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    Clinical Trial Results:
    Diagnostic accuracy of neuroblastoma patient imaging with 18F-mFBG PET-CT compared to 123I-mIBG scanning

    Summary
    EudraCT number
    		 2019-003713-33
    Trial protocol
    		 NL  
    Global end of trial date
    01 Sep 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    70903
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Dutch Trial Register: NL8152
    Sponsors
    Sponsor organisation name
    Princess Máxima Center for pediatric oncology
    Sponsor organisation address
    Heidelberglaan 25, Utrecht, Netherlands, 3584CS
    Public contact
    Dr. G.A.M. Tytgat, Princess Máxima Center for Pediatric Oncology, G.A.M.Tytgat@prinsesmaximacentrum.nl
    Scientific contact
    Dr. B. de Keizer, Princess Máxima Center for Pediatric Oncology, B.deKeizer@prinsesmaximacentrum.nl
    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
    02 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To perform 18F-MFBG PET-CT imaging in neuroblastoma patients and compare results with the current standard of imaging, 123I-MIBG imaging, using the SIOPEN score for skeletal lesions and the number of detected soft tissue lesions as endpoints.
    Protection of trial subjects
    - The final 18F-MFBG drug product batches underwent quality control testing, before batch release for patient administration. - Adverse events were not expected. However, patients were monitored after injection for 180 minutes. Furthermore, 3–7 days after the procedure a medical doctor conducted a telephone consultation to check for adverse events up to 72 hours after injection. - Monitors of the trial ensured that the clinical trial is conducted, recorded, and reported in accordance with the protocol, ICH-GCP, and the applicable regulatory requirement(s).
    Background therapy
    		 Recently, meta-18F-fluorobenzylguanidine (18F-mFBG), was developed to overcome the 123I-mIBG-associated disadvantages. As an analogue of mIBG, 18F-mFBG also targets the norepinephrine transporter, only 18F-MFBG is labelled with a positron-emitting radioisotope, fluorine-18, enabling imaging by positron emission tomography (PET) scanning. Compared to scintigraphy/SPECT, PET is a superior imaging technique that offers high resolution imaging, more accurate quantification of tracer uptake (using SUV measurements), whole-body 3D PET-CT range, a shorter acquisition time (10min) with less procedural sedation needed. In addition, the use of 18F-mFBG allows for a single-day protocol (possible to scan ≤2h after injection), and no need for thyroid-blocking medication. To date, there is only in-human study studying 18F-mFBG including five patients with neuroblastoma, with no adverse reaction in any of the patients. 18F-mFBG has a similar distribution as 123I-mIBG, with similar lesion uptake, but much faster uptake of the more hydrophilic 18F-MFBG enabling high-contrast visualisation of lesions as early as one hour after injection. In this small study, 18F-mFBG PET-CT detected more lesions 123I-mIBG scanning (122 vs. 63 lesions, respectively). Although 18F-mFBG is a promising tracer, there is limited experience of the use of 18F-mFBG imaging in neuroblastoma. Safety, optimal imaging time and diagnostic accuracy of 18F-mFBG scanning are yet to be established.
    Evidence for comparator
    		 meta-123I-iodobenzylguanidine (123I-mIBG) scanning is currently the first-line nuclear imaging technique that is routinely used for diagnosis, staging, and follow-up of neuroblastoma. MIBG is a norepinephrine analogue that can specifically detect tumours expressing the norepinephrine transporter, including neuroblastoma. 123I-mIBG uptake in the primary tumour and metastatic lesions is then visualized with gamma camera imaging. The addition of single-photon emission computed tomography with computed tomography (SPECT-CT) to planar whole-body scintigraphy has become standard in gamma camera imaging to increase certainty of interpretation and anatomical localization. Although worldwide 123I-mIBG scanning is the standard of care, it has several disadvantages. Scintigraphy and SPECT have limited image resolution (associated with gamma-camera imaging), resulting in no clear anatomical imaging. As the 3D SPECT-CT has a limited field-of-view and can only image about 40 cm, this requires a predefined area of interest, often only primary tumour. Another disadvantage is the long scan time (acquisition time of ~90 min) requiring sedation in young patients. Lastly, the use of iodine-123 also requires a two-day scanning protocol (scanning 24h after radiopharmaceutical injection) and thyroid blocking medication to prevent accumulation of free radioactive iodide.
    Actual start date of recruitment
    12 Jul 2020
    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
    Netherlands: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    7
    Children (2-11 years)
    15
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A prospective pilot study was conducted at the Princess Máxima Centre for Paediatric Oncology, Utrecht, the Netherlands, between July 2020 and July 2021. Paediatric patients with confirmed (or clinical suspicion of) neuroblastoma referred for standard 123I-mIBG scanning were prospectively recruited.

    Pre-assignment
    Screening details
    		 Paediatric patients with confirmed (or clinical suspicion of) neuroblastoma referred for standard MIBG scanning. Exclusion criteria were age ≥18 years, pregnancy, critical clinical condition (Lansky scale ≤20, organ failure, sepsis, hypoxia), and/or logistic planning reasons (if the MFBG scan could not be planned <2 weeks of MIBG scan).

    Pre-assignment period milestones
    Number of subjects started
    		 25
    Number of subjects completed
    		 25

    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
    		 Patient intended to undergo paired MIBG and MFBG scanning
    Arm description
    		 Single arm study
    Arm type
    		 Active comparator

    Investigational medicinal product name
    18F-meta-fluorobenzylguanidine
    Investigational medicinal product code
    not available
    Other name
    18F-mFBG
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bolus of 2 MBq/kg body weight

    Number of subjects in period 1
    		Patient intended to undergo paired MIBG and MFBG scanning
    Started
    25
    Completed
    20
    Not completed
    5
         Consent withdrawn by subject
    1
         MFBG production failed
    2
         MIBG not performed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Included patients to be scanned.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 25 25
    Age categorical
    Age per inclusion
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 3 3
        Children (2-11 years)
    		 14 14
        Adolescents (12-17 years)
    		 3 3
        Not recorded
    		 5 5
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 12 12
        Not recorded
    		 5 5
    Subject analysis sets

    Subject analysis set title
    Patients who underwent MIBG scanning
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who underwent MIBG scanning (as part of regular clinical care)

    Subject analysis set title
    Patients who underwent MFBG 1h scanning
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who underwent the 1h post-injection MFBG scan

    Subject analysis set title
    Patients who underwent MFBG 2h scanning
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who underwent the 2h post-injection MFBG scan

    Subject analysis sets values
    		 Patients who underwent MIBG scanning Patients who underwent MFBG 1h scanning Patients who underwent MFBG 2h scanning
    Number of subjects
    20
    20
    19
    Age categorical
    Age per inclusion
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    3
    3
    3
        Children (2-11 years)
    14
    14
    13
        Adolescents (12-17 years)
    3
    3
    3
        Not recorded
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    8
    8
    8
        Male
    12
    12
    11
        Not recorded

    End points

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    End points reporting groups
    Reporting group title
    Patient intended to undergo paired MIBG and MFBG scanning
    Reporting group description
    		 Single arm study

    Subject analysis set title
    Patients who underwent MIBG scanning
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who underwent MIBG scanning (as part of regular clinical care)

    Subject analysis set title
    Patients who underwent MFBG 1h scanning
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who underwent the 1h post-injection MFBG scan

    Subject analysis set title
    Patients who underwent MFBG 2h scanning
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who underwent the 2h post-injection MFBG scan

    Primary: Detection of skeletal lesions

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    End point title
    		 Detection of skeletal lesions
    End point description
    SIOPEN score for skeletal lesions
    End point type
    Primary
    End point timeframe
    Maximum of 2 weeks between the paired MIBG and MFBG scan
    End point values
    		 Patients who underwent MIBG scanning Patients who underwent MFBG 1h scanning Patients who underwent MFBG 2h scanning
    Number of subjects analysed
    20
    20
    19
    Units: SIOPEN points
        median (inter-quartile range (Q1-Q3))
    1 (0 to 5)
    11 (0 to 21)
    6 (0 to 17)
    Statistical analysis title
    		 SIOPEN score MIBG vs. MFBG 1h scan
    Comparison groups
    Patients who underwent MIBG scanning v Patients who underwent MFBG 1h scanning
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.2
         upper limit
    		 9.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.6
    Notes
    [1] - pilot

    Primary: Detection of soft tissue lesions

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    End point title
    		 Detection of soft tissue lesions
    End point description
    Absolute number of soft tissue lesions
    End point type
    Primary
    End point timeframe
    Maximum of 2 weeks between the MFBG and MIBG scan
    End point values
    		 Patients who underwent MIBG scanning Patients who underwent MFBG 1h scanning Patients who underwent MFBG 2h scanning
    Number of subjects analysed
    20
    20
    19
    Units: N/A
        number (not applicable)
    18
    52
    50
    Statistical analysis title
    		 Number of soft tissue lesions MIBG vs. MFBG 1h
    Comparison groups
    Patients who underwent MIBG scanning v Patients who underwent MFBG 1h scanning
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.017
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 3.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Notes
    [2] - pilot

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Follow-up was up to 72 hours after the MFBG scan.
    Adverse event reporting additional description
    Serious adverse events that occured within 72 hours were reported within one week to the sponsor. The patient was followed up untill SAE resolved.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Patient intended to undergo MFBG scanning
    Reporting group description
    		 -

    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: For this pilot study there were no non serious adverse events observed / reported
    Serious adverse events
    		 Patient intended to undergo MFBG scanning
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 22 (13.64%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
    Additional description: Patient was intubated (hypoxia due to PJP). Hypoxia CTCAE grade 4
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
    Additional description: Line infection, Sepsis CTCAE grade 3
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
    Additional description: Viral infection, with normal ANC or grade 1 or 2 neutrophils. CTCAE grade 3.
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Patient intended to undergo MFBG scanning
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2021
    Version 2.1, with the following content: 1) Clarification of section "Safety Reporting" in the protocol 2) Adding possibility of procedural sedation when scanning younger children. 3) Administrative corrections, updates and clarifications. 4) Update of the Investigator’s Brochure on [18F]MFBG 5) Adjustment of the informed consent form due to above-mentioned changes. 6) Annual progress report

    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.
    Six out of 14 patients were included twice in the study.
    For support, Contact us.
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