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    Clinical Trial Results:
    ALICE: A randomized placebo-controlled phase II study evaluating atezolizumab combined with immunogenic chemotherapy in patients with metastatic triple-negative breast cancer.

    Summary
    EudraCT number
    		 2016-003570-40
    Trial protocol
    		 DK  
    Global end of trial date
    25 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Oct 2024
    First version publication date
    18 Oct 2024
    Other versions
    Summary report(s)
    		 Published article

    Trial information

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    Trial identification
    Sponsor protocol code
    ML39079_ALICE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03164993
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oslo University Hospital, Department of Oncology
    Sponsor organisation address
    Ullernchausseen 70, Oslo, Norway, 0379
    Public contact
    Dr. Jon Amund Kyte (Principal Investigator), Oslo University Hospital, +47 97569619, jonky@ous-hf.no
    Scientific contact
    Dr. Jon Amund Kyte (Principal Investigator), Oslo University Hospital, +47 97569619, jonky@ous-hf.no
    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
    05 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Co-primary objectives: Assessment of toxicity of combined treatment with atezolizumab, pegylated liposomal doxorubicin and cyclophosphamide. Assessment of clinical response: Progression-free survival; descriptive comparison of the PFS rates in the total per protocol population, and the PD-L1+ PP population
    Protection of trial subjects
    The trial was conducted according to the guidelines of Good Clinical Practice and the principles of the World Medical Association’s Declaration of Helsinki. All patients provided written informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Aug 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 47
    Country: Number of subjects enrolled
    Denmark: 21
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    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)
    53
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial enrolled 68 patients at 5 academic hospitals in Norway (n = 47) and Denmark (n = 21): Oslo University Hospital (Oslo, NO), Stavanger University Hospital (Stavanger, NO), St.Olavs Hospital (Trondheim, NO), Vejle Hospital (Vejle, DK) and Rigshospitalet (Copenhagen, DK).

    Pre-assignment
    Screening details
    		 Eligible patients were adult women and men with metastatic or incurable locally advanced, histologically confirmed triple-negative breast cancer who had received a maximum of one previous line of chemotherapy in the metastatic setting.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    Placebo treatment consisted of an identical-looking intravenous infusion of NaCl 0.9% administered in the same manner. The preparation of active drug dilution/placebo, according to the respective randomization code, was facilitated by the hospital pharmacy, in order to maintain the double blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo-chemotherapy
    Arm description
    		 Placebo plus pegylated liposomal doxorubicin plus cyclophosphamide
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated liposomal doxorubicin 20 mg/m2 i.v. every 2nd week. An upper limit of 44 mg per dose will be applied to patients with a body surface area >2.2 m2

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cyclophosphamide tablets 50 mg per day, daily as continuous treatment for the first 2 weeks in each 4 week period (i.e. every second 2-week cycle)

    Arm title
    		 Atezolizumab-chemotherapy
    Arm description
    		 Atezolizumab plus pegylated liposomal doxorubicin plus cyclophosphamide
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab will be administered intravenously 840 mg every 2nd week

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated liposomal doxorubicin 20 mg/m2 i.v. every 2nd week. An upper limit of 44 mg per dose will be applied to patients with a body surface area >2.2 m2

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cyclophosphamide tablets 50 mg per day, daily as continuous treatment for the first 2 weeks in each 4 week period (i.e. every second 2-week cycle)

    Number of subjects in period 1
    		Placebo-chemotherapy Atezolizumab-chemotherapy
    Started
    28
    40
    Completed
    0
    2
    Not completed
    28
    38
         Physician decision
    1
    1
         Adverse event, non-fatal
    1
    2
         Still on treatment at data lock
    -
    2
         Lack of efficacy
    26
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo-chemotherapy
    Reporting group description
    		 Placebo plus pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group title
    Atezolizumab-chemotherapy
    Reporting group description
    		 Atezolizumab plus pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy Total
    Number of subjects
    		 28 40 68
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 24 29 53
        From 65-84 years
    		 4 11 15
    Age continuous
    Units: years
        median (full range (min-max))
    		 52.5 (28 to 74) 58.5 (31 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 28 39 67
        Male
    		 0 1 1
    PD-L1 status
    Programmed death ligand 1 expression by the SP-142 assay
    Units: Subjects
        Positive
    		 10 21 31
        Negative
    		 17 19 36
        Missing
    		 1 0 1
    ECOG performance status
    Eastern Oncology Group Performance status
    Units: Subjects
        ECOG 0
    		 21 27 48
        ECOG 1
    		 7 13 20
    De novo metastatic disease
    Units: Subjects
        Yes
    		 8 10 18
        No
    		 20 30 50
    Bone metastases
    Units: Subjects
        Yes
    		 16 17 33
        No
    		 12 23 35
    Liver metastases
    Units: Subjects
        Yes
    		 13 12 25
        No
    		 15 28 43
    Lung metastases
    Units: Subjects
        Yes
    		 10 18 28
        No
    		 18 22 40
    Lymph node metastases
    Units: Subjects
        Yes
    		 13 22 35
        No
    		 15 18 33
    CNS metastases
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 27 39 66
    Number of metastatic sites
    Units: Subjects
        ≤2
    		 15 27 42
        >2
    		 13 13 26
    Line of chemotherapy
    Units: Subjects
        1st
    		 16 24 40
        2nd
    		 12 16 28
    Previous anthracycline treatment
    Units: Subjects
        Yes
    		 20 28 48
        No
    		 8 12 20
    Intrinsic breast cancer subtype
    Units: Subjects
        Lum A
    		 2 0 2
        Lum B
    		 1 1 2
        HER2E
    		 2 4 6
        Basal
    		 12 22 34
        Missing
    		 11 13 24
    BRCA mutation status
    Units: Subjects
        BRCA1 mutation
    		 1 2 3
        Normal variant
    		 12 22 34
        Missing
    		 15 16 31
    Subject analysis sets

    Subject analysis set title
    Placebo-chemo per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in placebo-chemotherapy arm evaluated for tumor response and received a minimum of 4 doses of atezolizumab/placebo and a minimum of 3 doses with pegylated liposomal doxorubicin

    Subject analysis set title
    Atezolizumab-chemo per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in atezolizumab-chemotherapy arm evaluated for tumor response and received a minimum of 4 doses of atezolizumab/placebo and a minimum of 3 doses with pegylated liposomal doxorubicin

    Subject analysis sets values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects
    23
    36
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    19
    25
        From 65-84 years
    4
    11
    Age continuous
    Units: years
        median (full range (min-max))
    52 (28 to 74)
    59 (31 to 77)
    Gender categorical
    Units: Subjects
        Female
    23
    35
        Male
    0
    1
    PD-L1 status
    Programmed death ligand 1 expression by the SP-142 assay
    Units: Subjects
        Positive
    8
    19
        Negative
    14
    17
        Missing
    1
    0
    ECOG performance status
    Eastern Oncology Group Performance status
    Units: Subjects
        ECOG 0
    16
    25
        ECOG 1
    7
    11
    De novo metastatic disease
    Units: Subjects
        Yes
    6
    9
        No
    17
    27
    Bone metastases
    Units: Subjects
        Yes
    13
    14
        No
    10
    22
    Liver metastases
    Units: Subjects
        Yes
    9
    10
        No
    14
    26
    Lung metastases
    Units: Subjects
        Yes
    9
    16
        No
    14
    20
    Lymph node metastases
    Units: Subjects
        Yes
    13
    20
        No
    10
    16
    CNS metastases
    Units: Subjects
        Yes
    1
    1
        No
    22
    35
    Number of metastatic sites
    Units: Subjects
        ≤2
    12
    26
        >2
    11
    10
    Line of chemotherapy
    Units: Subjects
        1st
    12
    23
        2nd
    11
    13
    Previous anthracycline treatment
    Units: Subjects
        Yes
    17
    25
        No
    6
    11
    Intrinsic breast cancer subtype
    Units: Subjects
        Lum A
    2
    0
        Lum B
    1
    1
        HER2E
    2
    4
        Basal
    11
    20
        Missing
    7
    11
    BRCA mutation status
    Units: Subjects
        BRCA1 mutation
    1
    2
        Normal variant
    11
    22
        Missing
    11
    12

    End points

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    End points reporting groups
    Reporting group title
    Placebo-chemotherapy
    Reporting group description
    		 Placebo plus pegylated liposomal doxorubicin plus cyclophosphamide

    Reporting group title
    Atezolizumab-chemotherapy
    Reporting group description
    		 Atezolizumab plus pegylated liposomal doxorubicin plus cyclophosphamide

    Subject analysis set title
    Placebo-chemo per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in placebo-chemotherapy arm evaluated for tumor response and received a minimum of 4 doses of atezolizumab/placebo and a minimum of 3 doses with pegylated liposomal doxorubicin

    Subject analysis set title
    Atezolizumab-chemo per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in atezolizumab-chemotherapy arm evaluated for tumor response and received a minimum of 4 doses of atezolizumab/placebo and a minimum of 3 doses with pegylated liposomal doxorubicin

    Primary: PFS, per-protocol population

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    End point title
    		 PFS, per-protocol population
    End point description
    PFS in the per-protocol population. PFS is defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per immune-modified RECIST (iRECIST), or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the last tumor assessment date. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after randomization, data will be censored at the date of randomization +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression. The HR for disease progression or death (atezo-chemo versus placebo-chemo) will be estimated using a Cox proportional hazards model.
    End point type
    Primary
    End point timeframe
    Until data cutoff 5 th of July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    23 [1]
    36 [2]
    Units: Months
        median (confidence interval 95%)
    3.5 (2.6 to 5.5)
    4.3 (3.5 to 7.3)
    Notes
    [1] - Per-protocol population Placebo-chemo
    [2] - Per-protocol population Atezo-chemo
    Statistical analysis title
    		 Cox proportional hazards model
    Comparison groups
    Placebo-chemo per-protocol population v Atezolizumab-chemo per-protocol population
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.047
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.99

    Primary: PFS, PD-L1 positive per-protocol population

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    End point title
    		 PFS, PD-L1 positive per-protocol population
    End point description
    PFS in the PD-L1 positive patients (SP142 assay) of the PP population. PFS is defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per immune-modified RECIST (iRECIST), or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the last tumor assessment date. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after randomization, data will be censored at the date of randomization +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression. The HR for disease progression or death will be estimated using a Cox proportional hazards model.
    End point type
    Primary
    End point timeframe
    Until data cutoff 5th July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    8 [3]
    19 [4]
    Units: Months
        median (confidence interval 95%)
    3.9 (3.6 to 99)
    5.5 (2.9 to 9.6)
    Notes
    [3] - PD-L1 pos PP-population
    [4] - PD-L1 pos PP population
    Statistical analysis title
    		 Cox proportional hazards model
    Comparison groups
    Placebo-chemo per-protocol population v Atezolizumab-chemo per-protocol population
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.54

    Secondary: PFS, full analysis set population

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    End point title
    		 PFS, full analysis set population
    End point description
    Progression-free survival in the full analysis set population (n = 68). PFS is defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per immune-modified RECIST (iRECIST), or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the last tumor assessment date. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after randomization, data will be censored at the date of randomization +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression. The HR for disease progression or death (atezo-chemo versus placebo-chemo) will be estimated using a Cox proportional hazards model.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July
    End point values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Number of subjects analysed
    28
    40
    Units: Months
        median (confidence interval 95%)
    3.1 (1.8 to 5.4)
    3.9 (3.5 to 5.9)
    Statistical analysis title
    		 Cox proportional hazards model
    Comparison groups
    Placebo-chemotherapy v Atezolizumab-chemotherapy
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.95

    Secondary: OS, full analysis set population

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    End point title
    		 OS, full analysis set population
    End point description
    Overall survival in the full analysis set population (n = 68). Overall survival (OS) will be calculated from the time of randomization until death. Patients alive at the time of data analysis will be treated as censored. The HR for OS will be estimated using a Cox proportional hazards model. The CI for the HR will be provided. Kaplan-Meier methodology will be used to estimate the median OS for each treatment arm.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July 2022
    End point values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Number of subjects analysed
    28 [5]
    40 [6]
    Units: Months
        median (confidence interval 95%)
    14.6 (8.1 to 21.3)
    15.3 (10.9 to 25.5)
    Notes
    [5] - Full analysis set
    [6] - Full analysis set
    Statistical analysis title
    		 Cox proportional hazards model
    Statistical analysis description
    Overall survival (OS) will be calculated from the time of randomization until death. Patients alive at the time of data analysis will be treated as censored. The HR for OS will be estimated using a Cox proportional hazards model.
    Comparison groups
    Placebo-chemotherapy v Atezolizumab-chemotherapy
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.3

    Secondary: OS, per-protocol population

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    End point title
    		 OS, per-protocol population
    End point description
    Overall survival in the per-protocol population (n = 59). Overall survival (OS) will be calculated from the time of randomization until death. Patients alive at the time of data analysis will be treated as censored. The HR for OS will be estimated using a Cox proportional hazards model. The CI for the HR will be provided. Kaplan-Meier methodology will be used to estimate the median OS for each treatment arm.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    23 [7]
    36 [8]
    Units: Months
        median (confidence interval 95%)
    15.6 (8.1 to 21.3)
    15.3 (11.2 to 27.0)
    Notes
    [7] - Per-protocol population
    [8] - Per protocol population
    Statistical analysis title
    		 Cox proportional hazards model
    Statistical analysis description
    Overall survival (OS) will be calculated from the time of randomization until death. Patients alive at the time of data analysis will be treated as censored. The HR for OS will be estimated using a Cox proportional hazards model.
    Comparison groups
    Placebo-chemo per-protocol population v Atezolizumab-chemo per-protocol population
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.3

    Secondary: ORR, full analysis set population

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    End point title
    		 ORR, full analysis set population
    End point description
    The proportion of patients in each arm with best overall response either "iPR" or "iCR" by iRECIST in the full analysis set population.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July 2022
    End point values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Number of subjects analysed
    28 [9]
    40 [10]
    Units: Objective responders
        iPR/iCR
    5
    11
        Non-iPR/iCR
    23
    29
    Notes
    [9] - Full analysis set
    [10] - Full analysis set
    No statistical analyses for this end point

    Secondary: ORR, per-protocol population

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    End point title
    		 ORR, per-protocol population
    End point description
    The proportion of patients in each arm with best overall response either "iPR" or "iCR" by iRECIST in the per-protocol population
    End point type
    Secondary
    End point timeframe
    Until 5th of July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    23
    36
    Units: Objective responders
        iCR/iPR
    5
    11
        Non-iCR/iPR
    18
    25
    No statistical analyses for this end point

    Secondary: Clinical benefit rate, full analysis set population

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    End point title
    		 Clinical benefit rate, full analysis set population
    End point description
    The proportion in each arm of the full analysis set population with clinical benefit (CBR). CBR was defined as the proportion of patients who had either an objective response (iPR/iCR) by iRECIST or stable disease lasting at least until the radiological evaluation at 24 weeks ± 7 days.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July 2022
    End point values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Number of subjects analysed
    28
    40
    Units: Subjects
        CB
    10
    20
        Non-CB
    18
    20
    No statistical analyses for this end point

    Secondary: Clinical benefit rate, per-protocol population

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    End point title
    		 Clinical benefit rate, per-protocol population
    End point description
    The proportion in each arm of the per-protocol population with clinical benefit (CBR). CBR was defined as the proportion of patients who had either an objective response (iPR/iCR) by iRECIST or stable disease lasting at least until the radiological evaluation at 24 weeks ± 7 days.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    23
    36
    Units: Subjects
        CB
    10
    19
        Non-CB
    13
    17
    No statistical analyses for this end point

    Secondary: Durable response rate, full analysis set population

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    End point title
    		 Durable response rate, full analysis set population
    End point description
    The number of subjects in each arm of the full analysis set population with durable response. Durable response rate (DRR) was defined as the proportion of patients with a duration of response of ≥6 months.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July 2022
    End point values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Number of subjects analysed
    28
    40
    Units: Subjects
        Durable response
    1
    6
        Non-durable response
    27
    34
    No statistical analyses for this end point

    Secondary: Durable response rate, per-protocol population

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    End point title
    		 Durable response rate, per-protocol population
    End point description
    The number of subjects in each arm of the per-protocol population with durable response. Durable response rate (DRR) was defined as the proportion of patients with a duration of response of ≥6 months.
    End point type
    Secondary
    End point timeframe
    Until data cut-off 5th of July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    23
    36
    Units: Subjects
        Durable response
    1
    6
        Non-durable response
    22
    30
    No statistical analyses for this end point

    Secondary: Median duration of response, full analysis set population

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    End point title
    		 Median duration of response, full analysis set population
    End point description
    The median duration of response (iPR/iCR by iRECIST) in each arm of the full analysis set population. The duration of response was defined as the time from the first documentation of an objective response to the time of progression or death.
    End point type
    Secondary
    End point timeframe
    Until 5th of July 2022
    End point values
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Number of subjects analysed
    28
    40
    Units: Months
        median (inter-quartile range (Q1-Q3))
    3.7 (1.6 to 4.8)
    7.3 (2.1 to 19.6)
    No statistical analyses for this end point

    Secondary: Median duration of response, per-protocol population

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    End point title
    		 Median duration of response, per-protocol population
    End point description
    The median duration of response (iPR/iCR by iRECIST) in each arm of the per-protocol population. The duration of response was defined as the time from the first documentation of an objective response to the time of progression or death.
    End point type
    Secondary
    End point timeframe
    Until data cutoff 5th of July 2022
    End point values
    		 Placebo-chemo per-protocol population Atezolizumab-chemo per-protocol population
    Number of subjects analysed
    23
    36
    Units: Months
        median (inter-quartile range (Q1-Q3))
    3.7 (1.6 to 4.8)
    7.3 (2.1 to 19.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 24th AUG 2017 until data lock 5th of JUL 2022.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo-chemotherapy
    Reporting group description
    		 -

    Reporting group title
    Atezolizumab-chemotherapy
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 28 (28.57%)
    19 / 40 (47.50%)
         number of deaths (all causes)
    23
    28
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 28 (3.57%)
    5 / 40 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 40 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo-chemotherapy Atezolizumab-chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 28 (96.43%)
    40 / 40 (100.00%)
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Hypotension
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 28 (42.86%)
    20 / 40 (50.00%)
         occurrences all number
    15
    23
    Pyrexia
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 40 (7.50%)
         occurrences all number
    3
    5
    Malaise
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Oedema
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Pain
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Thirst
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Reproductive system and breast disorders
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 28 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    4
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 28 (14.29%)
    5 / 40 (12.50%)
         occurrences all number
    4
    5
    Dyspnoea
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 40 (10.00%)
         occurrences all number
    3
    8
    Painful respiration
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    10 / 28 (35.71%)
    18 / 40 (45.00%)
         occurrences all number
    16
    19
    Neutrophil count decreased
         subjects affected / exposed
    4 / 28 (14.29%)
    4 / 40 (10.00%)
         occurrences all number
    5
    9
    Weight decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    2
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 40 (10.00%)
         occurrences all number
    1
    4
    Headache
         subjects affected / exposed
    4 / 28 (14.29%)
    4 / 40 (10.00%)
         occurrences all number
    4
    4
    Neuropathy peripheral
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Dysgeusia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Parosmia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Amnesia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Dysarthria
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Leukopenia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 28 (53.57%)
    21 / 40 (52.50%)
         occurrences all number
    16
    25
    Mucosal inflammation
         subjects affected / exposed
    6 / 28 (21.43%)
    19 / 40 (47.50%)
         occurrences all number
    6
    25
    Constipation
         subjects affected / exposed
    12 / 28 (42.86%)
    18 / 40 (45.00%)
         occurrences all number
    12
    19
    Dyspepsia
         subjects affected / exposed
    3 / 28 (10.71%)
    8 / 40 (20.00%)
         occurrences all number
    3
    9
    Diarrhoea
         subjects affected / exposed
    6 / 28 (21.43%)
    4 / 40 (10.00%)
         occurrences all number
    6
    4
    Dry mouth
         subjects affected / exposed
    2 / 28 (7.14%)
    6 / 40 (15.00%)
         occurrences all number
    2
    6
    Abdominal pain
         subjects affected / exposed
    2 / 28 (7.14%)
    5 / 40 (12.50%)
         occurrences all number
    2
    6
    Dysphagia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 28 (39.29%)
    26 / 40 (65.00%)
         occurrences all number
    14
    36
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 28 (10.71%)
    21 / 40 (52.50%)
         occurrences all number
    3
    22
    Pruritus
         subjects affected / exposed
    2 / 28 (7.14%)
    7 / 40 (17.50%)
         occurrences all number
    2
    7
    Hair growth abnormal
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Nail ridging
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Pigmentation disorder
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 28 (7.14%)
    5 / 40 (12.50%)
         occurrences all number
    2
    5
    Hyperthyroidism
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Cushingoid
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    6 / 28 (21.43%)
    11 / 40 (27.50%)
         occurrences all number
    9
    17
    Infections and infestations
    Skin infection
         subjects affected / exposed
    2 / 28 (7.14%)
    7 / 40 (17.50%)
         occurrences all number
    2
    8
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    6 / 40 (15.00%)
         occurrences all number
    0
    9
    Urinary tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
    5 / 40 (12.50%)
         occurrences all number
    3
    16
    Oral fungal infection
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Mastitis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 28 (10.71%)
    7 / 40 (17.50%)
         occurrences all number
    3
    7
    Hyperglycaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2020
    Updated inclusion/exclusion criteria. Specification of endpoints and hypotheses.
    12 Feb 2021
    Update in primary objectives and efficacy measures, and inclusion/exclusion criteria. Interim analysis of PD-L1 negative patients.
    22 Feb 2022
    Premature end of patient recruitment. Update in planned statistical analyses.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36482103
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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