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    Clinical Trial Results:
    A multicenter, randomised, open-label Phase II study to evaluate the clinical benefit of a post-operative treatment associating radiotherapy + Nivolumab + Ipilimumab versus radiotherapy + Capecitabine for triple negative breast cancer patients with residual disease after neoadjuvant chemotherapy.

    Summary
    EudraCT number
    		 2017-003151-34
    Trial protocol
    		 FR  
    Global end of trial date
    13 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2025
    First version publication date
    30 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ET17-093
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Léon Bérard
    Sponsor organisation address
    28 Rue Laënnec, Lyon, France,
    Public contact
    DRCI, Centre Léon Bérard, +33 426556824,
    Scientific contact
    DRCI, Centre Léon Bérard, +33 426556824,
    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
    12 Nov 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical benefit of a post-operative adjuvant therapy combining radiotherapy + Nivolumab + Ipilimumab versus radiotherapy + Capecitabine in in triple negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy.
    Protection of trial subjects
    Study treatments will continue to be administered as long as patient experiences clinical benefit in the opinion of the investigator or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent. The investigator will have to inform the patient of the study treatment, the objectives and the design of tthe study, as well as the biological samples collection, provide the patient information leaflet / Informed consent form, answer to any questions that the patient may have and ensure that she understands the potential risks and benefits of participating in the study before signing the informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 95
    Worldwide total number of subjects
    95
    EEA total number of subjects
    95
    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)
    95
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The screening period lasts for up to 28 days starting when the ICF is signed and ending before the first administration of study drugs (C1D1).

    Period 1
    Period 1 title
    Overall study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    last for up to 24 weeks (or at maximum 36 weeks in case of dose delay) starting at first study drugs intake and ending when the decision is made to permanently discontinue the study drugs.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OPDIVO®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Maximum of 8 doses Intravenous (IV).over a 24-week (or 36-week in case of dose delays) period or until disease recurrence, unacceptable toxicity, patient willingness to stop or withdrawal of consent

    Investigational medicinal product name
    Yervoy®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.

    Arm title
    		 Arm B
    Arm description
    		 Capecitabine (1000 mg/m2 twice a day, Bis In Die [BID]), 14 days on / 7 days off for 8 cycles
    Arm type
    		 Standard treatment

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine, oral, 1000 mg/m2, twice a day for 14 days followed by a 7-day rest period. Up to 8 cycles over a 24-week period (or 36-week in case of dose delays) or until disease recurrence, unacceptable toxicity, patient willingness to stop, or withdrawal of consent

    Number of subjects in period 1
    		Arm A Arm B
    Started
    45
    50
    Treatment period
    Follow-up period
    Completed
    45
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine (1000 mg/m2 twice a day, Bis In Die [BID]), 14 days on / 7 days off for 8 cycles

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 45 50 95
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 45 50 95
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 47 (29 to 79) 46 (31 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 45 50 95
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.

    Reporting group title
    Arm B
    Reporting group description
    		 Capecitabine (1000 mg/m2 twice a day, Bis In Die [BID]), 14 days on / 7 days off for 8 cycles

    Primary: Disease free survival

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    End point title
    		 Disease free survival [1]
    End point description
    The primary endpoint is the Disease free survival. DFS is defined as the time from randomization until the date of the first relapse (local/regional recurrence or distant metastasis) or death (from any cause) whichever comes firsts and regardless of whether the patient withdraws from randomised study treatment or receives another anti-cancer therapy prior to disease relapse. Patients with no event at the time of the analysis will be censored at the date of the last adequate tumor assessment. It will be analysed based on the data from the ITT population. DFS will be estimated using the Kaplan-Meier method and will be described in terms of median and 2-year DFS per arm.Associated 2-sided 95% CI for the estimates will be provided. DFS distributions will be compared between the 2 study arms using a 2-sided Log-Rank test (significance level of5%) stratified by centers,PS ECOG and RCB Class, supported by a stratified Cox regression. Hazard ratio will be provided its 95% CI.
    End point type
    Primary
    End point timeframe
    DFS is defined as the time from randomization until the date of the first relapse (local/regional recurrence or distant metastasis) or death (from any cause)
    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: No difference was observed between the 2 arms (HR=0.84 ; CI95%=0.45-1.59 ; log-rank test pvalue =0.59).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45
    50
    Units: Proportion
    number (confidence interval 95%)
        12 months
    0.67 (0.51 to 0.78)
    0.64 (0.49 to 0.76)
        36 months
    0.62 (0.46 to 0.75)
    0.60 (0.45 to 0.72)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The investigator collects (spontaneous patient report or questionning) and immediately notifies the sponsor of all SAEs, in a written report, wether or not theay are deemed to be attributable to research and wich occur during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Grade 2 AEs were reported in 43 patients (96%) treated by NIVO+IPI vs 43 patients (86%) treated by Capecitabine and grade 3 AEs related to treatment were reported in 22 patients (49%) treated by NIVO+IPI vs 22 patients (44%) treated by Capecitabine. The most commons Grade 2 AEs were Lymphocytes count decreased (43%), Radiation skin injury (28%), Fatigue (25%), Hyperthyroidism. AEs causing permanent treatment discontinuation occurred in 38% (17 pts) of NIVO+IPI vs 14% (7 pts) of Capecitabine.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2019
    Ancillary study on physical activity: addition of monthly monitoring for 6 months by a qualified teacher Updated list of investigators (Addition of 4 new centers and 25 investigators + Addition of two investigators in two already declared research locations) Resubmission of amendment to the CPP (06/08/2019) with the addition of details in the information note on the molecular analyses which will be carried out as part of the biological study associated with this trial, including gene analyses (expression and/or anomalies). These analyses were planned since the initial version of the protocol (Section 9.2) but not mentioned in the information note.
    25 Oct 2019
    Updated investigator brochure (Nivolumab requires specific monitoring and management of cardiac toxicities (myocarditis)). The risk of myocarditis was already mentioned in previous versions of the information notes. Updated investigator list (Change of principal investigator (PI) for the Paoli Calmette Institute center (Marseille) + Addition of 5 new centers and 24 investigators + Addition of an investigator for the Western Cancer Institute (Saint Herblain))
    03 Feb 2020
    Addition of a cortisol level measurement as recommended by the French Society of Endocrinology for patients undergoing immunotherapy Update of the list of investigators (declaration of 2 new centers and a new investigator in a research location already declared)
    12 May 2020
    Establishment of the additional monitoring committee after randomization and treatment for at least 1 cycle of the first 9 and 20 patients randomized in arm A. Update of the BI of ipilimumab Edition 23 of 03/11/2020 without impact on the protocol and transmission of the BI Edition 22 of 03/11/2019 for information purposes also without impact on the protocol. Request to resume the test after a temporary stop.
    10 Nov 2020
    Modification of inclusion criterion I6 to allow the inclusion of patients with residual disease of RCB class II (see justification below and in protocol V8.0 of 16/10/2020), consequently, modification of the hypotheses, the number and the duration of inclusions. Updating the list of investigators (Change of name and address of the Paul Strauss Centre + Addition of a center attached to the already declared participating center + Error found on an email address)
    14 Sep 2021
    Updating the list of investigators (declaration of a new participating center) The extension of the inclusion period by 12 months and consequently, of the total duration of the study. To date, 71 patients have been included out of the 114 planned.
    09 Nov 2021
    An urgent safety measure (USM) notification: Definitive cessation of inclusions with continuation of experimental treatments for patients still undergoing treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Oct 2021
    The definitive cessation of recruitment in the study
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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