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    Clinical Trial Results:
    A Phase II Trial Testing Durvalumab Combined With Endocrine Therapy in Patients With ER+/Her2- Breast Cancer Eligible for Neoadjuvant Endocrine Therapy And Who Present CD8+ T Cell Infiltration After 4-6 Weeks Exposure to Immune-Attractant.

    Summary
    EudraCT number
    2016-000764-42
    Trial protocol
    FR   ES  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UC-0140/1606
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02997995
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 171936704, n.ait-rahmoune@unicancer.fr
    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
    21 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of durvalumab combined with exemestane in patients with CD8+ T cells on pathological response at surgery after a lymphocyte attraction phase.
    Protection of trial subjects
    In order to ensure the protection of the rights, safety and well-being of trial subjects, this clinical trial was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws. Furthermore, independent Ethics Committees in France, Sweden and Belgium reviewed and gave a favorable opinion to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Mar 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    Spain: 9
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    31
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Multicentric, open-label phase II trial testing an aromatase inhibitor in combination with durvalumab in &#8805;18 years old men or post-menopausal women eligible to neoadjuvant endocrine therapy for T2-4 ER+/HER2- breast cancer with CD8+T cell infiltration (>10% CD8+T cells in the tumour). patient recruitment: 02-Mar-2017 to 10-Apr-2020.

    Pre-assignment
    Screening details
    The study consisted of a screening phase of up to 30 days before treatment initiation to establish eligibility and document baseline measurements, a part 1 treatment phase (6-week), a part 2 treatment phase (28-day cycle; 6 months), a surgery and a long-term follow-up to monitor pathological complete response, CD8 infiltration, Ki67, and safety.

    Pre-assignment period milestones
    Number of subjects started
    61
    Intermediate milestone: Number of subjects
    Part 1: Chemo-attractant: 61
    Number of subjects completed
    24

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 3
    Reason: Number of subjects
    Protocol deviation: 3
    Reason: Number of subjects
    CD8+T cells infiltration lower than 10%: 31
    Period 1
    Period 1 title
    Part 2 : Immunotherapy (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Tremelimumab
    Arm description
    Part 1 used an open label, adaptive trial design of testing 4 to 6 weeks treatment with the immune attractants Tremelimumab plus Exemestane to increase CD8+T cell infiltration in the tumor site. Patients with >10% CD8+T cells in the tumor biopsy (3 weeks after Tremelimumab initiation) moved to the part 2 (core of the trial) of the study These patients received 6 months Exemestane plus Durvalumab before undergoing surgery.
    Arm type
    Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab was administered, concomitant to Exemestane, as an IV infusion over approximately 60 minutes (±5 minutes) every 4 weeks.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab was administered, concomitant to Exemestane (Section 9.4.1.2.1), as single IV infusion over approximately 60 minutes (±5 minutes).

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane was prescribed in the therapeutic indication of neoadjuvant therapy for hormone receptor positive disease in postmenopausal women. Thus, the posology was 25 mg/day per os (p.o.: oral) until the day prior surgery.

    Number of subjects in period 1 [1]
    Tremelimumab
    Started
    24
    Completed
    20
    Not completed
    4
         Adverse event, non-fatal
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Patients must have >10% CD8+T cell infiltration in the tumor site after Tremelimumab treatment (Part 1). 37 out of 61 patients treated with Tremelimumab were not included in part 2 of the study due to a CD8+T cells infiltration lower than 10% (n=31), adverse events (n=3), and non-compliance to treatment (n=3). Thus, only 24 patients were included in part 2. The Baseline period reported here correspond to the part 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 2 : Immunotherapy
    Reporting group description
    -

    Reporting group values
    Part 2 : Immunotherapy Total
    Number of subjects
    24 24
    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)
    14 14
        From 65-84 years
    10 10
        85 years and over
    0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    66 (61 to 71) -
    Gender categorical
    Units: Subjects
        Female
    24 24
        Male
    0 0
    Tumor localization
    Units: Subjects
        Right Breast
    10 10
        Left Breat
    14 14
    Histological type
    Units: Subjects
        Lobular
    7 7
        Invasive
    11 11
        Canalar
    3 3
        Mucinous
    1 1
        Other
    2 2
    Estrogen Allred score
    Units: Arbitrary
        median (inter-quartile range (Q1-Q3))
    8 (8 to 8) -
    Progesterone Allred score
    Units: Arbitrary
        median (inter-quartile range (Q1-Q3))
    8 (5 to 8) -

    End points

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    End points reporting groups
    Reporting group title
    Tremelimumab
    Reporting group description
    Part 1 used an open label, adaptive trial design of testing 4 to 6 weeks treatment with the immune attractants Tremelimumab plus Exemestane to increase CD8+T cell infiltration in the tumor site. Patients with >10% CD8+T cells in the tumor biopsy (3 weeks after Tremelimumab initiation) moved to the part 2 (core of the trial) of the study These patients received 6 months Exemestane plus Durvalumab before undergoing surgery.

    Primary: pathological Complete Response

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    End point title
    pathological Complete Response [1]
    End point description
    End point type
    Primary
    End point timeframe
    At surgery (7.5 months after inclusion)
    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: The Simon’s optimal two-stage design was used for the part 2 of this study. In the first stage, if 2 or more pathological complete responses (pCR) were observed in 23 patients, the part 2 could move to stage 2, otherwise the study had to be stopped . Only 1 patient had pCR, thus the futility criterion was met and the study was stopped.
    End point values
    Tremelimumab
    Number of subjects analysed
    24
    Units: subject
        Yes
    1
        No
    21
        Missing
    2
    No statistical analyses for this end point

    Secondary: Changes in CD8+ T-cells infiltration over time

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    End point title
    Changes in CD8+ T-cells infiltration over time
    End point description
    End point type
    Secondary
    End point timeframe
    3 weeks from Tremelimumab treatment initiation
    End point values
    Tremelimumab
    Number of subjects analysed
    24
    Units: percent
        arithmetic mean (confidence interval 95%)
    10.8 (6.8 to 14.7)
    No statistical analyses for this end point

    Secondary: Changes un Ki67 expression over time

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    End point title
    Changes un Ki67 expression over time
    End point description
    End point type
    Secondary
    End point timeframe
    3 weeks from Tremelimumab treatment initiation
    End point values
    Tremelimumab
    Number of subjects analysed
    24
    Units: percent
        arithmetic mean (confidence interval 95%)
    -6.0 (-8.8 to -3.3)
    No statistical analyses for this end point

    Secondary: Measurements of Tumour Infiltrating Lymphocytes (TILs)

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    End point title
    Measurements of Tumour Infiltrating Lymphocytes (TILs)
    End point description
    End point type
    Secondary
    End point timeframe
    3 weeks from Tremelimumab treatment initiation
    End point values
    Tremelimumab
    Number of subjects analysed
    24
    Units: percent
        arithmetic mean (confidence interval 95%)
    4.7 (0.7 to 8.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months from inclusion
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Tremelimumab
    Reporting group description
    Part 1 used an open label, adaptive trial design of testing 4 to 6 weeks treatment with the immune attractants Tremelimumab plus Exemestane to increase CD8+T cell infiltration in the tumor site. Patients with >10% CD8+T cells in the tumor biopsy (3 weeks after Tremelimumab initiation) moved to the part 2 (core of the trial) of the study These patients received 6 months Exemestane plus Durvalumab before undergoing surgery.

    Serious adverse events
    Tremelimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 24 (16.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tremelimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    Vascular disorders
    Hot flashes
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 24 (50.00%)
         occurrences all number
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    7
    Lactate dehydrogenase urine increased
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    5
    alkaline phosphatase increased
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Potassium increased
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Serum amylase increased
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Serum lipase increased
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Thyroid-stimulating hormone decreased
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Thyroid-stimulating hormone increased
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Urea urine increased
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    5
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    23 / 24 (95.83%)
         occurrences all number
    23
    Nausea
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Hyperglycaemia
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    6
    Hypokalaemia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Hypomagnesaemia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
         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
    09 Jan 2018
    A non-inclusion criterion has been added to exclude patients with previous malignancy within 5 years before inclusion in the study. Indeed, 5 years without recurrence is generally accepted as the minimum time to declare a person in remission. Basal cell carcinoma, squamous cell carcinoma of the skin and cervical carcinoma in situ, for which the cure rates are 100%, are not concerned by this measure.
    14 May 2019
    * An inclusion criterion has been reworded to make it clear that men can participate in this study. * To clarify the conditions for patient transition between the part 1 to part 2 of the study, the 3 inclusion criteria and 2 exclusion criteria related to patient safety which are to be reevaluated before inclusion in part 2 were specified in the study protocol. * A non-inclusion criterion was modified to exclude from Part 2 any patient who has experienced an adverse event of an immunological nature in Part 1. * Modification of the interim safety analysis section following the IDMC decision. The new version indicated that the inclusion of patients in the study was stopped on February 26th 2018 for the purpose of this analysis. On April 30th 2018, the IDMC decided that, according to the rules of the interim safety analysis, the study should continue.
    02 Jul 2019
    The inclusion criteria related to patient contraception has been modified in order to clarify the condition of contraception in men participating in the study
    22 Jun 2020
    The planned interim efficacy analysis was performed on 22 out of 24 patients included in the part 2 of the study. Results demonstrated that the study did not reach its primary objective thus, as planned in the protocol, the inclusion of new patients were definitively stopped

    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.
    Only 1 out of 4 cohorts of patients was tested in part 1 (immune attractant) of the study. Concerning adverse events the "Occurrences all number" was not reported, thus, the number of patients is noted in this field.
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