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    Clinical Trial Results:
    MOLECULAR FLUORESCENCE-GUIDED SURGERY (MFGS) USING BEVA800 FOR THE ASSESSMENT OF TUMOR MARGINS DURING BREAST CONSERVING SURGERY OF PATIENTS WITH PRIMARY BREAST CANCER (MARGIN-II)

    Summary
    EudraCT number
    		 2018-003614-40
    Trial protocol
    		 DE  
    Global end of trial date
    13 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2022
    First version publication date
    19 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SVB800_001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bracco Imaging SpA
    Sponsor organisation address
    Via Folli 50, Milan, Italy, 20134
    Public contact
    Paola Pianezzola, Bracco Imaging SpA, 0039 0221772324, Paola.Pianezzola@bracco.com
    Scientific contact
    Paola Pianezzola, Bracco Imaging SpA, 0039 0221772324, Paola.Pianezzola@bracco.com
    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
    15 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To assess the efficacy of fluorescence imaging using the 4.5 mg of the fluorescent tracer Beva800 at reducing the rate of positive tumor margins compared to standard-of-care (SOC) breast conserving surgery (BCS); • To obtain additional safety data on exposure of breast cancer patients to 4.5 mg Beva800.
    Protection of trial subjects
    Investigators agreed to make no informal changes to the protocol, except when necessary to protect the safety, the rights or the welfare of subjects. In addition, the Sponsor ensures insurance coverage for damages concerning the subject during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 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
    Germany: 51
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    34
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Informed consent was collected from 14 October 2019 to 13 September 2020. Female subjects >=18 years of age able to give informed consent and comply with the protocol requirements who were scheduled to undergo breast conserving surgery.

    Pre-assignment
    Screening details
    		 51 subjects enrolled, however 2 withdrew consent prior to dose administration, therefore 49 were included in the Safety Population (SAF Pop). 4 subjects were training cases, therefore 45 included in Intent-to-Treat Population (ITT Pop).

    Pre-assignment period milestones
    Number of subjects started
    		 51
    Number of subjects completed
    		 49

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    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
    		 Beva800
    Arm description
    		 The diagnostic agent Beva800 is an immune-conjugate consisting of the commercially available recombinant humanized anti-vascular endothelial growth factor A (VEGF-A) monoclonal antibody bevacizumab (Avastin®, Hofmann-La Roche, Switzerland) conjugated to the commercially available N-hydroxysuccinamide ester form of the near-infrared fluorescent dye IRDye800CW (LI-COR Biosciences, Lincoln, Nebraska, USA). The final concentration of Beva800 is 1 mg/mL in formulation buffer of 50 mM sodium phosphate and 101 mM sodium chloride at pH 7.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Beva800
    Investigational medicinal product code
    Other name
    bevacizumab-IRDye800CW
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Three days prior to surgery, intravenous injection of a single bolus of 4.5 mg Beva800, corresponding to 4.5 mL of volume was administered to the subject.

    Number of subjects in period 1 [1]
    		Beva800
    Started
    49
    Completed
    49
    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: Fifty-one (51) subjects enrolled in the study, however, 2 subjects withdrew consent prior to study agent administration, therefore, only 49 subjects are included in the Overall Trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 The safety analysis (SAF) population consisted of all subjects, including training cases, who received an injection of the diagnostic agent Beva800 in the study. The safety analysis was based on the safety population.

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 49 49
    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)
    		 32 32
        From 65-84 years
    		 17 17
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ( 10.91 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 49
        Male
    		 0 0
    Race
    Units: Subjects
        White
    		 49 49
        Black
    		 0 0
        Asian
    		 0 0
        Other
    		 0 0
    Menopausal status
    Units: Subjects
        Pre-menopausal
    		 14 14
        Surgical menopause
    		 2 2
        Peri-menopausal (last menses < 1 year)
    		 1 1
        Post-menopausal (last menses >= 1 year)
    		 32 32
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 165.2 ( 6.11 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 71.38 ( 12.10 ) -
    Age at Menopause
    Units: year
        arithmetic mean (standard deviation)
    		 49.9 ( 5.23 ) -
    Subject analysis sets

    Subject analysis set title
    ITT Pop
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population is defined as the subset of subjects in the safety population (excluding the 4 training cases) for whom the surgery after administration of Beva800 was completed in the study. If needed, this population was used for sensitivity analyses.

    Subject analysis sets values
    		 ITT Pop
    Number of subjects
    45
    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)
    31
        From 65-84 years
    14
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.0 ( 10.48 )
    Gender categorical
    Units: Subjects
        Female
    45
        Male
    0
    Race
    Units: Subjects
        White
    45
        Black
    0
        Asian
    0
        Other
    0
    Menopausal status
    Units: Subjects
        Pre-menopausal
    14
        Surgical menopause
    2
        Peri-menopausal (last menses < 1 year)
    1
        Post-menopausal (last menses >= 1 year)
    28
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    165.8 ( 5.69 )
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    71.57 ( 12.45 )
    Age at Menopause
    Units: year
        arithmetic mean (standard deviation)
    49.8 ( 5.53 )

    End points

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    End points reporting groups
    Reporting group title
    Beva800
    Reporting group description
    		 The diagnostic agent Beva800 is an immune-conjugate consisting of the commercially available recombinant humanized anti-vascular endothelial growth factor A (VEGF-A) monoclonal antibody bevacizumab (Avastin®, Hofmann-La Roche, Switzerland) conjugated to the commercially available N-hydroxysuccinamide ester form of the near-infrared fluorescent dye IRDye800CW (LI-COR Biosciences, Lincoln, Nebraska, USA). The final concentration of Beva800 is 1 mg/mL in formulation buffer of 50 mM sodium phosphate and 101 mM sodium chloride at pH 7.

    Subject analysis set title
    ITT Pop
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population is defined as the subset of subjects in the safety population (excluding the 4 training cases) for whom the surgery after administration of Beva800 was completed in the study. If needed, this population was used for sensitivity analyses.

    Primary: Proportion of Reduction of Subjects with Positive Margin by MFGS Using Beva800 in Comparison with the SOC BCS

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    End point title
    		 Proportion of Reduction of Subjects with Positive Margin by MFGS Using Beva800 in Comparison with the SOC BCS [1]
    End point description
    The proportion of reduction of subjects with positive margin by MFGS using Beva800 in comparison with the SOC BCS was estimated as follows: (Number of subjects with positive margin from SOC BCS - Number of subjects with positive margin from MFGS) / Number of subjects with positive margin from SOC BCS x 100%
    End point type
    Primary
    End point timeframe
    After SOC BCS
    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 statistical analysis was performed. The 2-sided 95% confidence interval was calculated based on the exact binomial distribution using Clopper-Pearson method. The 2-sided 95% confidence interval is 15.7%, 84.3%.
    End point values
    		 ITT Pop
    Number of subjects analysed
    8 [2]
    Units: Number of Subjects
        number (not applicable)
    4
    Notes
    [2] - Number of Subjects with Positive Margin after SOC BCS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects were monitored for any untoward medical occurrences from time of signing the Informed Consent Form through 30 days after Beva800 administration.
    Adverse event reporting additional description
    All untoward medical occurrences were recorded in the Adverse Event section of the case report form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    SAF Pop
    Reporting group description
    		 -

    Serious adverse events
    		 SAF Pop
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 49 (4.08%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Post procedural haematoma
    Additional description: Post resection and haematoma removal
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertensive crisis
    Additional description: Hypertensive crises
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 SAF Pop
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 49 (30.61%)
    Injury, poisoning and procedural complications
    Seroma
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences all number
    2
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Circulatory collapse
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Haemorrhage
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Malaise
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences all number
    2
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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