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    Clinical Trial Results:
    PET/CT imaging of angiogenesis in patients with neuroendocrine tumors using 68Ga-NODAGA-E[c(RGDyK)]2

    Summary
    EudraCT number
    		 2017-002512-14
    Trial protocol
    		 DK  
    Global end of trial date
    31 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jan 2023
    First version publication date
    30 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AK2017-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03271281
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Professor Andreas Kjær, Departement of Clinical Physiology and Nuclear Medicine, Rigshospitalet, akjaer@sund.ku.dk
    Scientific contact
    Professor Andreas Kjær, Departement of Clinical Physiology and Nuclear Medicine, Rigshospitalet, akjaer@sund.ku.dk
    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
    31 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In this study with integrin alphavbeta3 imaging we include patients diagnosed with neuroendocrine tumors in order to investigate tumor visualization and prognostic performance of integrin alphavbeta3 imaging by [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT
    Protection of trial subjects
    It is emphasized that participation in the study is voluntary and will have no influence on the otherwise planned treatment, whether the patient will participate or not. The study is conducted in accordance with the Helsinki Declaration and the Good Clinical Practice (GCP). All clinical information about the participants is protected under the act on processing of Personal Data and the Danish Health Legislation. Overall, it is considered that the project is ethically sound, as there are no significant risks associated with the integrin alphavbeta3 PET/CT imaging procedure.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2017
    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
    Denmark: 113
    Worldwide total number of subjects
    113
    EEA total number of subjects
    113
    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)
    45
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Prospective inclusion patients with lung or gastro-entero-pancreatic neuroendocrine neoplasms.

    Pre-assignment
    Screening details
    		 We prospectively included 113 patients, whereof 14 patients did not undergo a [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT due to worsening of disease (n=4), withdrawal of consent (n=2), died before PET/CT (n=3), logistically not possible to perform PET/CT (n=2), and not possible to perform PET/CT due to COVID-19 restrictions (n=3).

    Pre-assignment period milestones
    Number of subjects started
    		 113
    Number of subjects completed
    		 113

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    An experienced board-certified nuclear medicine physician together with an experienced board-certified radiologist analyzed side-by-side the [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT scans. The readers had access to previous imaging studies, but were blinded to other patient data and follow-up data.

    Arms
    Arm title
    		 Experimental arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    [68Ga]Ga-NODAGA-E[c(RGDyK)]2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    One injection of up to 226 MBq [68Ga]Ga-NODAGA-E[c(RGDyK)]2

    Number of subjects in period 1
    		Experimental arm
    Started
    113
    Completed
    99
    Not completed
    14
         Consent withdrawn by subject
    2
         worsening of disease
    4
         death before PET/CT
    3
         not possible to perform PET/CT due to COVID-19 res
    3
         logistically not possible to perform PET/CT
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 All patients fullfilling the inclusion/exclusion criteria and included in the study

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 113 113
    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)
    		 45 45
        From 65-84 years
    		 68 68
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 68 (44 to 83) -
    Gender categorical
    Units: Subjects
        Female
    		 49 49
        Male
    		 64 64
    Subject analysis sets

    Subject analysis set title
    Primary analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who underwent [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT and had evaluable lesions (visible lesions on PET and or CT)

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who underwent [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT

    Subject analysis set title
    Secondary analyses set - low integrin alphavbeta3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients were dicotomized by tumor uptake of 68Ga-NODAGA-E[c(RGDyK)]2 in a group of low and high uptake

    Subject analysis set title
    Secondary analyses set - high integrin alphavbeta3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients were dicotomized by tumor uptake of 68Ga-NODAGA-E[c(RGDyK)]2 in a group of low and high uptake

    Subject analysis sets values
    		 Primary analysis set Safety set Secondary analyses set - low integrin alphavbeta3 Secondary analyses set - high integrin alphavbeta3
    Number of subjects
    97
    99
    32
    65
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    67 (44 to 83)
    67 (44 to 83)
    63.5 (44 to 76)
    68 (44 to 83)
    Gender categorical
    Units: Subjects
        Female
    43
    44
    14
    29
        Male
    54
    55
    18
    36

    End points

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    End points reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 -

    Subject analysis set title
    Primary analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who underwent [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT and had evaluable lesions (visible lesions on PET and or CT)

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who underwent [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT

    Subject analysis set title
    Secondary analyses set - low integrin alphavbeta3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients were dicotomized by tumor uptake of 68Ga-NODAGA-E[c(RGDyK)]2 in a group of low and high uptake

    Subject analysis set title
    Secondary analyses set - high integrin alphavbeta3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients were dicotomized by tumor uptake of 68Ga-NODAGA-E[c(RGDyK)]2 in a group of low and high uptake

    Primary: 68Ga-NODAGA-E[c(RGDyK)]2 PET positive lesions

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    End point title
    		 68Ga-NODAGA-E[c(RGDyK)]2 PET positive lesions [1]
    End point description
    A tumor lesion to liver ratio (TLR) was calculated as tumor lesion SUVmax/normal liver SUVmean. A cutoff of TLR ≥ 2 was used to define positive lesions.
    End point type
    Primary
    End point timeframe
    Assessed following the performance 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT
    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: Descriptive analysis of the number of patients with 68Ga-NODAGA-E[c(RGDyK)]2 PET positive lesions
    End point values
    		 Primary analysis set
    Number of subjects analysed
    Units: number of patients
        Positive
    74
        Negative
    23
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    During at least 1 year follow-up after 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT
    End point values
    		 Primary analysis set Secondary analyses set - low integrin alphavbeta3 Secondary analyses set - high integrin alphavbeta3
    Number of subjects analysed
    97
    32
    65
    Units: number of patients
        Progressive disease
    61
    16
    45
        Non-progressive disease
    36
    16
    20
    Statistical analysis title
    		 Cox regression analysis
    Comparison groups
    Secondary analyses set - low integrin alphavbeta3 v Secondary analyses set - high integrin alphavbeta3
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 3.78

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    At least one year follow-up after 68Ga-NODAGA-E[c(RGDyK)]2
    End point values
    		 Primary analysis set Secondary analyses set - low integrin alphavbeta3 Secondary analyses set - high integrin alphavbeta3
    Number of subjects analysed
    97
    32
    65
    Units: number of patients
        Dead
    25
    2
    23
        Alive
    72
    30
    42
    Statistical analysis title
    		 Cox regression analysis
    Comparison groups
    Secondary analyses set - low integrin alphavbeta3 v Secondary analyses set - high integrin alphavbeta3
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    6.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.64
         upper limit
    		 29.51

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 24 hours of 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    All patients scanned
    Reporting group description
    		 -

    Serious adverse events
    		 All patients scanned
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 99 (0.00%)
         number of deaths (all causes)
    26
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All patients scanned
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 99 (3.03%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences all number
    1
    Infusion related reaction
    Additional description: in relation to injection of CT contrast
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 99 (1.01%)
         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
    25 Feb 2018
    New principal investigator

    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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