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    Clinical Trial Results:
    Abrogation of chronic monoclonal antibody treatment-induced T-cell exhaustion with DURVALUMAB (MEDI4736) in advanced HER-2 negative breast cancer: a pilot proof-of-concept trial

    Summary
    EudraCT number
    		 2015-005609-34
    Trial protocol
    		 ES  
    Global end of trial date
    09 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2020
    First version publication date
    30 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNIO-BR-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02802098
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundación CRIS de investigación para vencer el cáncer
    Sponsor organisation address
    Princesa de Eboli, 9, Madrid, Spain, 28050
    Public contact
    Marta Cardona, Fundación CRIS de investigación para vencer el cáncer, +34 911161312, mcardona@criscancer.org
    Scientific contact
    Marta Cardona, Fundación CRIS de investigación para vencer el cáncer, +34 911161312, mcardona@criscancer.org
    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 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the immunodynamics in peripheral blood and in the tumor of combined administration of DURVALUMAB and the monoclonal antibody bevacizumab in advanced HER-2- negative breast cancer patients that have progressed to bevacizumab-based treatment.
    Protection of trial subjects
    All patients have been treated according to GCP criteria. Patients were entitled to withdraw from the study at any time and for any reason without prejudice of their future medical care on the part of the doctor or the center. Any medication that patients needed for their correct clinical control (except prohibited therapies), according to investigator’s criteria were allowed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 May 2016
    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
    Spain: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    19
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient were recruited in the study from June 13th 2016 until July 9th 2018

    Pre-assignment
    Screening details
    		 The patients underwent PDL-1 analysis before signing the study informed consent form in order to check if the patient was elegible. A physical examination, serology, hematology, biochemistry, ECG and a tumor evaluation and biopsy were performed to participating patients.

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

    Arms
    Arm title
    		 Study treatment
    Arm description
    		 Treatment with DURVALUMAB, if ≥ 30 kg, commences on day 1 following confirmation of eligibility into the study and continues on a Q2W schedule + Bevacizumab 15 mg/ Kg Q3W or 10 mg/ Kg Q2W, IV infusion for a maximum duration of treatment of 12 months. Study treatment should be discontinued prior to 12 months if there is confirmed PD (unless the investigator considers the subject to continue to receive benefit from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study treatment occur.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg administrated once every 3 weeks or 10 mg/kg administrated once every 2 weeks.

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Patients with ≥ 30 kg, a fixed dose of 750 mg of DURVALUMAB was administered every 2 weeks (Equivalent dose of 10 mg/kg Q2W).

    Number of subjects in period 1
    		Study treatment
    Started
    25
    Completed
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 25 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 54.1 (34.5 to 77.4) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 1 1
    Race
    Units: Subjects
        Caucasian
    		 23 23
        Arabian
    		 1 1
        Latin
    		 1 1
    ECOG-PS at baseline
    Units: Subjects
        ECOG-PS 0
    		 15 15
        ECOG-PS 1
    		 10 10
    TNM at diagnosis
    T
    Units: Subjects
        Tx
    		 2 2
        T1
    		 4 4
        T2
    		 10 10
        T3
    		 5 5
        T4
    		 2 2
        ND
    		 2 2
    TNM at diagnosis
    N
    Units: Subjects
        Nx
    		 2 2
        N0
    		 6 6
        N1
    		 11 11
        N2
    		 1 1
        N3
    		 3 3
        ND
    		 2 2
    TNM at diagnosis
    M
    Units: Subjects
        M0
    		 16 16
        M1
    		 8 8
        ND
    		 1 1
    Stage at diagnosis
    Stage
    Units: Subjects
        IA
    		 2 2
        IIA
    		 4 4
        IIB
    		 5 5
        IIIC
    		 4 4
        IV
    		 7 7
        ND
    		 3 3
    TNM at study inclusion
    T
    Units: Subjects
        Tx
    		 2 2
        T0
    		 1 1
        T1
    		 1 1
        T2
    		 4 4
        T3
    		 1 1
        T4
    		 2 2
        ND
    		 14 14
    TNM at study inclusion
    N
    Units: Subjects
        Nx
    		 2 2
        N0
    		 3 3
        N1
    		 4 4
        N2
    		 2 2
        N3
    		 1 1
        ND
    		 13 13
    TNM at study inclusion
    M
    Units: Subjects
        M1
    		 24 24
        ND
    		 1 1
    Stage at study inclusion
    Units: Subjects
        IV
    		 24 24
        ND
    		 1 1
    Histology
    Units: Subjects
        Ductal
    		 18 18
        Lobular
    		 4 4
        Others
    		 3 3
    Differentation grade
    Units: Subjects
        G1
    		 3 3
        G2
    		 10 10
        G3
    		 7 7
        ND
    		 5 5
    Estrogen hormonal receptors
    Units: Subjects
        Positive
    		 16 16
        Negative
    		 9 9
    Previous surgery
    Units: Subjects
        Yes
    		 21 21
        No
    		 4 4
    Sentinel node biopsy result
    Units: Subjects
        Positive
    		 7 7
        Negative
    		 2 2
        Not biopsied
    		 16 16
    Previous local chemotherapy
    Units: Subjects
        Yes
    		 16 16
        No
    		 9 9
    Previous treatments: monotherapy and radiotherapy
    Units: Subjects
        Yes
    		 18 18
        No
    		 7 7
    Number of previous lines to advanced/metastatic disease
    Units: Subjects
        One
    		 4 4
        Two
    		 8 8
        Three
    		 4 4
        Four
    		 6 6
        Five
    		 2 2
        Seven
    		 1 1
    Number of locations
    Units: Subjects
        One
    		 4 4
        Two
    		 8 8
        Three
    		 3 3
        Four
    		 3 3
        Five
    		 4 4
        Six
    		 1 1
        Seven
    		 1 1
        Eight
    		 1 1
    Number of cycles administered
    Units: Subjects
        One
    		 2 2
        Two
    		 5 5
        Three
    		 9 9
        Four
    		 2 2
        Five
    		 1 1
        Six
    		 1 1
        Eight
    		 2 2
        Thirteen
    		 2 2
        Fourteen
    		 1 1
    Number of durvalumab infusion interruptions
    Non-hematological toxicity (N=4)
    Units: Subjects
        None
    		 22 22
        One
    		 2 2
        Two
    		 1 1
    Number of bevacizumab infusion interruptions
    Non-hematological toxicity (N=6), treatment not related (1), not related AE (1)
    Units: Subjects
        None
    		 18 18
        One
    		 6 6
        Two
    		 1 1
    Number of durvalumab infusions delayed
    Not related AE (N=3), Treatment not related reason (N=1)
    Units: Subjects
        None
    		 21 21
        One
    		 4 4
    Number of bevacizumab infusions delayed
    Not related AE (N=3), Treatment not related reason (N=2)
    Units: Subjects
        None
    		 20 20
        One
    		 5 5
    Progesterone receptors
    Units: Subjects
        Positive
    		 10 10
        Negative
    		 15 15
    Previous radiotherapy
    Units: Subjects
        Yes
    		 14 14
        No
    		 11 11
    PDL-1 Expression
    Units: Subjects
        Positive
    		 4 4
        Negative
    		 16 16
        Unknow
    		 5 5
    Cardiac frequency
    Units: bpm
        median (full range (min-max))
    		 75.0 (58.0 to 96.0) -
    Temperature
    Units: celsius temperature
        median (full range (min-max))
    		 36.1 (35.1 to 36.7) -
    Sistolic blood pressure
    Units: mmHg
        median (full range (min-max))
    		 125.0 (77.0 to 162.0) -
    Diastolic blood pressure
    Units: mmHg
        median (full range (min-max))
    		 75.0 (61.0 to 90.0) -
    Respiratory frequency
    Units: breaths per minute
        median (full range (min-max))
    		 16.0 (12.0 to 22.0) -
    Weight
    Units: Kg
        median (full range (min-max))
    		 57.0 (47.0 to 75.2) -
    Height
    Units: cm
        median (full range (min-max))
    		 160.0 (150.0 to 179.0) -
    Time from initial diagnosis
    Units: months
        median (full range (min-max))
    		 43.2 (4.7 to 116.0) -
    Time from metastatic diagnosis
    Units: months
        median (full range (min-max))
    		 18.1 (0.2 to 116.0) -
    Time from intial diagnosis to metastatic diagnosis
    Units: months
        median (full range (min-max))
    		 4.6 (0.0 to 97.2) -
    Time of previous treatment with bevacizumab
    Units: months
        median (full range (min-max))
    		 7.9 (1.6 to 24.7) -
    Time on treatment
    Units: Weeks
        median (full range (min-max))
    		 18.6 (4.1 to 57.3) -
    Bevacizumab dose intensity
    Units: mg/Kg/week
        median (full range (min-max))
    		 4.5 (2.4 to 4.95) -
    Durvalumab dose intensity
    Units: mg/week
        median (full range (min-max))
    		 332.7 (181.03 to 375.0) -
    Bevacizumab related dose intensity
    Units: NA
        median (full range (min-max))
    		 0.90 (0.48 to 0.99) -
    Durvalumab related dose intensity
    Units: NA
        median (full range (min-max))
    		 0.89 (0.48 to 1.0) -

    End points

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    End points reporting groups
    Reporting group title
    Study treatment
    Reporting group description
    		 Treatment with DURVALUMAB, if ≥ 30 kg, commences on day 1 following confirmation of eligibility into the study and continues on a Q2W schedule + Bevacizumab 15 mg/ Kg Q3W or 10 mg/ Kg Q2W, IV infusion for a maximum duration of treatment of 12 months. Study treatment should be discontinued prior to 12 months if there is confirmed PD (unless the investigator considers the subject to continue to receive benefit from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study treatment occur.

    Primary: Peripheral Blood Mononuclear Cells (PBMCS) differences after treatment between responders and non-responders

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    End point title
    		 Peripheral Blood Mononuclear Cells (PBMCS) differences after treatment between responders and non-responders [1]
    End point description
    Differences in CD4+, CD8+ and Treg cells
    End point type
    Primary
    End point timeframe
    From treatment initiation to first evaluation (8 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: One arm clinical trial. Only descriptive analyses performed. No comparisons.
    End point values
    		 Study treatment
    Number of subjects analysed
    25
    Units: p-value
    number (not applicable)
        CD4+ Naïve
    0.87
        CD4+ Effector
    0.01
        CD4+ Central memory
    0.09
        CD4+ Effector Memory
    0.04
        CD8+ Naive
    0.1
        CD8+ Effector
    0.02
        CD8+ Central memory
    0.02
        CD8+ Effector memory
    0.78
        T-reg
    0.11
    No statistical analyses for this end point

    Secondary: Clinical Benefit rate at 4 months

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    End point title
    		 Clinical Benefit rate at 4 months
    End point description
    End point type
    Secondary
    End point timeframe
    From treatment initiation to 4 months follow-up.
    End point values
    		 Study treatment
    Number of subjects analysed
    25 [2]
    Units: Patients
        Partial response
    2
        Stable disease
    5
        Not follow-up available
    18
    Notes
    [2] - Only 7 patients have a follow-up >=4 months
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the end of first treatment dose to 90 days after last dose of durvalumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Bevacizumab and Durvalumab treatment
    Reporting group description
    		 -

    Serious adverse events
    		 Bevacizumab and Durvalumab treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 25 (28.00%)
         number of deaths (all causes)
    12
         number of deaths resulting from adverse events
    1
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab and Durvalumab treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 25 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 25 (56.00%)
         occurrences all number
    14
    General physical health deterioration
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Peripheral swelling
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Mucosal dryness
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Chest pain
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    5 / 25 (20.00%)
         occurrences all number
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Depression
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 25 (20.00%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Leukopenia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Eye disorders
    Xerophthalmia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 25 (28.00%)
         occurrences all number
    7
    Abdominal pain upper
         subjects affected / exposed
    5 / 25 (20.00%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    4 / 25 (16.00%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    4 / 25 (16.00%)
         occurrences all number
    4
    Hepatobiliary disorders
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Proteinuria
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    4 / 25 (16.00%)
         occurrences all number
    4
    Musculoskeletal pain
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Bone pain
         subjects affected / exposed
    5 / 25 (20.00%)
         occurrences all number
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 25 (20.00%)
         occurrences all number
    5
    Hyperglycaemia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Hypothyroidism
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2017
    Modification toxicity management guidelines
    26 Oct 2017
    Inclusion criteria modified
    18 Dec 2018
    Updating protocol safety information according to new Investigator Brochure.

    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.
    The pilot design of the study and the sample size analyzed do not allow to detail a definitive conclusions. Only 7 patients of 25 could be followed up for 4 months.
    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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