         occurrences all number
    6
    0
    6
    Hyperuricaemia
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    3
    0
    3
    Hypokalaemia
         subjects affected / exposed
    4 / 114 (3.51%)
    0 / 3 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    0
    4
    Hypercalcaemia
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    4
    0
    4
    Hyperkalaemia
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 3 (0.00%)
    3 / 117 (2.56%)
         occurrences all number
    6
    0
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2019
    Section 5.1 (Inclusion criteria): Reference to hepatic metastasis alanine aminotransferase and aspartate aminotransferase limits for patients with hepatic metastases has been removed as patients are required to have non-metastatic disease. Section 5.1 and 5.2 (Eligibility criteria): Eligibility criteria have been updated to allow gemcitabine in combination with cisplatin or carboplatin as a prior sCRT treatment, provided there is no overlap between chemotherapy and radiation. Section 8.2.1 (Haematology safety laboratory assessments): Clarification of language related to coagulation testing at baseline on Day 1. Section 8.4.5.1 (Toxicity management related to durvalumab) and Appendix G: Section has been updated to reflect that Toxicity Management Guidelines (TMGs) are now provided as an Annex to the Protocol. Appendix G has been removed.
    20 Apr 2020
    Section 1.1 (Synopsis), Section 1.2, Table 1 (SoA), Section 1.3 (Figure 1), Section 4.1 (Overall Design), Section 4.1 (Overall Design) Figure 2, Section 4.2.5 (Timing of treatment with durvalumab (MEDI4736) relative to sequential chemoradiation therapy), Section 5.1 (Inclusion Criteria), Section 9.2 (Sample Size Determination) Table 13: The time window from end of sCRT to first dose of IP was extended from 28 to 42 days. Section 1.2, Table 1, Footnote l (SoA): The frequency of on study pregnancy testing was changed from “every 4 weeks” to “prior to every dosing visit (within 3 calendar days prior to dosing in line with other laboratory tests)”. Section 5.1 (Inclusion Criterion 7): Inclusion criterion 7 was amended to supplement guidance on acceptable baseline imaging. It was added that assessment of tumour response should be performed based on the latest scan performed per physician assessment/criteria). If the patient has an intermediate scan between chemotherapy and radiotherapy, this scan should be used as baseline scan provided it fulfils the RECIST-defined CT imaging acquisition parameters. Section 5.2 (Exclusion Criterion 11, option (a)): It was added to exclusion criterion 11 that patients with ≥Grade 2 lymphopenia will be evaluated on a case-by-case basis after consultation with the Study Physician. Section 8.2.2 (Physical Examination): Clarification was made that targeted physical examinations during the treatment cycles are not expected in asymptomatic patients. Section 8.2.3 (Vital Signs): Clarification that respiratory rate and temperature measurements are part of the vital signs assessments. Section 9.2 (Sample Size Determination): The sample size per cohort was changed: WHO/ECOG PS 0 to 1 cohort from 120 to 100-120 patients and WHO/ECOG PS 2 cohort from 30 to up to 30, depending on recruitment.
    06 Jul 2021
    Section 1.1 (Synopsis), Section 3 (Study objectives), Table 3 footnote: It was clarified that TRAEs and PRAEs are used interchangeably and PRAEs will be reported in the SAP, Tables, Figures, and Listings, and CSR Section 1.1 (Synopsis, Treatments and treatment duration), Section 4.1 (Overall design, Figure 2), and Section 6.1.2 (Dose and treatment regimens): It was clarified that treatment for up to a maximum of 24 months is referring to a maximum of 24 months from Cycle 1 Day 1. Section 4.1 (Overall design, Investigational product, dosage and mode of administration): It was clarified that treatment is for a maximum of 24 months from Cycle 1 Day 1. Section 6.1.1 (Investigational product, Preparation of durvalumab (MEDI4736) doses for administration with an IV bag) and Section 8.2.3 (Vital signs): A time window of ±10 minutes for the durvalumab infusion time was added based on latest AstraZeneca durvalumab protocol template. Section 6.1.3 (Treatment after the end of the study, Treatment after final overall survival data cut-off): The misleading sentence that no OS data will be recorded in the study database after DCO was deleted and it was clarified that in this section the DCO is referring to the final DCO Section 8.3.13 (Safety data to be collected following the final data cut-off of the study): It was clarified that in this section the DCO is referring to the final DCO. Section 8.4.1 (Reporting of serious adverse events): The guidance on how to proceed if the WBDC system is unavailable was updated to match the safety handling plan. Section 8.4.5.1 (Specific toxicity management and dose modification information – Durvalumab and durvalumab + tremelimumab): The reference to the website containing the current Dosing Modification and Toxicity Management Guidelines was removed.

    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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