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    Clinical Trial Results:
    A multicenter, single-arm, phase II study to evaluate the activity of pre-operative zoledronate in triple negative breast cancer patients, according to p53 level

    Summary
    EudraCT number
    		 2014-004194-16
    Trial protocol
    		 IT  
    Global end of trial date
    08 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2022
    First version publication date
    15 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IRFMN-BRC-6591
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    Via Mario Negri 2, Milan, Italy,
    Public contact
    Laboratorio di metodologia per la ricerca clinica, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 039 0239014645, eliana.rulli@marionegri.it
    Scientific contact
    Laboratorio di metodologia per la ricerca clinica, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 039 0239014645, eliana.rulli@marionegri.it
    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 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study is primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with triple negative breast cancer selected according to the p53 expression (high vs low p53 expression).
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2014
    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
    Italy: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    15
    From 65 to 84 years
    5
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients fulfilling the eligibility criteria will be registered using a centralized system and will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery . The interval between diagnostic core biopsy and study registration must be no more than 2 weeks.

    Pre-assignment
    Screening details
    		 NA

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

    Arms
    Arm title
    		 Single arm
    Arm description
    		 Patients fulfilling the eligibility criteria will be registered using a centralized system and will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery . The interval between diagnostic core biopsy and study registration must be no more than 2 weeks. Tumor tissue samples will be collected at diagnosis (core-biopsy) and at the time of definitive surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive a single, pre-operative dose of Zol (ATC code M05BA08) 4mg i.v., planned after TNBC diagnosis, 7 days before the scheduled definitive breast surgery.

    Number of subjects in period 1
    		Single arm
    Started
    21
    Completed
    21

    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
    		 21 21
    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)
    		 15 15
        From 65-84 years
    		 5 5
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 60.3 (50.2 to 67.0) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
    Subject analysis sets

    Subject analysis set title
    All subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The All Subjects Analysis Set included all participants who provided informed consent and who were enrolled in the study.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set included all subjects who provided informed consent, who were enrolled in the study, who had no major violations of eligibility criteria, and who received the dose of study treatment

    Subject analysis set title
    PP1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set included all patients registered who had received the dose of study treatment and who had undergone the definitive breast surgery, without major eligibility criteria or study conduction violations and with p53 level < 30%.

    Subject analysis set title
    PP2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set included all patients registered who had received the dose of study treatment and who had undergone the definitive breast surgery, without major eligibility criteria or study conduction violations and with p53 level >= 30%.

    Subject analysis sets values
    		 All subjects Safety PP1 PP2
    Number of subjects
    21
    20
    8
    8
    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)
    15
    14
    14
        From 65-84 years
    5
    5
    5
        85 years and over
    1
    1
    1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    60.3 (50.2 to 67.0)
    61.2 (52.5 to 71.6)
    61.2 (52.5 to 71.6)
    Gender categorical
    Units: Subjects
        Female
    21
    20
    20

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 Patients fulfilling the eligibility criteria will be registered using a centralized system and will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery . The interval between diagnostic core biopsy and study registration must be no more than 2 weeks. Tumor tissue samples will be collected at diagnosis (core-biopsy) and at the time of definitive surgery.

    Subject analysis set title
    All subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The All Subjects Analysis Set included all participants who provided informed consent and who were enrolled in the study.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set included all subjects who provided informed consent, who were enrolled in the study, who had no major violations of eligibility criteria, and who received the dose of study treatment

    Subject analysis set title
    PP1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set included all patients registered who had received the dose of study treatment and who had undergone the definitive breast surgery, without major eligibility criteria or study conduction violations and with p53 level < 30%.

    Subject analysis set title
    PP2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set included all patients registered who had received the dose of study treatment and who had undergone the definitive breast surgery, without major eligibility criteria or study conduction violations and with p53 level >= 30%.

    Primary: Proportion of responder patients at surgery

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    End point title
    		 Proportion of responder patients at surgery
    End point description
    Primary endpoint of the study is the proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis.
    End point type
    Primary
    End point timeframe
    Surgery with respect to core-biopsy evaluation
    End point values
    		 PP1 PP2
    Number of subjects analysed
    7
    7
    Units: Patients
    3
    1
    Statistical analysis title
    		 Proportion of responder patients
    Statistical analysis description
    Proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis, will be presented as point estimate and 95% confidence intervals (95% CIs) for each group.
    Comparison groups
    PP1 v PP2
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Proportion of responder
    Point estimate
    42.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.9
         upper limit
    		 81.6
    Statistical analysis title
    		 Proportion of responder patients
    Statistical analysis description
    Proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis, will be presented as point estimate and 95% confidence intervals (95% CIs) for each group.
    Comparison groups
    PP2 v PP1
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Proportion of responder
    Point estimate
    14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 57.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs, whether reported by the patient or noted by study personnel, will be recorded in the patient’s medical record and on the AE form. All AEs, regardless of relationship to study drug, will be reported until 30 days after the dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 21 (14.29%)
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Aphthous ulcer
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2016
    PRINCIPAL CHANGES: 1. DRUG CHANGE -> possibility to use generic Zoledronato 2. STUDY PROCEDURE-> change in the length of the study 3. CONTACTS -> changes regarding study referents 4. CENTERS -> change PI in a centre 5. STUDY PROCEDURE-> change in the centers number 6. CONTRACT -> change in the contract between Sponsor and centers
    04 Sep 2017
    PRINCIPAL CHANGES: 1. STUDY PROCEDURE: change in the centralized laboratory 2. STUDY PROCEDURE: change in a metodological procedure 3. STUDY PROCEDURE: changes in the administrative procedure 4. IMPD changes 5 and 6 CONTACTS: changes regarding study referents

    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
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