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    Clinical Trial Results:
    A phase II study investigating preoperative combination strategies for immunotherapy in patients with untreated, operable ER+, HER2-negative primary breast cancer.

    Summary
    EudraCT number
    		 2016-004424-38
    Trial protocol
    		 GB   DE  
    Global end of trial date
    18 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2024
    First version publication date
    04 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    011604QM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03395899
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    Mile End Road, London, United Kingdom, E1 2EF
    Public contact
    Charlotte Ackerman, Queen Mary University of London, +44 2078828197, bci-eclipse@qmul.ac.uk
    Scientific contact
    Charlotte Ackerman, Queen Mary University of London, +44 2078828197, bci-eclipse@qmul.ac.uk
    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
    17 Jul 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether adding immune-modulatory agents to atezolizumab increases the probability of an immune response over atezolizumab alone in patients with operable ER+ breast cancer.
    Protection of trial subjects
    All enrolled patients will be evaluated clinically before and during their participation in this study. Safety evaluations will consist of medical interviews, recording of adverse events and laboratory measurements. Eligibility criteria for this study were selected to enhance the safety of patients. A number of exclusion criteria are specifically based on the known safety profiles of the study treatment.
    Background therapy
    		 Atezolizumab (also known as MPDL3280A or TECENTRIQ) is a human IgG1 monoclonal antibody consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese hamster ovary cells. Atezolizumab targets PD-L1 on immune cells or tumour cells and prevents interaction with either PD-1 receptor or B7.1 (CD80), both of which function as inhibitory receptors expressed on T cells. Interference of the PD-L1:PD-1 and PD-L1:B7.1 interactions may enhance the magnitude and quality of the tumour-specific T-cell response through increased T-cell priming, expansion, and/or effector function. At the time of study design, atezolizumab was approved in the United States for urothelial cancer.
    Evidence for comparator
    		 PD1/PD-L1-targeting checkpoint inhibitors have shown limited single agent activity in ER+ breast cancer. There is increasing evidence that CIT combinations can increase the activity of CIT by converting cancers into a more inflamed phenotype. This is particularly relevant for ER+ breast cancers which are predominantly non-inflamed. A wide range of CIT combinations are undergoing investigation, but preclinical models are of limited use in prioritising treatments as they fail to represent the complex interactions between tumour and the immune system. Preoperative window trials provide a robust and efficient clinical model to rapidly evaluate and prioritise these novel CIT strategies. Enrolment of multiple experimental arms within a single study, rather than one or two experimental arms within multiple studies, will result in an overall reduction in the number of patients receiving control arm treatment. More importantly, this study will assess the importance of simultaneously targeting multiple mechanisms of immune escape through immune cell priming and activation, tumour infiltration, and/or recognition of tumour cells for elimination. To improve the confidence of clinical signal detection in the combination arms, this study will include a control arm in which patients will receive single agent atezolizumab. Only combinations with adequate clinical safety data will be tested within this trial.
    Actual start date of recruitment
    01 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Worldwide total number of subjects
    71
    EEA total number of subjects
    56
    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)
    71
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study opened to recruitment on 21Dec2017 and the first patient was consented on 30Jan2018. The study was halted to recruitment on 10 February 2022 due to low recruitment rate. However, enough data was collected in order to analyse the endpoints as planned.

    Pre-assignment
    Screening details
    		 78 patients were screened for the trial, with 71 patients randomised. 7 patients screen failed, 5 from Germany and 2 from UK.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atezolizumab only
    Arm description
    		 Control arm. Atezolizumab (1200 mg IV D1) .
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg (equivalent to an average body weight-based dose of 15mg/kg) administered by IV infusion every 3 weeks (21 days). Atezolizumab was delivered over 60 (± 15) minutes.

    Arm title
    		 Atezolizumab + Cobimetinib
    Arm description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg (equivalent to an average body weight-based dose of 15mg/kg) administered by IV infusion every 3 weeks (21 days). Atezolizumab was delivered over 60 (± 15) minutes.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib at a dose of 60 mg (three 20 mg tablets) orally once daily on Days 1−21.

    Arm title
    		 Atezolizumab + Ipatasertib
    Arm description
    		 Atezolizumab (1200 mg IV D1)+ Ipatasertib (400 mg OD D1 – 21)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg (equivalent to an average body weight-based dose of 15mg/kg) administered by IV infusion every 3 weeks (21 days). Atezolizumab was delivered over 60 (± 15) minutes.

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (two 200mg tablets) orally once a day on Days 1−21.

    Arm title
    		 Atezolizumab + Cobimetinib + Bevacizumab
    Arm description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21) + Bevacizumab (10 mg/kg IV D1)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg (equivalent to an average body weight-based dose of 15mg/kg) administered by IV infusion every 3 weeks (21 days). Atezolizumab was delivered over 60 (± 15) minutes.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib at a dose of 60 mg (three 20 mg tablets) orally once daily on Days 1−21.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg administered by IV infusion over 90 min on day 1 cycle 1

    Number of subjects in period 1
    		Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab
    Started
    27
    9
    27
    8
    Completed
    27
    9
    27
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab only
    Reporting group description
    		 Control arm. Atezolizumab (1200 mg IV D1) .

    Reporting group title
    Atezolizumab + Cobimetinib
    Reporting group description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21)

    Reporting group title
    Atezolizumab + Ipatasertib
    Reporting group description
    		 Atezolizumab (1200 mg IV D1)+ Ipatasertib (400 mg OD D1 – 21)

    Reporting group title
    Atezolizumab + Cobimetinib + Bevacizumab
    Reporting group description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21) + Bevacizumab (10 mg/kg IV D1)

    Reporting group values
    		 Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab Total
    Number of subjects
    		 27 9 27 8 71
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 27 9 27 8 71
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 27 9 27 8 71
        Male
    		 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analyis set of full trial population

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    71
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    71
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    71
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab only
    Reporting group description
    		 Control arm. Atezolizumab (1200 mg IV D1) .

    Reporting group title
    Atezolizumab + Cobimetinib
    Reporting group description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21)

    Reporting group title
    Atezolizumab + Ipatasertib
    Reporting group description
    		 Atezolizumab (1200 mg IV D1)+ Ipatasertib (400 mg OD D1 – 21)

    Reporting group title
    Atezolizumab + Cobimetinib + Bevacizumab
    Reporting group description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21) + Bevacizumab (10 mg/kg IV D1)

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analyis set of full trial population

    Primary: Proportion of patients with a two-fold increase in GzmB+ CD8+ T cell levels

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    End point title
    		 Proportion of patients with a two-fold increase in GzmB+ CD8+ T cell levels
    End point description
    To determine whether adding immune-modulatory agents to atezolizumab increases the probability of an immune response over atezolizumab alone in patients with operable ER+ breast cancer. Proportion of patients with a two-fold increase in GzmB+ CD8+ T cell levels.
    End point type
    Primary
    End point timeframe
    baseline to end of treatment sample
    End point values
    		 Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab Full Analysis Set
    Number of subjects analysed
    15 [1]
    6 [2]
    18 [3]
    6 [4]
    51 [5]
    Units: percent
        number (confidence interval 95%)
    71.43 (47.82 to 88.72)
    66.67 (22.28 to 95.67)
    44.44 (21.53 to 69.24)
    33.33 (4.33 to 77.72)
    56.68 (42.25 to 70.65)
    Notes
    [1] - Based on tissue for pre and post treatment available for immunohistochemistry.
    [2] - Based on tissue for pre and post treatment available for immunohistochemistry.
    [3] - Based on tissue for pre and post treatment available for immunohistochemistry.
    [4] - Based on tissue for pre and post treatment available for immunohistochemistry.
    [5] - Based on tissue for pre and post treatment available for immunohistochemistry.
    Statistical analysis title
    		 Proportion of patients
    Statistical analysis description
    Changes in GzmB+ CD8+ T cell levels was assessed by a central laboratory, comparing tumour samples taken from the pre- to end of study-treatment samples. The proportion of patients with a two-fold increase in GzmB+ CD8+ T cell level is presented here.
    Comparison groups
    Atezolizumab + Cobimetinib + Bevacizumab v Atezolizumab only
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0069
         upper limit
    		 1.1863

    Secondary: Geometric mean Ki67 suppression

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    End point title
    		 Geometric mean Ki67 suppression
    End point description
    The effect of CIT combinations and Atezolizumab alone from pre- and end of study-treatment samples in patients who received at least one dose of study treatment was assessed by a central laboratory. Geometric mean Ki67 suppression is presented. Geometric mean Ki67 suppression is calculated as 1 minus the back-transformation of the arithmetic mean of [ln(Ki67post) – ln(Ki67pre)].
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    		 Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab Full Analysis Set
    Number of subjects analysed
    25
    8
    23
    8
    64
    Units: cells
        arithmetic mean (confidence interval 95%)
    0.019 (-0.153 to 0.1666)
    0.025 (-0.538 to 0.382)
    -0.14 (-0.585 to 0.179)
    0.423 (-0.359 to 0.755)
    0.035 (-0.14 to 0.184)
    No statistical analyses for this end point

    Secondary: Geometric mean caspase-3 suppression

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    End point title
    		 Geometric mean caspase-3 suppression
    End point description
    Geometric mean EOT Caspase-3 expression is calculated as the back-transformation of the arithmetic mean of [ln(Caspase-3post)]
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment
    End point values
    		 Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab Full Analysis Set
    Number of subjects analysed
    25
    8
    23
    8
    64
    Units: cells
        number (confidence interval 95%)
    -0.465 (-1.778 to 0.227)
    -3.338 (-22.116 to 0.166)
    -0.346 (-2.404 to 0.467)
    -1.038 (-6.608 to 0.453)
    -0.713 (-1.689 to -0.0915)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to safety visit 135 days after last dose of atezolizumab
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Atezolizumab only
    Reporting group description
    		 Control arm. Atezolizumab (1200 mg IV D1) .

    Reporting group title
    Atezolizumab + Cobimetinib
    Reporting group description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21)

    Reporting group title
    Atezolizumab + Ipatasertib
    Reporting group description
    		 Atezolizumab (1200 mg IV D1)+ Ipatasertib (400 mg OD D1 – 21)

    Reporting group title
    Atezolizumab + Cobimetinib + Bevacizumab
    Reporting group description
    		 Atezolizumab (1200 mg IV D1) + Cobimetinib (60 mg PO D1 - 21) + Bevacizumab (10 mg/kg IV D1)

    Serious adverse events
    		 Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 27 (33.33%)
    4 / 9 (44.44%)
    14 / 27 (51.85%)
    4 / 8 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    thromboembolic event
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 9 (33.33%)
    4 / 27 (14.81%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 27 (14.81%)
    0 / 9 (0.00%)
    2 / 27 (7.41%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    1 / 27 (3.70%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    1 / 27 (3.70%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    1 / 27 (3.70%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    7 / 27 (25.93%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    0 / 27 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Port Infection
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 9 (0.00%)
    1 / 27 (3.70%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningoencephalitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 9 (11.11%)
    0 / 27 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 9 (11.11%)
    0 / 27 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 9 (0.00%)
    1 / 27 (3.70%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab only Atezolizumab + Cobimetinib Atezolizumab + Ipatasertib Atezolizumab + Cobimetinib + Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 27 (96.30%)
    9 / 9 (100.00%)
    22 / 27 (81.48%)
    6 / 8 (75.00%)
    Investigations
    Haemoglobin increased
         subjects affected / exposed
    9 / 27 (33.33%)
    6 / 9 (66.67%)
    11 / 27 (40.74%)
    1 / 8 (12.50%)
         occurrences all number
    9
    6
    11
    1
    General disorders and administration site conditions
    Rash
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 9 (11.11%)
    9 / 27 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    9
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    26 / 27 (96.30%)
    9 / 9 (100.00%)
    9 / 27 (33.33%)
    5 / 8 (62.50%)
         occurrences all number
    26
    9
    9
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2018
    1) Addition of optional stool sample collection 2) Change in statistician 3) Updated IBs 4) Changes to Protocol and PISICF post urgent safety measure
    23 Jan 2019
    Temporary halt and lift in randomisation due to notification of an immune related meningoencephalitis event that occurred in a South Korean patient randomised into the atezolizumab plus cobimetinib arm. The ECLIPSE TSC discussed this event and felt that although this is a serious event it did not at this stage warrant stopping the trial or amending its design. This was to inform authorities of the event and the steps taken during a temporary halt.
    07 Mar 2019
    Amendment only submitted in Germany to add EU Sponsor representative.
    28 Mar 2019
    Updated IBs and additional safety information for Protocol v4.0.
    30 Aug 2019
    Urgent safety measure. Protocol amendment to remove the Cobimetinib containing arms. Following an Urgent Safety Measure (USM), recruitment in the two cobimetinib arms was permanently discontinued. Patients were subsequently randomised in a 1:1 ratio to receive either atezolizumab alone or atezolizumab plus ipatasertib.
    15 Oct 2020
    Updated IBs (Atezolizumab IB v15 and Addendum 2 and Ipatasertib IB v11) and additional safety information for Protocol v6.0 and PIS/ICF v7.0.
    23 Feb 2022
    Recruitment end with the view to submit an early termination form once all visits have been completed due to slow recruitment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Jan 2019
    Following a notification of an immune related meningoencephalitis event that occurred in a South Korean patient randomised into the atezolizumab plus cobimetinib arm. This event was notified as a SUSAR to the relevant competent authorities and ethics committees. As per the atezolizumab IB, immune related meningoencephalitis is a known but rare side effect of atezolizumab. However, as in this case atezolizumab was combined with cobimetinib, it was felt this should be investigated further whether the combination exacerbated this known side effect. As a pre-cautionary immediate step we notified participating centres not to consent and randomise any new patients into the study (23 January 2019). The Trial Steering Committee, which also has DMC responsibilities, approved this decision. Discussions with the IMP manufacturer was subsequently held who informed us that there is no signal in their unpublished safety data from other trials investigating the same combination. We also looked into all safety data across all four of the ECLIPSE treatment arms and did not identify any signals that affect the benefit-risk assessment of this trial. The ECLIPSE TSC discussed this event and felt that although this is a serious event it did not warrant stopping the trial or amending its design. The Committee felt that more prominent guidance should be provided to participating investigators on identifying early signs of immune related meningoencephalitis to allow them to treat these patients immediately. A letter was sent out to investigators as per the TSC’s recommendations.
    25 Mar 2019

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early closure of the cobimetinib arm after 17 patients recruited into these arms has meant smaller numbers available for analysis. Covid-19 also had a significant impact on recruitment to the ECLIPSE study and the study closed to recruitment early.
    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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