Clinical trial NCT02043899
Conditions: Metastatic Neuroblastoma
Keywords: Neuroblastoma Positron emission tomography 124-iodine Meta-Iodobenzylguanidine
Sponsor: Cancer Research UK
Start date: 2014-02-01; Completion date: 2020-10-15
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study aims to show that 3-dimensional PET/CT imaging with a new novel PET tracer (called \[124I\]mIBG) can detect as many or more sites of neuroblastoma (a type of childhood cancer) compared to the recommended 1-dimensional routine scans (called \[123I\]mIBG planar scintigraphy).

Detailed description:
Neuroblastoma is the most common tumour of childhood after brain tumours. Approximately half of cases are high risk and despite extensive treatments outcome is very poor. More than 60% of high risk patients suffer relapse or further spread of their disease and long-term survival is below 10%. Existing imaging techniques are not sensitive enough to accurately assess the level of risk which is critical in determining the best choice of treatment. This study will compare a new type of imaging against the existing imaging techniques. The new scans use a new tracer called \[124I\]mIBG which is taken up by the cancer tissue much more than by normal tissues. This tracer can be used with a 3D imaging technique called PET/CT to pinpoint where the disease has spread and quantify the amount of disease. Patients will be those scheduled to have an \[123I\]mIBG scan for routine care during a planned break in treatment.

Arms: arm 1: This was a single arm trial, all patients were to undergo the same assessments and interventions.
Interventions: intervention 1: [124I]meta-Iodobenzylguanidine
Intervention descriptions: intervention 1: Single intravenous administration of \[124I\]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq \[124I\]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.

Protocol documents:
Prot_SAP_000.pdf: 


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©Cancer Research UK 2013 
 
 
 
 
 
CANCER RESEARCH UK 
Centre for Drug Development 
 
 
A Cancer Research UK Phase I/II study to compare 
[124I]mIBG PET/CT to [123I]mIBG imaging in patients 
with metastatic neuroblastoma 
 
Sponsor protocol number: 
CRUKD/12/002 
 
EudraCT number:  
2012-002029-31 
 
 
Chief Investigator: 
Dr Sue Chua 
Nuclear Medicine and PET 
Department 
Royal Marsden Hospital 
 
  
 
  
 
 
 
 
 
Sponsor: 
Cancer Research UK 
 
Centre for Drug Development 
 
 
 
 
 
      
 
      
 
 
 
 
 
 
 


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PARTICIPATING PRINCIPAL INVESTIGATORS AND 
INVESTIGATIONAL SITES 
Details of Principal Investigators and Investigational Sites are recorded on the Participating 
Investigators and Centres list in the Sponsor’s Trial Master File. 
 
Version History: 
 
Protocol amendment number 
and date 
Substantial/Non-substantial 
amendment 
Protocol incorporating 
amendment version and date 
1, 06 Feb 2014 
Non-substantial  
3, 06 Feb 2014 
2, 16 Jun 2014 
Substantial 
4, 16 Jun 2014 
3, 09 Mar 2015 
Substantial 
5, 09 Mar 2015  
(not implemented) 
4, 29 Apr 2015 (including 
changes from amendment 3) 
Substantial 
6, 29 Apr 2015  
5, 15 Jul 2015 
Substantial 
7, 15 Jul 2015 
6, 16 Sep 2015 
Non-substantial 
8, 16 Sep 2015 
7, 04 Apr 2016 
 Non-substantial 
9, 4 Apr 2016 
8, 20 Jun 2016 
Substantial 
10, 20 Jun 2016 
9, 19 Jun 2017 
Substantial 
11, 19 Jun 2017 
10, 06 Dec 2018 
Substantial 
12, 06 Dec 2018 
11, 12 Nov 2019 
Substantial 
13, 12 Nov 2019 
 
 


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TABLE OF CONTENTS 
 
 
 
 
 
TITLE PAGE 
 
TABLE OF CONTENTS 
 
LIST OF FIGURES AND TABLES 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
PROTOCOL SIGNATURES 
 
1 
PROTOCOL SYNOPSIS ..................................................................................................... 10 
1.1 
CLINICAL STUDY OBJECTIVES AND ENDPOINTS ......................................................... 10 
1.2 
STUDY DESIGN .................................................................................................................. 11 
1.3 
ADMINISTRATION SCHEDULE .......................................................................................... 12 
1.4 
PATIENT GROUP ................................................................................................................ 13 
2 
INTRODUCTION .................................................................................................................. 14 
2.1 
BACKGROUND ................................................................................................................... 14 
2.2 
INVESTIGATIONAL MEDICINAL PRODUCTS ................................................................... 15 
2.2.1 
[123I]mIBG ....................................................................................................................... 15 
2.2.2 
[124I]mIBG Solution for Injection ...................................................................................... 15 
2.3 
MECHANISM OF ACTION ................................................................................................... 15 
2.4 
PRECLINICAL DATA ON mIBG .......................................................................................... 16 
2.4.1 
Pharmacology ................................................................................................................. 16 
2.4.2 
Pharmacokinetics and Metabolism ................................................................................. 16 
2.4.3 
Toxicology ...................................................................................................................... 16 
2.5 
CLINICAL EXPERIENCE WITH [124I]mIBG  ........................................................................ 17 
2.5.1 
Pharmacology ................................................................................................................. 17 
2.5.2 
Pharmacokinetics and Metabolism ................................................................................. 17 
2.5.3 
Safety ............................................................................................................................. 18 
2.5.4 
Dosimetry ....................................................................................................................... 18 
2.6 
RATIONALE FOR THE PROPOSED STUDY ..................................................................... 19 
2.6.1 
 
2.6.2 
 
2.6.3 
Anticipated impact of the study on UK clinical practice .................................................. 22 
3 
STUDY DESIGN .................................................................................................................. 23 
3.1 
CLINICAL STUDY OBJECTIVES AND ENDPOINTS ......................................................... 23 
3.2 
PATIENT EVALUABILITY .................................................................................................... 24 
3.3 
DESIGN OF THE CLINICAL STUDY ................................................................................... 24 
3.3.1 
 
3.3.2 
 
4 
PATIENT SELECTION ........................................................................................................ 26 
4.1 
ELIGIBILITY CRITERIA ....................................................................................................... 26 
4.1.1 
Inclusion Criteria ............................................................................................................. 26 
4.1.1.1 
 
4.1.1.2 
 
4.1.2 
Exclusion Criteria............................................................................................................ 26 
4.1.3 
Clinical Criteria for [124I]mIBG imaging ........................................................................... 27 
4.2 
PATIENT ENROLMENT ...................................................................................................... 28 
5 
DOSE AND ADMINISTRATION .......................................................................................... 29 
5.1 
[123I]mIBG DOSE AND ADMINISTRATION ......................................................................... 29 
5.2 
[124I]mIBG DOSE AND ADMINISTRATION ......................................................................... 29 
5.2.1 
Selection of the Dose of radioactivity to be administered .............................................. 29 


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5.3 
DOSE SCHEDULE .............................................................................................................. 29 
5.4 
DOSE MODIFICATIONS ..................................................................................................... 30 
5.5 
REPLACEMENT OF PATIENTS ......................................................................................... 30 
5.6 
CONCOMITANT MEDICATION ........................................................................................... 30 
6 
PHARMACEUTICAL INFORMATION ................................................................................. 31 
6.1 
SUPPLY OF [123I]mIBG ........................................................................................................ 31 
6.2 
SUPPLY OF [124I]mIBG SOLUTION FOR INJECTION ....................................................... 31 
6.3 
PHARMACEUTICAL DATA ................................................................................................. 31 
6.3.1 
Pharmaceutical Presentation of [123I]mIBG .................................................................... 31 
6.3.2 
Pharmaceutical Presentation of [124I]mIBG Solution for Injection .................................. 31 
6.3.3 
Storage conditions .......................................................................................................... 31 
6.4 
[123I]mIBG ADMINISTRATION ............................................................................................. 32 
6.5 
[124I]mIBG SOLUTION FOR INJECTION ADMINISTRATION ............................................. 32 
6.6 
VEIN EXTRAVASATION/ ACCIDENTAL SPILLAGES ........................................................ 32 
6.7 
DRUG ACCOUNTABILITY .................................................................................................. 33 
6.7.1 
Accountability of [123I]mIBG ............................................................................................ 33 
6.7.2 
Accountability of [124I]mIBG Solution for Injection .......................................................... 33 
7 
INVESTIGATIONS SCHEDULE .......................................................................................... 34 
7.1 
OBTAINING WRITTEN INFORMED CONSENT ................................................................. 34 
7.2 
SCREENING EVALUATIONS (DAY -28 TO ENROLMENT) ............................................... 35 
7.3 
EVALUATIONS DURING THE STUDY (DAY -21 TO -3) .................................................... 36 
7.4 
EVALUATIONS DURING THE STUDY (DAY -7 TO DAY 1) ............................................... 36 
7.5 
SUPPLY OF [124I]mIBG SOLUTION FOR INJECTION ....................................................... 36 
7.6 
EVALUATIONS DURING THE STUDY (NOVEL IMAGING) ............................................... 37 
7.6.1 
[124I]mIBG PET/CT scan ................................................................................................. 37 
7.6.2 
 
7.6.3 
 
7.7 
‘OFF-STUDY’ ASSESSMENT (DAY 3 TO DAY 7) .............................................................. 38 
7.8 
FOLLOW-UP ........................................................................................................................ 38 
7.9 
SCHEDULE OF EVENTS .................................................................................................... 39 
8 
ASSESSMENT OF SAFETY ............................................................................................... 41 
8.1 
INVESTIGATOR RESPONSIBILITIES ................................................................................ 41 
8.2 
MEDICAL COVER ............................................................................................................... 41 
8.3 
ADVERSE EVENT DEFINITIONS ....................................................................................... 41 
8.3.1 
Adverse event (AE) ........................................................................................................ 41 
8.3.2 
Serious adverse event (SAE) ......................................................................................... 41 
8.3.3 
Determining AE causality ............................................................................................... 42 
8.3.4 
Expectedness ................................................................................................................. 43 
8.3.5 
Suspected, unexpected, serious, adverse reactions (SUSARs) .................................... 43 
8.4 
COLLECTION OF SAFETY INFORMATION ....................................................................... 43 
8.4.1 
Screening failures ........................................................................................................... 43 
8.4.2 
Eligible patients .............................................................................................................. 43 
8.4.3 
Follow-up of AEs and SAEs ........................................................................................... 43 
8.4.4 
Other safety information of interest ................................................................................ 43 
8.5 
EXPEDITED REPORTING OF SAEs TO PHARMACOVIGILANCE ................................... 44 
8.5.1 
Events exempt from reporting as SAEs to Pharmacovigilance ...................................... 44 
8.6 
RECORDING OF AEs AND SAEs IN eCRFs ...................................................................... 44 
8.7 
FOLLOW-UP OF AEs AND SAEs ....................................................................................... 44 
8.8 
URGENT SAFETY MEASURES .......................................................................................... 45 
8.9 
PREGNANCY ...................................................................................................................... 45 
9 
ASSESSMENT OF IMAGING TECHNIQUES ..................................................................... 47 
9.1 
PRIMARY ANALYSIS .......................................................................................................... 47 
9.2 
SECONDARY ANALYSIS .................................................................................................... 47 
9.3 
TERTIARY ANALYSES ....................................................................................................... 47 
10 
PATIENT WITHDRAWAL BEFORE COMPLETION OF IMAGING SCHEDULE .............. 49 


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11 
DEFINING THE END OF TRIAL ......................................................................................... 50 
12 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................. 51 
12.1 
SAMPLE SIZE ...................................................................................................................... 51 
12.2 
INTERIM AND FINAL ANALYSIS ........................................................................................ 51 
12.2.1 
Statistical Analysis of Primary Endpoint ......................................................................... 52 
12.2.2 
Statistical Analysis of Secondary Endpoint .................................................................... 52 
12.2.3 
Statistical Analyses of Tertiary Endpoints ...................................................................... 52 
12.2.4 
Safety ............................................................................................................................. 53 
12.3 
PRESENTATION OF DATA ................................................................................................. 53 
13 
ADMINISTRATION .............................................................................................................. 54 
13.1 
PROTOCOL DEVIATIONS AND AMENDMENTS ............................................................... 54 
13.2 
COMPLETION OF THE ELECTRONIC CASE REPORT FORM (ECRF) ........................... 54 
13.3 
STUDY PERFORMANCE AND MONITORING ................................................................... 54 
13.4 
SOURCE DOCUMENT VERIFICATION .............................................................................. 55 
13.5 
CLINICAL STUDY REPORT ................................................................................................ 55 
13.6 
RECORD RETENTION ........................................................................................................ 55 
13.7 
ETHICAL CONSIDERATIONS ............................................................................................ 56 
13.8 
INDEMNITY ......................................................................................................................... 56 
13.9 
PUBLICATION POLICY AND PRESS RELEASES ............................................................. 56 
14 
REFERENCES ..................................................................................................................... 57 
15 
APPENDICES ...................................................................................................................... 60 
15.1 
APPENDIX 1: DECLARATION OF HELSINKI ..................................................................... 60 
15.2 
APPENDIX 2: WHO PERFORMANCE SCALE ................................................................... 63 
15.3 
APPENDIX 3: LANSKY PLAY SCALE ................................................................................. 64 
15.4 
APPENDIX 4: DRUG INTERACTIONS WITH mIBG ........................................................... 65 
15.5 
APPENDIX 5: CURIE & SIOPEN SCORING METHODS FOR NEUROBLASTOMA ......... 67 
 
 
LIST OF FIGURES AND TABLES 
 
Figure 1 
Radiosynthesis of [124I]mIBG ................................................................................................ 15 
Table 1 
Effective doses (mSv/MBq) for different age models ........................................................... 18 
Table 2 
Recommended diagnostic activity levels for mIBG scans ................................................... 19 
Table 3 
Total doses from proposed levels of [124I]mIBG to be administered .................................... 19 






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PROTOCOL SIGNATURES 
Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities 
as an Investigator under the UK (United Kingdom) Clinical Trials Regulations1, the guidelines of Good 
Clinical Practice (GCP)2, the Declaration of Helsinki (Appendix 1), the applicable regulations of the 
relevant NHS Trusts and the study protocol.  I agree to conduct the study according to these 
regulations and guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study, and ensure that all staff members are aware of their clinical study 
responsibilities. 
 
INVESTIGATOR'S NAME: 
 
 
 
 
 
 
 
SIGNATURE: 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent 
amendments to it. 
2 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice 
E6(R2) Step 4 dated 09 November 2016.  


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PROTOCOL SIGNATURES  
Sponsor Signature: 
The Sponsor has read and agrees to the protocol, as detailed in this document.  I am aware of my 
responsibilities as the Sponsor under the UK (United Kingdom) Clinical Trials Regulations3, the 
guidelines of Good Clinical Practice (GCP)4, the Declaration of Helsinki (Appendix 1), the applicable 
regulations of the UK law and the study protocol.  The Sponsor agrees to conduct the study according 
to these regulations and guidelines and to appropriately direct and assist sponsor’s staff who will be 
involved in the study and ensure that all staff members are aware of their clinical study responsibilities. 
Signed by the Director of the Sponsor’s Centre for Drug Development at Cancer Research UK: 
 
NAME: 
 
 
 
 
 
DIRECTOR OF DRUG DEVELOPMENT  
 
 
 
SIGNATURE: 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
3 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent 
amendments to it. 
4 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice 
E6(R2) Step 4 dated 09 November 2016.  






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until resolution, recovery to baseline, or stabilisation of these events, unless the patient starts another 
anti-cancer therapy. 
Interpretation of imaging  
The imaging review will be performed separately by an agreed number of observers who are Nuclear 
Medicine physicians experienced in the assessment of neuroblastoma.  Two observers will be study 
Investigators and all others will be independent from the study to prevent subjective bias in the 
interpretation of the nuclear medicine mIBG scans.  Lesions will be identified and scored by each 
observer using a diagnostic confidence level.  The observers will review the lesions identified and 
where there is a difference in their separate scores they will return to the imaging in order to reach a 
consensus score.  The number of lesions identified as positive by this scoring will be used to meet the 
primary objective of comparison of the novel [124I]mIBG PET/CT modality with the recommended 
standard mIBG imaging modality for neuroblastoma which is [123I]mIBG planar scintigraphy (see 
Section 9.1). 
The majority of patients treated for neuroblastoma will have [123I]mIBG scintigraphy using 3D SPECT 
over the chest and abdomen in addition to planar scintigraphy of the full body.  The imaging review 
performed for the assessment of the primary objective will be repeated to read and score lesions 
identified by the available [123I]mIBG SPECT.  The number of positive lesions identified by SPECT will 
be used to meet the secondary objective of comparison of [124I]mIBG PET/CT with [123I]mIBG 
scintigraphy with 3D SPECT. 
The imaging review will then be repeated to read and score all the available conventional imaging 
taken together including [123I]mIBG planar and SPECT scintigraphy and cross sectional imaging with 
CT and MRI. 
 
 
  
 
  
 
  
 
  
 
 
   
 
 
  
 
  
 
 
   
1.3 
ADMINISTRATION SCHEDULE 
Patients will receive one intravenous injection of [123I]mIBG administered as per standard clinical 
practice and according to the SPC one day before the planned conventional planar scintigraphy 
± SPECT performed on Day -21 to -3 for the routine assessment of neuroblastoma. 
Patients who fulfil the clinical criteria for [124I]mIBG imaging described in section 4.1.3 will receive one 
intravenous injection on Day 1. All patients will receive a minimum injected dose of 10 MBq and a 
maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 µg of 
stable mIBG. The maximum activity administered to adult patients will be 50 MBq. This maximum 
activity, 50 MBq, will be requested for each adult patient as the specified target dose. On occasions 
that the maximum activity, 50 MBq, is not met, but is still within the required range of 10 to 50 MBq, 
patient administration will proceed and the scanning time adjusted accordingly. The maximum activity 
administered to paediatric patients will be scaled according to weight using the European Association 
of Nuclear Medicine (EANM) paediatric dose card (see section 5.3). This maximum activity will be 


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requested for each paediatric patient as the specified target dose. With reference to the EANM 
scheme for paediatric patients, a baseline activity of 3.5 MBq, a minimum activity of 10 MBq and 
class B scaling factors are deemed appropriate. This will result in administration of an activity between 
10 and 50 MBq depending on the patient’s weight. On Day 2 patients will undergo a low dose, 
non-diagnostic CT followed sequentially by PET acquisition.  The scanning schedule will take between 
30 and 75 minutes, depending on whether the scanning time is to be adjusted to account for 
administration of lower activity than specified target dose.  If the scan schedule is likely to exceed 
75 minutes then this should be discussed with the patient prior to the injection of [124I]mIBG to seek 
verbal consent. Any discussions should be documented in the patients’ medical notes. 
1.4 
PATIENT GROUP 
A minimum of 9 (if stopped after interim analysis) or 33 evaluable patients aged over 1 year, with 
histologically proven neuroblastoma with stage 4 disease (as defined by the International 
Neuroblastoma Staging System (INSS)), will be entered into the study.  A patient must have a 
minimum of 1 neuroblastoma lesion identified on routine conventional [123I]mIBG planar scintigraphy to 
be evaluable for the primary objective. 


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2 
INTRODUCTION 
2.1 
BACKGROUND 
Neuroblastoma is the most frequent solid extracranial tumour of childhood.  More than 1200 new 
cases per year are diagnosed in the United States of America (USA) and Europe (Maris, Hogarty et al. 
2007, Gatta, Zigon et al. 2009).  Approximately 50% of the cases are considered high risk (i.e. 
metastatic or harbouring v-myc myelocytomatosis viral-related oncogene (MYCN) amplification) and 
for those, outcome after multimodal treatment (chemotherapy, surgery, high-dose chemotherapy with 
haemopoietic stem cell rescue, radiotherapy and minimal residual disease therapy) is still poor.  
Five-year overall survival has remained below 40% in larger multicentre trials (Matthay 2008, Pearson, 
Pinkerton et al. 2008).  Despite initial promise, the long-term beneficial effect of immunotherapy on 
overall survival is still unknown (Yu, Gilman et al. 2010).  Hence, more than 60% of patients with high 
risk neuroblastoma experience relapse or progression and in this setting outcome is extremely poor 
with long-term survival below 10% (London, Castel et al. 2011).  There is therefore an unmet need to 
develop new imaging modalities for these poor prognosis patients. 
Accurate staging using imaging is critical to the risk stratification of patients with neuroblastoma, and 
functional imaging plays a crucial role in both the diagnostic evaluation of primary tumours and the 
identification and quantification of metastatic disease.  Further along the treatment pathway, the high 
sensitivity offered by functional scans is essential to the detection of small volume residual disease, 
which results in changes to therapy.  Scan findings are therefore crucial in guiding type, intensity and 
timing of treatment.  The mainstay of functional imaging of staging and response to therapy 
investigations is scintigraphy using [123I]mIBG (meta-Iodobenzylguanidine), an analogue of 
catecholamine precursors which is taken up specifically by tumour cells (Hadley and Rabe 1986, 
Lumbroso, Guermazi et al. 1988, Brodeur, Pritchard et al. 1993, Leung, Shapiro et al. 1997, Hero, 
Hunneman et al. 2001). 
There is a strong rationale for research aimed at improved imaging modalities employing mIBG, which 
is the only sensitive and specific tumour imaging biomarker available for neuroblastoma. There are 
currently a number of initiatives to rationalise the evaluations involved in staging neuroblastoma and 
identifying response to therapy, and mIBG scanning is pivotal and essential to these.  Although other 
imaging modalities have been investigated as possible alternatives to mIBG scanning including 
technetium-99m bone scintigraphy, SPECT, [18F]FDG PET/CT and others, these have failed to 
achieve a significant overall improvement in neuroblastoma imaging.  Although superior to planar 
scintigraphy, SPECT has several disadvantages which are that resolution still remains relatively poor 
and the quantification of uptake is difficult.  SPECT or SPECT/CT imaging is also time-consuming, 
with a single body region taking up to 30 minutes; which is a particular problem in children as they are 
less able to comply with lying still for extended periods of time than adults.   
For other tumours apart from neuroblastoma, [18F]FDG (fluorine-18 radiolabelled fluorodeoxyglucose) 
PET/CT’s unique ability to synthesise structural and metabolic information has established its routine 
use for staging and post treatment assessment.  It is also very rapid, with the entire body being 
imaged in 20 minutes in the latest scanners.  However, [18F]FDG, unlike mIBG, is not a 
tumour-specific biomarker and suffers from poor specificity in neuroblastoma as a result.  Iodine-124, 
as a positron emitting radiotracer with a long half-life, offers the potential to take full advantage of the 
high sensitivity and specificity of mIBG in conjunction with the excellent spatial and anatomical 
resolution offered by PET/CT. 
Iodine-124 is cyclotron generated, with a relatively long half-life of 4.18 days.  Early work was carried 
out at the Royal Marsden in 1992 on its possible use as a PET tracer in radioiodine therapy planning 
for neuroblastoma using an early multi-wire proportional chamber position emission tomography 
(MUP-PET) positron camera (Ott, Tait et al. 1992).  Since that time iodine-124 has been virtually 
ignored by researchers until its favourable radiochemical properties and long half-life focused renewed 
interest on its use in the imaging of antibodies using PET.  There is currently increasing interest in this 
radioisotope as a potential imaging tool in thyroid cancer, which has led to iodine-124 (as sodium 
iodide) having been successfully applied to radioiodine dosimetry in that setting (Freudenberg, 
Jentzen et al. 2007, Jentzen, Weise et al. 2008, Hobbs, Wahl et al. 2009).  Optimal acquisition 


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settings for iodine-124 detection by PET in the clinical setting have now been published (Freudenberg, 
Antoch et al. 2008, Lubberink, Abdul Fatah et al. 2008, Phan, Jager et al. 2008, Capoccetti, Criscuoli 
et al. 2009, Gregory, Hooker et al. 2009) and [124I]mIBG has already been manufactured in the USA 
and Manchester for use in a number of in vitro gene expression studies (Lee, Hall et al. 2001, 
Robinson, Julyan et al. 2004, Keen, Dekker et al. 2005, Dekker, Keen et al. 2005a, Dekker, Keen et 
al. 2005b, Williams, Julyan et al. 2007), but there are no published data in the clinical context of 
children with neuroblastoma to date. 
2.2 
INVESTIGATIONAL MEDICINAL PRODUCTS 
2.2.1 [123I]mIBG 
Administration of [123I]mIBG for planar scintigraphy imaging is routine standard of care for the group of 
patients eligible for this study.  However, as this assessment will form part of this clinical trial as a 
comparator imaging modality, [123I]mIBG is classified as an IMP.  Clinical supplies will be obtained 
through the Radiopharmacy at each investigational site through routine supply mechanisms.   
The active substance [123I]mIBG, also known as Iodine-123 (123I) Iobenguane, is licensed in the UK for 
use as a diagnostic imaging agent for the localisation of tumours originating in tissue that 
embryologically stems from the neural crest (e.g. pheochromocytomas, paragangliomas, 
chemodectomas and ganglioneuromas) and for the detection, staging and follow-up of therapy of 
neuroblastoma.  It is marketed by multiple suppliers in the UK.  [123I]mIBG will be identified by active 
substance in this protocol. 
2.2.2  [124I]mIBG Solution for Injection 
[124I]mIBG Solution for Injection will be produced in accordance with European Union (EU) Good 
Manufacturing Practice (GMP). 
The radiosynthetic route for the preparation of the active substance [124I]mIBG in [124I]mIBG Solution 
for Injection will be a based on the method developed by Vaidyanathan et al. (Vaidyanathan and 
Zalutsky 1993) which uses iododesilylation as the mode of iodine-124 incorporation.  In brief, [124I]NaI 
is reacted with meta-trimethylsilylbenzylguanidine and the resultant [124I]mIBG is purified and isolated 
by reverse-phase chromatography.  The product is buffered and formulated in an isotonic medium 
then aseptically filtered to give [124I]mIBG Solution for Injection suitable for human administration.  
 
 
 
2.3 
MECHANISM OF ACTION 
mIBG acts as stable radiolabelled mimetic of endogenous noradrenaline. After administration it is 
taken up by neuroendocrine cells by an active uptake mechanism via the noradrenaline transporter 
and is stored in the neurosecretory granules, resulting in a specific concentration in contrast to cells of 
other tissues. 


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mIBG has been used extensively in man primarily radiolabelled with either iodine-123 or iodine-131.  
mIBG radiolabelled with iodine-124 has previously been administered to two patients (Ott, Tait et al. 
1992). 
2.4 
PRECLINICAL DATA ON mIBG 
2.4.1 Pharmacology 
mIBG has a similar chemical structure to noradrenaline and as a result selectively concentrates in 
tissues with rich adrenergic innervation - such as tumours of neuro-ectodermal origin.  Similarly to 
noradrenaline, mIBG is taken up into cells by the noradrenaline transporter (NAT) and is then 
transferred from intracellular cytoplasm to neurosecretory vesicles.  Unlike noradrenaline, mIBG is 
poorly metabolised and is excreted largely as the unchanged parent molecule (Wafelman, Hoefnagel 
et al. 1994, GE Healthcare Limited 2009).  mIBG radiolabelled with iodine-123 and iodine-131 has 
been used extensively as a diagnostic imaging agent in man since the 1980s. 
In the proposed study mIBG radiolabelled with iodine-124 will be administered at low chemical doses 
(maximum of 10 µg stable mIBG) for diagnostic imaging purposes only.  At these low doses mIBG is 
not expected to have any significant pharmacodynamic effect on the patient.  
2.4.2 Pharmacokinetics and Metabolism 
In preclinical models, mIBG is rapidly distributed from the blood and accumulates in adrenergically 
innervated tissues, including the adrenal medulla, salivary glands, heart, spleen and lungs.  
Accumulation of mIBG is predominately via the noradrenaline transporter (NAT), in the adrenergic 
neurons.  Non-neural accumulation is lost in a matter of hours while neural accumulation is retained 
for much longer (over 24 hours).  Prolonged retention is strongly associated with the level of tissue 
adrenergic innervation (Wafelman, Hoefnagel et al. 1994, GE Healthcare Limited 2009). 
Based on studies with [123I]mIBG, after administration 70 to 90% of the dose of radioactivity is 
recovered in urine within four days.  This radioactivity is predominately unaltered mIBG.  Metabolites 
of 
mIBG 
detected 
in 
urine 
include 
radiolabelled 
iodide, 
meta-iodohippuric 
acid, 
hydroxy-iodobenzylguanidine and meta-iodobenzoic acid, however, these only account for 
approximately 5 to 15% of the administered dose. 
The distribution of intravenously administered mIBG includes rapid initial uptake in liver (33% of the 
administered dose) and much less in lungs (3%), myocardium (0.8%), spleen (0.6%), and salivary 
glands (0.4%).  Uptake in normal adrenals (adrenal medulla) can lead to visualisation with 
radiolabelled mIBG and hyperplastic adrenals show a high uptake(GE Healthcare Limited 2009). 
Recent preclinical imaging studies have suggested that in non-clinical species [124I]mIBG PET does 
indeed give superior images compared with [123I]mIBG SPECT (Moroz, Serganova et al. 2007).  The 
superior distribution data obtained by [124I]mIBG PET, especially at later time points, has also been 
assessed preclinically as a method to improve dosimetry estimates for [131I]mIBG radiotherapy (Seo, 
Gustafson et al. 2012). 
2.4.3 Toxicology 
The toxicity of [124I]mIBG can be split into two components; that arising from the administered 
chemical dose of mIBG and that arising from the radioactive dose of iodine-124.  The former 
component has been characterised preclinically in studies of mIBG toxicity, however, this has largely 
been superseded by extensive clinical use of radiolabelled mIBG both as a diagnostic 
radiopharmaceutical and as a targeted radiotherapeutic.  The dosimetry of [124I]mIBG has been 
calculated with reference to published biokinetic data (see Section 2.5.4). 
In rats administration of intravenous mIBG at 20 to 40 mg/kg/day (120 to 240 mg/m2/day) induces 
signs of serious toxicity with 20 mg/kg considered to be the maximum tolerated dose.  At doses of 5 to 


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20 mg/kg/day (30 to 120 mg/m2) some acute effects were observed, including respiratory distress, but 
the only long-term effects documented were a slight increase in weight of the liver and heart. 
In dogs intravenous administration of mIBG at 20 mg/kg/day (400 mg/m2/day) was a lethal dose.  
Lower dose levels (14 mg/kg, 280 mg/m2) produced transient toxic cardiac effects.  Repeated 
intravenous administration of mIBG to dogs at 2.5 to 10 mg/kg (50 to 200 mg/m2) was also found to 
induce some cardiovascular effects, including increased blood pressure, increases in heart rate and in 
cardiac pulse propagation, but all signs were of a transient nature (Smets, Bout et al. 1988, 
GE Healthcare Limited 2009). 
The [124I]mIBG prepared for this study will have a maximum possible administered chemical dose of 
10 µg per patient.  This chemical dose will be well within the range of human exposure to mIBG and is 
likely to be lower than that administered during the [123I]mIBG scan the patient will have received prior 
to inclusion in this study.  As a consequence the safety of mIBG can be directly inferred from the 
extensive and current routine use of [123I]mIBG and [131I]mIBG in clinical practice. 
2.5 
CLINICAL EXPERIENCE WITH [124I]mIBG  
2.5.1 Pharmacology 
mIBG was developed in the early 1980s as a noradrenaline mimic to visualise tumours of the adrenal 
medulla.  Diagnostic imaging with radiolabelled mIBG is widely used to image tumours of 
neuroendocrine origin primarily those of the neuro-ectodermal system (phaeochromocytomas, 
paragangliomas and neuroblastomas); although other neuroendocrine tumours (e.g. carcinoid, 
medullary thyroid carcinoma) can also be visualised.  For clinical diagnostic imaging mIBG is usually 
radiolabelled with iodine-123 or, more rarely, iodine-131 (Bombardieri, Giammarile et al. 2010). 
2.5.2 Pharmacokinetics and Metabolism 
The pharmacokinetics of mIBG labelled with iodine-124 are expected to be identical to mIBG labelled 
with iodine-123 or iodine-131, i.e. rapid initial uptake in liver, lungs, myocardium, spleen and salivary 
glands (GE Healthcare Limited 2009). 
After administration of mIBG, uptake of radioactivity generally reflects organs and tissues of either rich 
adrenergic innervation or with a role in catecholamine excretion.  High levels of uptake are observed in 
the liver with lower levels observed in the spleen, lungs, salivary glands, skeletal muscle and 
myocardium.  Myocardial uptake may be particularly high, especially in children under 1 year old 
(although patients under 1 year old will be excluded from this study).  Radioactivity may accumulate to 
a variable degree in nasal mucosa, lungs, gallbladder, colon and uterus.  No skeletal uptake is 
observed.  Uptake in the thyroid was only observed when pre-treatment with non-radioactive iodide to 
competitively block the thyroid had been omitted.  Distribution in patients and healthy subjects was 
comparable (Nakajo, Shapiro et al. 1983, Shapiro, Copp et al. 1985, Wafelman, Hoefnagel et al. 1994, 
Shulkin and Shapiro 1998, Bombardieri, Giammarile et al. 2010). 
Data has been published on the pharmacokinetics of radioactivity after both diagnostic and 
radiotherapeutic [131I]mIBG administration.  After intravenous administration of radiolabelled mIBG, 
radioactivity is distributed from the vascular compartment within one hour followed by a slow 
redistribution from the peripheral compartment into the central compartment.  Terminal elimination 
half-live of radioactivity from blood has been reported to be 9 to 130 h in neuroblastoma patients 
(Wafelman, Hoefnagel et al. 1994, Vallabhajosula and Nikolopoulou 2011). 
The excretion of radioactivity after administration of radiolabelled mIBG has been established clinically 
and the subject of published reviews (Shapiro and Gross 1987, Wafelman, Hoefnagel et al. 1994, 
Vallabhajosula and Nikolopoulou 2011).  Following intravenous administration of radiolabelled mIBG 
radioactivity is rapidly and almost entirely excreted in urine.  The importance of renal excretion is 
confirmed by faecal recoveries of radioactivity of less than 2%.  As might be expected glomerular 
filtration rate (GFR) has a major influence with higher plasma/blood cell distribution ratios observed in 
renally impaired patients. 


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The composition of the excreted radioactivity has been investigated clinically.  mIBG represented 60% 
to 92% of total radioactivity.  Radiolabelled meta-iodohippuric acid was the main excreted metabolite 
together with small amounts of radioiodide (2% to 6%). 
2.5.3 Safety 
The safety of mIBG itself has not been clinically addressed while data on radiolabelled mIBG has 
focussed on the use of high radioactive dose [131I]mIBG for radiotherapy.  However, this safety data 
will be predominately related to the radioactive absorbed dose of iodine-131 and is of limited 
relevance to this study.  Rapid administration of high doses of mIBG can lead to pharmacological 
effects such cardiovascular side-effects, nausea and vomiting; particularly in [131I]mIBG radiotherapy 
where high chemical doses (greater than 10 mg) have been administered (Lynn, Shapiro et al. 1984, 
Barrett, Joyal et al. 2010), 200-fold higher than the proposed maximum chemical dose of 50 µg.  
However, these adverse effects are very rare when slow injection is used (Bombardieri, Giammarile et 
al. 2010). 
Probably the most relevant safety data comes from a clinical study of AdreView™ (Iobenguane (I 123) 
injection), the diagnostic [123I]mIBG produced by GE Healthcare.  This study was performed in 251 
patients with known or suspected pheochromocytoma or neuroblastoma who were given a single 
administration of [123I]mIBG and monitored for adverse reactions over a 24 hour period.  The average 
age was 49 years for adults and 4 years for paediatric patients.  Adverse reactions were all mild to 
moderate in severity and were predominantly isolated occurrences (occurring in no more than two 
patients) of one of the following reactions: dizziness, rash, pruritus, flushing or injection site 
haemorrhage. 
Hypersensitivity reactions have uncommonly been reported during the post-marketing use of 
AdreView™ [123I]mIBG and it is contraindicated in patients with known hypersensitivity to iobenguane 
or iobenguane sulphate. 
In the proposed study [124I]mIBG will be administered at radioactive doses suitable for diagnostic 
imaging.  The efficacy of mIBG in an imaging context is well established.  No anti-tumour efficacy of 
mIBG is expected in this study. 
2.5.4 Dosimetry 
Please refer to the current SPC for dosimetry information for [123I]mIBG.    
Absorbed and effective doses have been calculated using mIBG biokinetic data from the International 
Commission on Radiological Protection (ICRP) 53 (ICRP 2007).  Effective doses for mIBG labelled 
with the three radionuclides of iodine for all age models are summarised in Table 1.  It can be seen 
from these results that [124I]mIBG delivers effective doses that are approximately 15 times higher than 
that of diagnostic [123I]mIBG and 1.5 times higher than for [131I]mIBG. 
Table 1 Effective doses (mSv/MBq) for different age models 
 
[123I]mIBG 
[131I]mIBG 
[124I]mIBG 
Adult 
0.011 
0.106 
0.159 
15 Year 
0.014 
0.143 
0.207 
10 Year 
0.021 
0.218 
0.313 
5 Year 
0.032 
0.332 
0.472 
1 Year 
0.059 
0.637 
0.872 
 
European Association of Nuclear Medicine (EANM) recommendations for administered activities at 
diagnostic levels are scaled from those recommended for adults (Bombardieri, Giammarile et al. 
2010).  These recommend a minimum of 80 MBq and a maximum of 400 MBq for [123I]mIBG, and a 
minimum of 35 MBq and a maximum of 80 MBq for [131I]mIBG.  The equivalent activities delivering the 
same effective doses for [124I]mIBG are shown in Table 2. 


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Table 2 Recommended diagnostic activity levels for mIBG scans 
Recommended administered dose of radioactivity for [123I]mIBG and [131I]mIBG diagnostic scans and the radioactivity dose of 
[124I]mIBG which would deliver the equivalent effective dose 
Age 
Weight 
(kg) 
[123I]mIBG (MBq) 
Equivalent 
[124I]mIBG (MBq) 
[131I]mIBG (MBq) 
Equivalent 
[124I]mIBG (MBq) 
Adult 
73.70 
400.0 
26.7 
80.0 
53.3 
15 Year 
56.80 
336.0 
22.6 
67.2 
46.4 
10 Year 
33.20 
216.2 
14.6 
43.2 
30.1 
5 Year 
19.80 
136.1 
9.2 
35.0 
24.6 
1 Year 
9.72 
80.0 
5.4 
35.0 
25.6 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EANM recommendations for the timing of diagnostic [123I] and [131I]mIBG scans are at 24 h and 24 h to 
48 h respectively.  An advantage of iodine-124 is that, due to its relatively long physical half-life and 
superior imaging quality, high quality scans are possible at both 24 h and 48 h.  This study will enable 
the optimal scan times for [124I]mIBG PET/CT to be determined and will also provide additional 
information on the retention as well as the uptake of the radiopharmaceutical.  Scans will be 
performed at 4 h, 24 h, 48 h and 72 h post-administration of [124I]mIBG in a sub-group of up to six 
patients.  [124I]mIBG is a biomarker of both the burden of disease and treatment effect.  
The absorbed and effective doses used for radiation protection calculations are based on data from 
ICRP 53.  Absorbed doses to some organs, particularly the heart and spleen, are significantly higher 
than those to other organs, including the adrenals and lungs, due to greater retention.  The accuracy 
of these biokinetic data is marred by the lack of spatial resolution in the case of [131I]mIBG imaging 
and by a low half life in the case of [123I]mIBG. This [124I]mIBG PET/CT study would update these 
values and would permit the range of absorbed doses to be determined.  This would be of significant 
benefit to future studies involving [124I]mIBG. 
2.6 
RATIONALE FOR THE PROPOSED STUDY  
A new targeted imaging technique for neuroblastoma is proposed using the positron-emitter [124I]mIBG 
as a novel PET radiotracer.  Prognostic stratification and treatment decisions for patients with 
neuroblastoma are critically dependent on accurate imaging, but the current standard modality, 


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[123I]mIBG scintigraphy including 3D imaging by SPECT, suffers from significant shortcomings 
including poor spatial resolution and a lack of ability to accurately quantify results.  
This study will demonstrate whether [124I]mIBG PET/CT is able to detect an equivalent number of 
mIBG avid lesions in neuroblastoma more accurately compared to conventional [123I]mIBG imaging.  
Should this study be successful, the role of [124I]mIBG PET/CT in children with neuroblastoma will be 
fully evaluated in a large prospective international clinical trial that will study in a homogeneous 
population, the prognostic and predictive roles of this novel technique.  The [124I]mIBG PET/CT 
imaging will take place approximately 3-21 days after [123I]mIBG imaging during a scheduled break in 
anti-cancer therapy. The metastatic patient population undergoing re-staging has been selected 
because there is frequently a sufficient time window after their routine scanning to perform additional 
imaging without causing any delay in the start of subsequent anti-cancer therapy.  Patients will have 
stopped previous anti-cancer therapy at least seven days before the routine [123I]mIBG scanning used 
for comparison in this study in order to minimise the effects of this therapy on the residual lesions.  
The interval from cessation of previous therapy and the time between the mIBG modalities will be 
considered in the interpretation of the imaging data.  The results of the novel [124I]mIBG PET/CT 
imaging will not be reported to the local oncologist and will not be used to inform the management of 
patients. 
A more accurate technique will have a number of advantages: 
1. Currently, 60% of children with high-risk neuroblastoma experience relapse and most of these 
(>90%) die.  New therapeutic approaches are being developed.  A more accurate diagnostic 
tool will help to improve risk stratification and represent a more robust predictive biomarker.  
2. All children with high-risk neuroblastoma currently receive the same intensive multimodal 
therapy.  The International Neuroblastoma Risk Group (INRG) and International 
Neuroblastoma Response Criteria initiatives are now developing a consensus document to 
define an ultra-high risk group (UHR) of patients based on imaging criteria at diagnosis (mIBG 
score) who will be able to receive novel experimental drugs in the frontline setting with the aim 
of improving outcome.  Whereas non-UHR patients with a better outcome will continue with 
conventional high-risk therapy.  Therefore better risk stratification is likely to lead to earlier 
access to novel drugs for these poor prognosis children.  
3. Yanik et al. (Yanik, Parisi et al. 2010, Decarolis, Schneider et al. 2013, Yanik, Parisi et al. 
2013) and others have shown that patients who achieve a complete metastatic response (CR) 
on conventional [123I]mIBG imaging after induction have a significantly better prognosis than 
non-CR patients (3-years event free survival (EFS) was 44.9% for those with Curie score 0 to 
2 after induction versus EFS 15.4% for those with Curie score >2 after induction (see 
Appendix 5 for Curie scoring system)).  If [124I]mIBG is better than [123I]mIBG in detecting 
metastatic lesions, it will be a more powerful discriminative tool between CR and non-CR 
patients, therefore guiding therapy after induction. 
4. Children with localised neuroblastoma based on [123I]mIBG scanning currently receive 
intermediate risk therapy.  A more sensitive technique will potentially detect those patients 
with a low level of metastatic disease who would then receive high-risk therapy that will 
improve their outcome. 
5. In the minimal residual disease setting (after myeloablative therapy or during follow-up), a 
more sensitive technique will guide therapy (i.e. patients only benefit from immunotherapy if 
they have cleared their metastatic disease) and also detect early relapses.  While early 
detection of relapses might not translate into an increase in overall survival, it might provide 
improved access to early clinical trials (patients with better performance). 
6. In early clinical trials, the definition of response and identification of the most effective agents 
will be improved. 
A contrast enhanced CT (CECT) scan of diagnostic quality using intravenous and oral contrast is 
routinely performed as part of a combination of assessments for the staging or restaging of 
neuroblastoma.  Hybrid PET/CT imaging includes a CT of lower ionizing radiation dose than CECT, 
which provides anatomical localisation and attenuation correction for the PET component of the scan.  
Access to the new generation of PET/CT scanners is now common at paediatric oncology 


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departments where patients with neuroblastoma are treated.  Thus PET/CT could potentially replace 
the current two imaging techniques: [123I]mIBG scanning and CECT. 
The long-term objective for this Phase I/II study is that, subject to its being possible to demonstrate a 
sufficiently high degree of diagnostic accuracy for [124I]mIBG PET/CT, it would form the basis of further 
studies to evaluate this technique involving larger series of patients, initially through the National 
Cancer Research Institute Children's Cancer and Leukaemia Clinical Studies Group (NCRI CCLG) 
Neuroblastoma Subgroup and then International Society of Paediatric Oncology Europe 
Neuroblastoma (SIOPEN).  This would allow a more detailed assessment of its value in the 
pre-treatment staging and post-treatment assessment of neuroblastoma, and proper evaluation of the 
potential role of [124I]mIBG PET/CT as a guide to response-adapted therapy.   
Should further research demonstrate [124I]mIBG PET/CT to be a valuable advance in neuroblastoma 
imaging, we anticipate that it would be a relatively easy technique to introduce to clinical practice at 
centres with access to PET/CT.  This is because it would require no special adaptation to PET/CT 
scanners already widely used throughout the UK.  [124I]mIBG has already been manufactured for 
research use and could be produced in any cyclotron facility.  Its long half-life of 4.18 days compares 
very favourably with the two hour half-life of [18F]FDG which would represent a significant advantage 
from a practical and logistical point of view, allowing the radiotracer to be produced in a single 
cyclotron in the UK and then realistically transported with ease to other centres.  We also anticipate 
that, should [124I]mIBG PET/CT become part of routine clinical management of neuroblastoma, tracer 
production costs would quickly reduce due to greater demand.  
Radioiodine therapy with [131I]mIBG is increasingly a component of trials for high risk neuroblastoma 
and recent evidence has shown that individualised treatment planning based on absorbed whole-body 
and tumour doses can be performed to prevent under-treatment or unnecessary toxicity from over-
treatment (Gaze, Chang et al. 2005, Buckley, Chittenden et al. 2009).  The increased spatial 
resolution of three dimensional [124I]mIBG PET/CT imaging over 3D [123I]mIBG SPECT would improve 
the accuracy of quantitative imaging on which patient-specific absorbed dose calculations are based. 
In summary, the hypothesis of this study is that [124I]mIBG PET/CT will achieve high sensitivity and 
specificity in detecting neuroblastoma tumour, deliver the excellent spatial resolution required to 
precisely localise small disease foci, offer reliable and reproducible quantitative assessment of 
disease extent, and enable better evaluation of disease response to existing and new therapies for 
neuroblastoma.  In the future it could provide more functional and anatomical data than routine 
[123I]mIBG scintigraphy, where full body planar scintigraphy is performed alone or combined with 3D 
SPECT scintigraphy of the thorax and abdomen, and conventional cross sectional CT or MRI 
scanning.  This would minimise the need to perform two or more scans of different modality. 
2.6.1 
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 


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2.6.2 
 
 
 
  
 
 
  
 
  
 
 
   
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
2.6.3 Anticipated impact of the study on UK clinical practice 
If [124I]mIBG PET/CT is shown to be a significant advance on [123I]mIBG scintigraphy this would have a 
major impact on current clinical practice in neuroblastoma in the UK and internationally.  The potential 
clinical benefits of [124I]mIBG PET/CT to neuroblastoma patients may be summarized as follows: 
➢ It would offer increased sensitivity for predicting outcome and accurately stratifying therapy.  
Accurate disease staging is particularly critical, because of the very different therapies 
employed for the various risk groups. Failure to detect even very small disease foci, as 
currently occurs with [123I]mIBG planar scintigraphy and 3D SPECT, even in expert hands, 
may lead to incorrect understaging, leading to insufficient first line therapy and early disease 
recurrence, with a major reduction in the chance of long term cure. Conversely, inappropriate 
overstaging leading to unnecessary treatment for high-risk disease may lead to growth 
reduction, thyroid function disorders, learning difficulties, and a greater risk of secondary 
cancers in these children.  
➢ A major international strategy to improve the prognosis of high risk disease involves 
stratification of therapy based on response to indicial induction therapy based on response on 
[123I]mIBG scintigraphy. The improved accuracy of [124I]mIBG PET/CT would substantially 
strengthen this approach. 
➢ It would replace the visual assessment of disease used in [123I]mIBG scintigraphy with 
objective and reproducible quantitative measurement (SUV mean and max). Accurate 
quantitative assessment of disease extent would enable more rigorous and effective 
assessment of the efficacy of both existing and novel therapies. 
➢ At least two investigations ([123I]mIBG scintigraphy and CT scanning, and in some cases also 
bone scanning and MRI) would be replaced by one. This would speed up the diagnostic 
pathway and, as these scans often involve general anaesthetics in children, mean that only 
one rather than two (or more if other imaging techniques such as MRI are employed) general 
anaesthetics would be required. 






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were also identified using [124I]mIBG PET/CT is less than 45 out of 50 the trial will be stopped early for 
futility. If all lesions (e.g. 50 out of 50) were also identified using [124I]mIBG PET/CT the trial may be 
stopped early for efficacy. Otherwise recruitment will continue until a minimum of 100 lesions have 
been identified by [123I]mIBG planar scintigraphy from a minimum of 33 evaluable patients. 
The imaging review will be performed separately by an agreed number of observers who are Nuclear 
Medicine physicians experienced in the assessment of neuroblastoma.  Two observers will be study 
Investigators and all others will be independent from the study to prevent subjective bias in the 
interpretation of the nuclear medicine mIBG scans.  Lesions will be identified and scored by each 
observer using a diagnostic confidence level.  The observers will review the lesions identified and 
where there is a difference in their separate scores they will return to the imaging in order to reach a 
consensus score.  The number of lesions identified as positive by this scoring will be used to meet the 
primary objective of comparison of the novel [124I]mIBG PET/CT modality with the recommended 
standard mIBG imaging modality for neuroblastoma which is [123I]mIBG planar scintigraphy (see 
Section 9.1).   
The majority of patients treated for neuroblastoma will have [123I]mIBG scintigraphy using 3D SPECT 
over the chest and abdomen in addition to planar scintigraphy of the full body.  The imaging review 
performed for the assessment of the primary objective will be repeated to read and score lesions 
identified by the available [123I]mIBG SPECT.  The number of positive lesions identified by SPECT will 
be used to meet the secondary objective of comparison of [124I]mIBG PET/CT with [123I]mIBG 
scintigraphy with 3D SPECT. 
 
 
   
All patients will be monitored for safety reporting from the time the patient / parent or guardian (as 
applicable) provides informed consent until the Off-Study assessment on Day 3 (the day after the 
[124I]mIBG PET/CT scan) to Day 7.  The Off-Study assessment should either take place during a 
routine clinic visit or by telephone prior to the start of subsequent anti-cancer therapy.  If there are any 
reported events considered to be related (highly probably, probably or possibly) to [123I]mIBG and/or 
[124I]mIBG which are still present at the Off-Study assessment, the patient will be followed by their 
Paediatric Oncologist until resolution, recovery to baseline, or stabilisation of these events, unless the 
patient starts another anti-cancer therapy. 
3.3.1 
 
 
  
 
 
 
  
 
  
 
 
  
 
   
3.3.2 
 
  
 
 
  
 
 
 


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4 
PATIENT SELECTION 
4.1 
ELIGIBILITY CRITERIA 
The patient must fulfil the eligibility criteria presented in Sections 4.1.1 and 4.1.2 prior to enrolment on 
the clinical trial and the subsequent administration of [123I]mIBG.  
 
 
 
Following [123I]mIBG planar scintigraphy ± SPECT for routine clinical care of neuroblastoma, patients 
will only continue in the study and undergo [124I]mIBG imaging if they fulfil the additional clinical criteria 
outlined in Section 4.1.3.  
4.1.1 Inclusion Criteria 
4.1.1.1  
 
 
 
 
 
 
 
    
4.1.1.2  
 
 
 
 
 
 
 
 
 
    
4.1.2 Exclusion Criteria 
1. 
Treatment with any medications contra-indicated with mIBG scanning as listed in Appendix 4.  
For 
example, 
decongestants 
containing 
pseudoephedrine, 
phenylpropalomine 
and 
phenylephrine, sympathomimetics, cocaine, antihypertensives, tricyclic antidepressants. 
These drugs should be stopped before administration as indicated in this list (usually for four 
biological half-lives to allow almost complete wash-out but refer to list).  The Investigator 
should seek prospective approval of any planned variation from this list from the responsible 
Nuclear Medicine Consultant, CI and sponsor Medical Advisor.   
2. 
Stage 4S neuroblastoma as defined by the INSS. 
 
1. 
Histologically proven neuroblastoma with stage 4 disease as defined by the International 
Neuroblastoma Staging System (INSS) 
 
2. 
Aged ≥ 1 year at the time that written informed consent is given. 
 
3. 
Planned to undergo conventional [123I]mIBG planar scintigraphy for routine clinical care of 
neuroblastoma. 
 
4. 
Life expectancy of at least 12 weeks. 
 
5. 
World Health Organisation (WHO) performance status of 0, 1 or 2 (Appendix 2) for patients 
aged > 12 years old or Lansky play scale score of ≥ 50% (Appendix 3) for patients aged ≤ 12 
years old. 
6. 
Written (signed and dated) informed consent from patient ≥ 16 years old and/or parent or legal 
guardian for patients <16 years old and the patient be capable of co-operating with scanning 
requirements.  (N.B. Written or verbal assent as appropriate should be sought from all patients 
who are under 16 years old). 




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4.2 
PATIENT ENROLMENT 
Recruitment to the study will be competitive between centres.  There is no minimum time interval 
required between patients after review of the imaging data from the first patient. 
Informed Consent from the patient’s parent or guardian is required for all patients under 16 years old. 
Written or verbal assent will be sought from all patients under 16 years old.  Informed consent is 
required for all patients aged 16 or older.  All patients for whom informed consent has been provided 
must be added to the study clinical database via the electronic data capture (EDC) system by the site 
staff.  This includes those patients who fail screening and do not go on to be enrolled on the study.  
Through this process a screening number will be automatically allocated for all consented patients. 
The Investigator or designated representative should determine the eligibility of the patient during 
Screening.  The Investigator should inform the Clinical Study Manager (CSM) at the Centre for Drug 
Development (CDD) of the outcome of the Screening assessment.  Eligible patients must be enrolled 
in the study clinical database by completing the Enrolment and date of Pre-study i.e. Screening visit.  
A subject number will be automatically allocated to eligible patients.  The patient will be registered by 
the CSM at the CDD as sponsor.  The CSM will send confirmation of the patient registration by email 
to the Investigator after which the patient can start the thyroid blockade.  


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5 
DOSE AND ADMINISTRATION 
5.1 
[123I]mIBG DOSE AND ADMINISTRATION 
[123I]mIBG will be administered according to the current SPC.  The radioactive dose will be selected 
according to the EANM dosage card for paediatric patients and according to the SPC for adult patients.  
5.2 
[124I]mIBG DOSE AND ADMINISTRATION 
5.2.1 Selection of the Dose of radioactivity to be administered 
The proposed activities to be administered have been calculated based on previous studies with 
iodine-124 and on the calculation of activities that would deliver a similar effective dose to that 
delivered by a standard diagnostic [18F]FDG PET scan but greater that delivered by an [123I]mIBG 
scan.  It is proposed to administer activities of [124I]mIBG of 50 MBq for adult patients and paediatric 
patients will be scaled appropriately according to the EANM dosage card (Lassmann, Biassoni et al. 
2007) such that the absorbed dose will be less than that of a [131I]mIBG scan.  
To date the relatively few clinical studies using [124I] have been restricted to adults and have largely 
been limited to dosimetry studies for ablation or therapy of thyroid cancer.  As yet there are no 
guidelines regarding recommended administered doses of radioactivity.  Phan et al. administered 
74 MBq for diagnostic imaging of advanced thyroid cancer (Phan, Jager et al. 2008), Freudenberg et 
al. administered 24 to 100 MBq of [124I]NaI to predict absorbed doses delivered to lung metastases 
from thyroid cancer (Freudenberg, Antoch et al. 2008), and Sgouros et al. administered 74 to 158 MBq 
for a similar purpose (Sgouros, Kolbert et al. 2004).  In a two patient study of [124I]mIBG imaging for 
radionuclide therapy treatment planning for adult neuroendocrine tumours, 22 MBq and 40 MBq were 
administered (Ott, Tait et al. 1992). 
5.3 
DOSE SCHEDULE 
Patients will receive one intravenous injection of [124I]mIBG Solution for Injection on Day 1.   
All patients will receive a minimum injected dose of 10 MBq and a maximum injected dose of 50 MBq 
[124I]mIBG equating to a maximum chemical dose of 10 µg of stable mIBG. The maximum activity 
administered to adult patients will be 50 MBq. This maximum activity, 50 MBq, will be requested for 
each adult patient as the specified target dose. On occasions that the maximum activity, 50 MBq, is 
not met, but is still within the required range of 10 to 50 MBq, patient administration will proceed and 
the scanning time adjusted accordingly. The maximum activity to paediatric patients will be scaled by 
weight based upon the EANM paediatric dose card (Lassmann, Biassoni et al. 2007). This maximum 
activity will be requested for each paediatric patient as the specified target dose.  With reference to the 
EANM scheme, a baseline activity of 3.5 MBq, a minimum activity of 10 MBq and class B scaling 
factors are deemed appropriate. This will result in an administered activity between 10 MBq and 
50 MBq depending on the patient’s weight. 
Administration of [124I]mIBG Solution for Injection on Day 1 will be approximately 3-21 days after the 
routine [123I]mIBG scan.  A minimum interval of 72 hours is required between injection of [123I]mIBG 
tracer and the  [124I]mIBG PET/CT scan.  There is no minimum interval between patients. 
The scanning schedule will take between approximately 30 and 75 minutes depending on whether the 
scanning time is to be adjusted to account for administration of lower activity than specified target 
dose.  If the scan schedule is likely to exceed 75 minutes then this should be discussed with the 
patient prior to the injection of [124I]mIBG to seek verbal consent. Any discussions should be 
documented in the patients’ medical notes. 


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5.4 
DOSE MODIFICATIONS  
The [124I]mIBG PET/CT scans of the first patient will be assessed shortly after being performed to 
determine whether a lesser amount of radioactivity can be administered.  Any reduction will then be 
implemented from the second patient onwards.  The maximum injected dose will then be fixed and will 
not be further reduced for subsequent patients. 
5.5 
REPLACEMENT OF PATIENTS 
Patients who do not complete the [124I]mIBG PET/CT scan or who are subsequently found to have 
been ineligible for the study will be replaced. 
5.6 
CONCOMITANT MEDICATION 
Concomitant medication may be given as medically indicated, with the exception of the drugs listed in 
Appendix 4 which are contra-indicated with mIBG scanning.  These drugs should be stopped before 
administration as indicated in this list (usually for four biological half-lives to allow almost complete 
wash-out but refer to list).  The Investigator should seek prospective approval of any planned 
variation from this list from the responsible Nuclear Medicine Consultant, CI and sponsor 
Medical Advisor.  They include of note: reserpine, labetalol, calcium-channel blockers (diltiazem, 
nifedepine, verapamil), tricyclic antidepressants (amitryptiline, imipramine and derivatives), 
sympathomimetic agents (present in nasal decongestants, such as phenylephrine, ephedrine or 
phenylpropanolamine), cocaine, phenothiazine. 
Blood and platelet transfusions and granulocyte-colony stimulating factor (G-CSF) are allowed. 
The patient should not receive any anti-cancer therapy or investigational drugs until the Investigator 
has assessed whether there are ongoing toxic manifestations related to [124I]mIBG Solution for 
Injection administration unless this therapy is required in response to an urgent medical need.  This 
assessment should take place between Day 3 to Day 7 either during a routine visit to the clinic or by 
telephone.   
Details of all concomitant medications given should be recorded in the patient’s medical records.  
Relevant details of concomitant medications should be entered in the electronic case report form 
(eCRF). 


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6 
PHARMACEUTICAL INFORMATION 
6.1 
SUPPLY OF [123I]mIBG 
[123I]mIBG is available commercially from multiple suppliers.  The Investigators will be responsible for 
their own supply of [123I]mIBG.  Dispensed [123I]mIBG will be labelled by the Radiopharmacy according 
to the requirements of Article 14 of EU directive 2001/20/EC and paragraph 32 Eudralex volume 4: 
Annex 13 ‘Investigational Medicinal Products of the EU guide to GMP’.  An example of the label(s) will 
be approved by the CDD before use and filed in the Pharmacy Folder.   
6.2 
SUPPLY OF [124I]mIBG SOLUTION FOR INJECTION 
The maximum shelf-life of the IMP is 96 h from the end of manufacture when stored in a vial shield 
(lead or tungsten) in the absence of light and at ≤ 25°C.  A certificate of analysis and Qualified Person 
(QP) certification must be provided for each batch of [124I]mIBG Solution for Injection prior to patient 
administration.  [124I]mIBG Solution for Injection must be used before the expiry date and time stated 
(use within period) on the shield label. 
Refer to Section 7.5 Supply of [124I]mIBG Solution for Injection and to the [124I]mIBG Supply Guidelines 
for details of the ordering process and logistics of supply to the investigational site.  For information on 
[124I]mIBG and re-ordering of supplies, contact the Clinical Research Associate (CRA) or Clinical 
Study Manager (CSM) responsible for the study who will arrange further supplies.  The IMP will be 
manufactured in compliance with GMP and supplied by: 
Wolfson Molecular Imaging Centre (WMIC) 
  
  
  
 
 
The primary and secondary packaging for the IMP will be labeled according to Eudralex Volume 4: 
Annex 13 ‘Investigational Medicinal Products’ of the EU guide to GMP.  
6.3 
PHARMACEUTICAL DATA 
6.3.1 Pharmaceutical Presentation of [123I]mIBG 
Details for [123I]mIBG can be found in the current SPC provided by the manufacturer of [123I]mIBG.  
 
6.3.2 Pharmaceutical Presentation of [124I]mIBG Solution for Injection 
[124I]mIBG Solution for Injection is prepared as a single patient dose unit just prior to clinical use.  
 
 
 
 the maximum concentration of mIBG per vial will be 10 µg.  The product is 
aseptically filtered into a type I glass vial sealed with a Type I synthetic rubber closure and aluminium 
overseal.  Each drug product vial will be stored within a vial shield (lead or tungsten) container in the 
absence of light at a temperature of ≤ 25 °C. 
6.3.3 Storage conditions 
Both IMPs must be stored in a secure, limited access storage area. 
Storage conditions for [123I]mIBG will be stated in the current SPC supplied by the manufacturer and 
on the vial shield label.   


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[124I]mIBG Solution for Injection must be used before the expiry date and time stated on the shield 
label.  The vials of [124I]mIBG Solution for Injection must be stored and transported within a vial shield 
(lead or tungsten).  The IMP must be maintained at a temperature of ≤ 25°C. 
6.4 
 [123I]mIBG ADMINISTRATION 
[123I]mIBG should be administered in accordance with the dosage scheme described in the current 
SPC supplied by the manufacturer.   
6.5 
 [124I]mIBG SOLUTION FOR INJECTION ADMINISTRATION 
Aseptic technique must be employed when preparing the drug for administration.   
[124I]mIBG Solution for Injection is radioactive and must be handled to ensure the safety of the 
operators and patients.  This will be achieved by adhering to the local rules and Ionising Radiation 
(Medical Exposure) Regulations (IRMER) requirements which define practice, and the IRR99 
regulations which cover radiation doses to staff. 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
[124I]mIBG Solution for Injection must be used before the expiry date and time stated (use within 
period) on the shield label. 
Before administering [124I]mIBG Solution for Injection, the exact radioactive dosage must always be 
double-checked by a second suitably qualified healthcare professional.  All checks and double-checks 
must be documented (signed and dated) and the documentation must be available for the CRA/CSM 
to verify. 
The [124I]mIBG Solution for Injection must be administered slowly over several minutes by intravenous 
infusion either into a peripheral vein or through an existing central line.  This must occur before the 
expiry date and time stated on the vial shield label.  The start and end time of the infusion must be 
recorded. 
6.6 
VEIN EXTRAVASATION/ ACCIDENTAL SPILLAGES 
Please refer to the current SPC and Patient Information Leaflet for instructions for [123I]mIBG. 


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[124I]mIBG Solution for Injection is not a vesicant agent.  Vein extravasation should be managed 
according to hospital policy for extravasation of non-vesicant agents.  As the total levels of [124I]mIBG 
and radioactivity being administered to each patient are low there is no significant radiation risk even 
in the event that the full dose is extravasated.  Accidental spillages should be dealt with according to 
hospital policy and local Nuclear Medicine Departmental procedure. 
6.7 
DRUG ACCOUNTABILITY 
6.7.1 Accountability of [123I]mIBG 
Accurate records relating to the dispensing and administration (including the exact date and time the 
[123I]mIBG was administered) to the patient must be maintained.  These records must be available for 
inspection at any time by a CRA/CSM of the CDD.  [123I]mIBG employed for imaging of patients must 
be used in accordance with the SPC and under the supervision of the Investigator.  Any discrepancies 
between the number of vials dispensed and the volumes administered to patients must be accounted 
for in the Radiopharmacy records and Investigator Trial File (ITF). 
As [123I]mIBG is a marketed product and used as an IMP in this trial any unused [123I]mIBG should be 
retained as per local policy/procedures before being destroyed when radioactivity levels are safe. 
Destroyed vials and unused [123I]mIBG must be accounted for on an IMP Destruction Form and IMP 
accountability records. 
6.7.2 Accountability of [124I]mIBG Solution for Injection 
Accurate records relating to the receipt for the IMP, dispensing of the IMP, and administration 
(including the exact date and time the IMP was administered) to the patient must be maintained.  
These records must be available for inspection at any time by a CRA/CSM of the CDD.  IMP 
employed for imaging of patients must be used in accordance with this protocol and under the 
supervision of the Investigator.  Any discrepancies between the number of vials dispensed and the 
volumes administered to patients must be accounted for in the Radiopharmacy records and 
Investigator Trial File (ITF). 
If there is any [124I]mIBG Solution for Injection left after the administration this should be retained for 
six months as per GMP requirements in an appropriate controlled storage area at ≤ 25°C.  Any 
unused [124I]mIBG Solution for Injection should be retained for six months as per GMP requirements in 
an appropriate controlled storage area at ≤ 25°C and then must be destroyed according to hospital 
procedures and properly accounted for using the IMP Destruction Form and IMP Accountability 
Record.  At the conclusion of the study the overall numbers of vials of [124I]mIBG Solution for Injection 
shipped to the centre and the number destroyed will be provided by the pharmacy, and an account 
given of any discrepancy. 
 


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7 
INVESTIGATIONS SCHEDULE 
All required assessments for Screening through to Follow-up are shown in the tabulated Schedule of 
Events in Section 7.9 as well as being described here. 
Details of all evaluations/investigations for enrolled patients, including relevant dates, required by the 
protocol must be recorded in the medical records so that the eCRF can be checked against the source 
data. 
In cases where a patient has investigations at a different hospital, for example blood samples, then it 
is the Investigator’s responsibility to ensure he/she receives and reviews the results.  The results 
should be recorded on the eCRF and the reports from the other hospitals should be made available for 
source data verification.  Laboratory reference ranges, including effective dates, and evidence of 
laboratory accreditation must be obtained from all laboratories used. 
7.1 
OBTAINING WRITTEN INFORMED CONSENT 
Patients of 16 years of age or older must provide written informed consent for the study.  Parents or 
guardians of patients under 16 years of age must provide written informed consent.  Written or verbal 
assent will be sought from patients under 16 years of age.  Information sheets and consent or assent 
forms will be provided as below. 
• 
Patients 16 years of age or older (information sheet and consent form) 
• 
Parents / legal guardians of patients under 16 years of age (information sheet and consent 
form) 
• 
Patients below 16 years of age (information sheet and assent form) 
o 
Patients 13-15 years of age 
o 
Patients 8-12 years of age 
o 
Patients < 8 years of age 
Written informed consent / assent must be obtained from the patient and / or the patient’s parent or 
guardian before any protocol-specific procedures are carried out.  The patient and/or the patient’s 
parent or guardian must be given adequate time to think about their commitment to the study.  If more 
than 28 days has passed since informed consent was obtained before the patient receives the 
[124I]mIBG intravenous injection then the Investigator should consider whether repeat consent should 
be sought.   
Only the Principal Investigator (PI) and those Sub-Investigator(s) delegated responsibility by the PI as 
documented on the Study Team Responsibilities Signature Log are permitted to take informed 
consent from patients or the patient’s parent / guardian and to sign the consent form.  All signatures 
must be obtained before the occurrence of any medical intervention required by the protocol 
(International Conference on Harmonisation of Good Clinical Practice (ICH GCP) 4.8.8 and 8.3.1.2).  
The patient or parent/guardian should sign and date the consent form in the presence of the 
Investigator, followed by the Investigator signature. The date of the signatures of the patient, patient’s 
parent / guardian and the PI/Sub-Investigator should be the same.  
The PI or the Sub-Investigator must inform the patient about the background to the study and must 
also ensure that the patient and/or parent(s)/ legal guardian(s) are aware of the following points: 
• 
The known toxicity of [123I]mIBG and [124I]mIBG scanning and the possibility of experiencing 
side-effects. 


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• 
That [124I]mIBG PET/CT scanning is new and that because the accuracy of diagnosis of 
neuroblastoma using this modality is at present unknown the results of the scanning will not 
be used to inform the staging of their disease and so will have no direct benefit for them but 
that scanning him/her will contribute to further knowledge of this imaging modality. 
• 
For menarchal female patients the potential dangers of becoming pregnant, or for male 
patients the potential dangers of their partner becoming pregnant and that he/she has been 
given information about appropriate medically approved contraception (refer to Section 8.8). 
• 
That he/she may refuse to receive [123I]mIBG or [124I]mIBG or participate in the study scan(s) 
during the study and that refusal to participate will involve no penalty or loss of benefits to 
which they are otherwise entitled nor impact on their treatment. 
• 
Who to contact for answers to questions about the research and their rights, and also who to 
contact in the event of a research-related injury. 
A copy of the consent / assent form(s) and patient information sheet must be given to the 
patient/parent(s) or guardian(s) to keep.  The original consent / assent form (s) and patient information 
sheet should be filed in the Investigator Trial File (ITF) unless otherwise agreed to be filed in the 
medical records with copies kept in the ITF. 
If the scan schedule is likely to exceed 75 minutes as described in the study information sheets and 
consent or assent forms then this should be discussed with the patient prior to the injection of 
[124I]mIBG to seek verbal consent. Any discussions should be documented in the patients’ medical 
notes. 
7.2 
SCREENING EVALUATIONS (DAY -28 TO ENROLMENT) 
The following assessments must be performed before administration of [123I]mIBG in preparation for 
routine diagnostic [123I]mIBG planar scintigraphy performed as part of standard disease assessment. 
• 
Written informed consent / assent (as detailed in Section 7.1.2) 
• 
Demographic details 
• 
Relevant medical history including prior diagnosis, genetic findings to include MYCN, 11q, 17q 
and other segmental chromosomal abnormalities of prognostic impact in neuroblastoma,  
histological findings according to The International Neuroblastoma Pathology Classification 
(the Shimada system), prior treatments for neuroblastoma (stage 4 disease only), concomitant 
diseases. 
• 
Routine imaging for assessment of neuroblastoma including conventional cross sectional CT 
and/or MRI as clinically indicated.  This routine imaging must be performed during a break in 
treatment and within the 28 days before administration of [124I]mIBG.  If a diagnostic CECT 
has not already been performed as part of this routine imaging assessment this should be 
performed sequentially following the [124I]mIBG PET/CT scan where possible. 
• 
Adverse events (AEs), including serious adverse events (SAEs), must be monitored from the 
time that consent is given.  The Investigator should determine the start and stop date of an AE 
together with the relationship of the event to [123I]mIBG and/or [124I]mIBG.  All AEs must be 
graded according to NCI CTCAE Version 4.02.  All AEs and any concomitant treatment must 
be recorded in the medical records and in the eCRF. (See Section 8.3 for further details 
regarding the definition of AEs and reporting requirements.) 
• 
Schedule [124I]mIBG PET/CT scan and any applicable sub-study scans.   
N.B. A minimum interval of 72 hours is required between the planned injection of [123I]mIBG 
and the performance of the novel [124I]mIBG PET/CT scan.   
• 
Physical examination 


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• 
Height in cm and weight in kg 
• 
World Health Organisation (WHO) performance status (see Appendix 2) or Lansky play scale 
score (see Appendix 3) 
• 
Assessment of eligibility criteria (see sections 4.1.1 and 4.1.2) 
 
At this point eligible patients should be enrolled on the trial.  Site staff should enrol patients in the 
clinical database by completing the Enrolment form and entering the date of the Pre-study (i.e. 
Screening) visit following the guidance in Section 4.2 Patient Enrolment.  Confirmation of the patient 
registration from the CSM at the CDD must be received by the site staff before administration of 
[123I]mIBG for routine diagnostic imaging because this is classified as an IMP for this clinical imaging 
study. 
7.3 
EVALUATIONS DURING THE STUDY (DAY -21 TO -3) 
• 
Administration of thyroid blockade given in accordance with local standard operating 
procedure for diagnostic use of [123I]mIBG 
• 
Administration of [123I]mIBG   
• 
[123I]mIBG planar scintigraphy with 3D SPECT as available, performed for the routine 
assessment of neuroblastoma.  N.B. This should be performed following an interval of at least 
7 days from previous anti-cancer therapy between Day -21 to Day -3. 
7.4 
EVALUATIONS DURING THE STUDY (DAY -7 TO DAY 1) 
• 
Menarchal female patients should have a serum or urine human chorionic gonadotrophin 
(HCG) test; a negative result is required before administration of [124I]mIBG 
• 
Temperature, blood pressure (BP) and pulse rate 
• 
Blood sample for full blood count and biochemistry (refer to criteria in Section 4.1.3 for 
required values) to include: 
o 
Haematology – haemoglobin, white blood cells (WBC) with differential count (absolute 
neutrophil count (ANC) and lymphocytes) and platelets 
o 
Biochemistry – serum bilirubin, alanine aminotransferase (ALT) and/or aspartate 
amino-transferase (AST) and/or alkaline phosphatase (ALP), creatinine 
• 
PLEASE NOTE: All evaluations required during the study between Day -7 and Day 1 must be 
completed and all results received prior to administration of [124I]mIBG. 
7.5 
SUPPLY OF [124I]mIBG SOLUTION FOR INJECTION 
Please refer to the current version of the [124I]mIBG Solution for Injection Supply Guidelines available 
through the CRA or CSM at the Centre for Drug Development (CDD).  The Investigator should inform 
the CSM and CRA when informed consent has been obtained from a patient.  The Investigator should 
inform the CSM and CRA of the planned dates of the [123I]mIBG planar scintigraphy ± SPECT scan 
and  the [124I]mIBG PET/CT scan as soon as they are known.  The CSM or CRA will complete a 
manufacture request form and submit this to the WMIC.  The Investigator must not submit a request 
for manufacture directly to the WMIC as this must be approved by the CDD as sponsor.  The 
Investigator should inform the CSM and CRA as soon as they are aware that a patient will not be 
participating in the [124I]mIBG scanning.   


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Each imaging centre will agree the local scheduling options for [124I]mIBG PET/CT scanning with the 
WMIC and the CSM at the CDD before they open to recruitment of patients.  The agreed schedules 
will be based on the [124I]mIBG Solution for Injection Supply Guidelines and the schedule of the local 
imaging department with scenarios for the main study and the appropriate sub-study. 
7.6 
EVALUATIONS DURING THE STUDY (NOVEL IMAGING) 
Following [123I]mIBG planar scintigraphy ± SPECT for routine clinical care of neuroblastoma, patients 
will only continue in the study and undergo [124I]mIBG imaging if they fulfil the additional clinical criteria 
outlined in Section 4.1.3.  
7.6.1 [124I]mIBG PET/CT scan 
Day -1 Thyroid blockade 
All patients will receive thyroid blockade (i.e. potassium iodide) for five consecutive days, starting the 
day before administration of [124I]mIBG solution injection, i.e. one dose of potassium iodide taken on 
the day before the administration of [124I]mIBG solution and 4 once daily doses of potassium iodide 
following the administration of [124I]mIBG solution for a total of 4 days (please see section 7.9 
Schedule of Events). Apart from the duration of dosing (i.e. the total number of days), the thyroid 
blockade administration should be administered according to the standard local practice for [131I]mIBG 
therapy. 
 
Day 1 [124I]mIBG administration  
A minimum interval of 72 hours is required between injection of [123I]mIBG and the [124I]mIBG PET/CT 
scan to ensure scan quality.  See Sections 5.2 and 6.3 for guidance on dose and administration.   
 
Day 2 [124I]mIBG PET/CT scan  
To be performed 24 h (± 3 h) post-administration of [124I]mIBG.  The patient’s temperature, BP and 
pulse should be measured and an assessment of AEs and concomitant medications made during this 
visit to assess the safety of the [124I]mIBG tracer administered on the previous day. If the scan 
schedule is likely to exceed 75 minutes as described in the study Information sheets and consent or 
assent forms then this should be discussed with the patient prior to the injection of [124I]mIBG to seek 
verbal consent. Any discussions should be documented in the patients’ medical notes. 
 
7.6.2 
  
 
 
 
 
 
  
 
   
 
 
7.6.3 
 
 
  
 
 


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7.7 
‘OFF-STUDY’ ASSESSMENT (DAY 3 TO DAY 7) 
The patient should not receive any anti-cancer therapy or investigational drugs until the Investigator 
has assessed whether there are any ongoing toxic manifestations related to [123I]mIBG or [124I]mIBG 
administration unless this therapy is required in response to an urgent medical need.  This 
assessment of AEs and concomitant medications should either take place between Day 3 to Day 7, 
either during a routine visit to the clinic or by telephone.  Anti-cancer therapy or investigational drugs 
may commence at the earliest on Day 3 after the Off-Study assessment has been completed.  
7.8 
FOLLOW-UP 
AEs considered to have a highly probable, probable or possible causal relationship to [123I]mIBG 
and/or [124I]mIBG  present at the time of the Off-Study assessment should be followed until resolution, 
recovery to baseline, or stabilisation of these events, unless the patient starts another anti-cancer 
therapy. 




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Footnotes: 
 
a   
Informed consent from the patient’s parent or guardian is required for all patients under 16 years of age. Written or verbal assent will be sought form 
all patients under 16 years of age. Informed consent is required from all patients aged 16 or above. 
b   
Relevant medical history including prior diagnosis, genetic findings to include MYCN, 11q, 17q and other segmental chromosomal abnormalities of 
prognostic impact in neuroblastoma,  histological findings according to The International Neuroblastoma Pathology Classification (the Shimada 
system), prior treatment for neuroblastoma (stage 4 disease only) and concomitant diseases. 
c 
Routine imaging for assessment of neuroblastoma including conventional cross sectional CT and/or MRI as clinically indicated.  This routine imaging 
must be performed during a break in treatment and within the 28 days before administration of [124I]mIBG.   
d 
Adverse events (AEs), including serious adverse events (SAEs), must be monitored from the time the patient consents/assents to any 
protocol-specific procedure.  The Investigator should determine the start and stop date of an AE together with the relationship of the event to 
[124I]mIBG.  All AEs must be graded according to NCI CTCAE Version 4.02.  All AEs and any concomitant treatment must be recorded in the medical 
records and in the eCRF. (See Section 8.3 for further details regarding the definition of AEs and reporting requirements.) 
e 
[123I]mIBG planar scintigraphy ± SPECT should be performed following an interval of at least 7 days from previous anti-cancer therapy.  A minimum 
interval of 72 hours is required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan.  Thyroid blockade should be given according to 
local practice for administration of [123I]mIBG. 
f 
Day -7 to 1 assessments should only be performed after the results of [123I]mIBG planar scintigraphy confirm the presence of at least 1 lesion. 
g 
Menarchal females should have a serum or urine HCG test to rule out pregnancy.  A negative result must be obtained before the administration of 
[124I]mIBG.  
h 
Full blood count to include haemoglobin, WBC with differential count (ANC and lymphocytes) and platelets, and biochemistry to include serum 
bilirubin, ALT or AST or ALP, creatinine). Refer to Section 4.1.3 Clinical Criteria for [124I]mIBG imaging for required values. 
i 
For administration of [123I]mIBG thyroid blockade should be given according to local practice.  For administration of [124I]mIBG, potassium iodide 
should be given for five consecutive days, starting the day before [124I]mIBG administration, according to local practice for administration of [131I]mIBG. 
j 
[124I]mIBG PET/CT scan to be performed 24 h (± 3 h) after the administration of [124I]mIBG.  A minimum interval of 72 hours is required between 
injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan. 
 The Investigator must ensure patients meet the Clinical Criteria for [124I]mIBG 
imaging described in section 4.1.3 before administration of [124I]mIBG Solution for Injection. 
k 
 
 
 
l 
 
 
m 
The Investigator should make an assessment of AEs and record concomitant medications either during a routine visit to the clinic or by telephone 
between Day 3 to Day 7.  Patients should not receive any anti-cancer therapy or investigational drugs until after this Off-Study Assessment. AEs 
considered to have a highly probable, probable or possible causal relationship to [124I]mIBG still present at the Off-study assessment should be 
followed until resolution, recovery to baseline, or stabilisation of these events, unless the patient starts another anti-cancer therapy. 


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8 
ASSESSMENT OF SAFETY 
8.1 
INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for monitoring the safety of patients who have enrolled in the study and 
for accurately documenting and reporting information as described in the following sections. 
8.2 
MEDICAL COVER 
The Principal Investigator (PI) is responsible for ensuring patients have access to 24 hour advice 
and/or care.  Patients will be provided with the necessary contact numbers for both normal working 
and out of hours care.  A copy of the protocol must be made available out of hours to ward staff and 
clinicians on call so that the appropriate advice may be given to the patient, the patient’s relative or 
other care giver (for example General Practitioner (GP)).  The CI/PI must ensure that should the on 
call clinician or ward staff require more advice than is in this protocol, that they have access to the 
Investigator or delegated members of the clinical team who can answer any questions. 
8.3 
ADVERSE EVENT DEFINITIONS 
8.3.1 Adverse event (AE) 
An AE is any untoward, undesired or unplanned occurrence in a patient administered an IMP, a 
comparator product or an approved drug.  An AE can be a sign, symptom, disease, and/or laboratory 
or physiological observation that may or may not be related to the IMP or comparator.   
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition.  This includes conditions that 
may resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• 
AEs occurring from lack of efficacy of an IMP, for example, if the Investigator suspects that a 
drug batch is not efficacious. 
Other reportable events that must be treated as AEs are listed below.   
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a patient or a patient’s partner 
during exposure to an IMP or occurring within 7 days of the last IMP administration, must be 
reported to the Pharmacovigilance Department in the same timelines as an SAE.  These 
should be reported even if the patient is withdrawn from the study. 
• 
Overdose with or without an AE. 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for example, 
spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct 
of the study. 
8.3.2 Serious adverse event (SAE) 
An SAE is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 


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• 
is life-threatening*; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – see Section 8.4); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event.** 
* A life-threatening event is defined as an event when the patient was at substantial risk of dying at 
the time of the adverse event, or use or continued use of the device or other medical product might 
have resulted in the death of the patient. 
** A medically important event is defined as any event that may jeopardise the patient or may 
require intervention to prevent one of the outcomes listed above. Examples include allergic 
bronchospasm (a serious problem with breathing) requiring treatment in an emergency room, 
serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in 
hospitalization. The development of drug dependence or drug abuse would also be examples of 
important medical events. 
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome rather 
than reporting death as the SAE term.  When available the autopsy report will be provided to the 
Sponsor. 
 
If during the course of the study, other medically important events are identified and there is a 
requirement to report specific events outside of the standard criteria, this will be communicated to 
site and the protocol will be updated to reflect this. 
 
8.3.3 Determining AE causality 
The relationship of an AE to the IMP is determined as follows. 
Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the study drug is not 
likely to have had an association with the observed effect. 
Not related 


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• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP(s), other illness, progressive malignancy etc) and must provide his/her opinion of the causal 
relationship between each AE and each IMP(s).  This may require instituting supplementary 
investigations of significant AEs based on their clinical judgement of the likely causative factors and/or 
include seeking a further opinion from a specialist in the field of the AE. 
8.3.4 Expectedness 
Assessment of expectedness will be made by the Pharmacovigilance Department against the current 
version of the Investigator Brochure for [124I]mIBG and the current SmPC for [123I]mIBG.   
8.3.5 Suspected, unexpected, serious, adverse reactions (SUSARs) 
A SUSAR is a suspected, unexpected, serious adverse reaction.  All AEs and SAEs will be assessed 
by CDD for seriousness, causality and expectedness.  The Pharmacovigilance Department will 
expedite all SUSARs to the relevant Competent Authority/Authorities and the relevant Research Ethics 
Committee (REC) within the timelines specified in legislation (SI 2004/1031 as amended).  
8.4 
COLLECTION OF SAFETY INFORMATION 
8.4.1 Screening failures 
For patients who fail screening, SAEs must be reported to the Pharmacovigilance Department, CDD 
from the date of consent until the date the patient is confirmed as ineligible. 
8.4.2 Eligible patients 
For eligible patients, SAE and AE collection and monitoring will commence at the time the patient 
gives their written consent to participate in the trial by signing the main study consent form and will 
continue until 7 days after the last administration of IMP or until the patient starts another anti-cancer 
therapy.   
Should an Investigator become aware of any drug-related SAEs after this 7 day period, these must 
also be reported to the CDD within the expedited timelines in Section 9.4. 
8.4.3 Follow-up of AEs and SAEs 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve, stabilise or the patient starts another anti-cancer therapy.   
The Pharmacovigilance Department will make requests for further information on SAEs to the trial site 
at regular intervals.  Requested follow-up information should be reported to the Pharmacovigilance 
Department in a timely manner and as soon as possible after receipt of the follow-up request.  For 
fatal or life-threatening cases, follow-up information must be reported to the Pharmacovigilance 
Department as soon as possible. 
8.4.4 Other safety information of interest 
We will also collect information on the following situations, whether they are associated with an AE or 
not: 
• 
Overdose (any dose above that specified in the protocol, not necessarily intentional) 


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• 
Abuse or misuse 
• 
Medication error (any unintentional error in the dispensing or administration of an IMP) 
• 
Occupational exposure (to a person other than the patient, for example spilling of IMP on 
hands of nurse or splashing in the eye) 
Any occurrences of these should be reported in the same manner as SAEs (Section 9.4). 
8.5 
EXPEDITED REPORTING OF SAEs TO PHARMACOVIGILANCE 
All SAEs, regardless of causality, must be reported to the Pharmacovigilance Department in an 
expedited manner. 
SAEs should be documented on an SAE report form, using the completion guidelines provided. 
The SAE report form should be emailed to Pharmacovigilance Department within 24 hours of 
site staff becoming aware of the SAE. 
Email: SAE@cancer.org.uk 
Each episode of an SAE must be recorded on a separate SAE report form.  The NCI CTCAE 
Version 4.02 must be used to grade each SAE, and the worst grade recorded.  If new or amended 
information on a previously reported SAE becomes available, the Investigator should report this to the 
Pharmacovigilance Department on a new SAE report form. 
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added 
on the email cover sheet when sending the SAE report form to the Pharmacovigilance Department. 
Should the Investigator become aware of any drug-related SAEs after the patient goes ‘off study’, 
these must also be reported to the Pharmacovigilance Department within the specified timelines 
above. 
8.5.1 Events exempt from reporting as SAEs to Pharmacovigilance 
Events specified in this section do not require reporting as SAEs in this study, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed.  The events must still be 
recorded in the appropriate section of the eCRF. 
Elective admissions – Elective admissions to hospital for procedures which were planned prior to 
entering the trial are not SAEs.  Hospitalisation for administration of an IMP and conduct of scans 
according to the study protocol is also exempt from being reported as an SAE. 
8.6 
RECORDING OF AEs AND SAEs IN eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients.  All concomitant 
medications, including herbal medications and supplements must be recorded.  Any therapy used to 
treat the event must be recorded.  The eCRF will be reconciled with the safety database during and at 
the end of the study.  Therefore, the sites should ensure the data entered on the SAE report form and 
the data entered into the eCRF are consistent.  The CDD Medical Advisor and the Investigator(s) will 
regularly review the safety data from both the safety and the clinical database. 
8.7 
FOLLOW-UP OF AEs AND SAEs 
Follow-up will continue until all the necessary safety data for the event has been gathered and until 
resolution, recovery to baseline, or stabilisation of these events, unless the patients starts another 


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anti-cancer therapy.  The Pharmacovigilance Department will make requests for further information to 
the study site at regular intervals.  Requested follow-up information should be reported to the 
Pharmacovigilance Department in a timely manner and as soon as possible after receipt of the 
follow-up request.  For fatal or life-threatening cases, follow-up information should be reported to the 
Pharmacovigilance Department as soon as possible. 
8.8 
URGENT SAFETY MEASURES 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical study against any immediate hazard to their health or safety.  This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. 
The Medicines and Healthcare products Regulations Agency (MHRA) and the REC must be notified 
within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
• 
email: sae@cancer.org.uk; or 
• 
telephone: 0203 469 6905;   
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The Sponsor will then notify the MHRA and the REC within three days of USM initiation. 
8.9 
PREGNANCY 
Female patients who become pregnant from the time of informed consent being signed to off-study, 
must be withdrawn from study treatment immediately. 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for seven days afterwards.  This 
should be done as part of the consent process by explaining clearly to the patient the potential 
dangers of becoming pregnant and also providing each patient with information about appropriate 
medically approved contraception. Two forms of medically approved contraception should be used, 
such as:   
• 
oral contraceptives and condom; 
• 
intra-uterine device (IUD) and condom; 
• 
diaphragms with spermicidal gel and condom. 
• 
Contraception should be effective before the patient is enrolled on the trial, throughout the trial 
and for six months after the administration of [124I]mIBG. 


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• 
It should be explained to the patient that if his partner is pregnant or breast-feeding when he is 
enrolled on the trial, the patient should use barrier method contraception (condom plus 
spermicidal gel) to prevent the unborn baby or the baby being exposed to the [124I]mIBG.  
• 
However, if a patient or a partner of a patient does become pregnant, the reporting 
procedures below must be followed. 
Any pregnancy occurring in a patient or a patient’s partner occurring within seven days of 
administration of either [123I]mIBG or [124I]mIBG must be reported to the Pharmacovigilance 
Department within 24 hours of the site staff becoming aware of it using a Pregnancy Report Form 
(provided in the ITF). It is the Investigator’s responsibility to obtain consent for follow-up from the 
patient or patient’s partner.  In addition, the Investigator must be made aware of the need to obtain 
contact details for the patient’s partner’s General Practitioner. The Pharmacovigilance Department will 
follow-up all pregnancies for the pregnancy outcome via the Investigator, using a Pregnancy Report 
Form.  
The Investigator must ensure that all patients are aware at the start of a clinical trial of the importance 
of reporting all pregnancies (in themselves and their partners) that occur whilst being treated with the 
IMP and occurring up to seven days after the last [124I]mIBG administration.  The Investigator should 
offer counselling to the patient and/or the partner, and discuss the risks of continuing with the 
pregnancy and the possible effects on the foetus.  Monitoring of the patient should continue until the 
conclusion of the pregnancy, if the patient or patient’s partner has consented to this. Monitoring of the 
baby should continue until 12 months after birth, if the patient or patient’s partner has consented to 
this.  
 


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9 
ASSESSMENT OF IMAGING TECHNIQUES 
9.1 
PRIMARY ANALYSIS 
Analysis of [124I]mIBG PET/CT and [123I]mIBG planar scintigraphy will be performed retrospectively by 
an agreed number of observers who are experienced in the assessment of neuroblastoma.  The 
observers will perform the analysis separately from each other and will be blinded from the scores of 
the other observers.  An observer will perform their review of each modality for a patient several 
weeks apart.  [123I]mIBG imaging and [124I]mIBG PET/CT imaging will be reviewed on a Hermes 
workstation (Hermes Medical Solutions, Sweden).  Observers may perform their assessment of study 
imaging data in batches throughout the study but will not share their scores until the conditions are 
met to trigger the interim and final analyses as described in section 12.2.   
For each modality, suspected lesions will be judged positive, negative, or equivocal with regard to 
neuroblastoma involvement by each observer.  A final determination of each lesion as positive, 
negative or equivocal will be established through consensus between all observers:  
• Positive – all reviewers consider it positive 
• Negative – all reviewers consider it negative 
• Equivocal – fewer than all reviewers can agree on whether the lesion is positive or negative 
The scores for each modality will be submitted to the statistician at the interim and final analyses to 
meet the primary endpoint.  The percentage of positive findings identified on routine [123I]mIBG planar 
scintigraphy also identified by the novel [124I]mIBG PET/CT will be determined.  Recruitment will cease 
during the interim analysis. 
9.2 
SECONDARY ANALYSIS 
The agreed number of experienced observers will perform the same analysis of [123I]mIBG 
scintigraphy by 3D SPECT where this was performed as part of the routine imaging for a patient.  
Using the method described in Section 9.1 the observers will score suspected lesions for this modality.  
The percentage of positive findings identified on routine [123I]mIBG scintigraphy by 3D SPECT also 
identified by the novel [124I]mIBG PET/CT will be determined. 
9.3 
TERTIARY ANALYSES 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  


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10 
PATIENT WITHDRAWAL BEFORE COMPLETION OF IMAGING 
SCHEDULE 
The Investigator must make every reasonable effort to keep each patient on study for the whole 
duration of the study (i.e. until the Off-Study assessment has been completed).  However, if the 
Investigator removes a patient from the study or if the patient declines further participation, the 
‘off-study’ assessments should ideally be performed before any subsequent therapeutic intervention.  
All the results of the evaluations and observations, together with a description of the reasons for 
withdrawal from the study, must be recorded in the medical records and in the eCRF. 
Patients who are removed from the study due to AEs (clinical or laboratory) will be treated and 
followed according to accepted medical practice.  All pertinent information concerning the outcome of 
such treatment must be recorded in the eCRF and on the SAE report form where necessary. 
The following are justifiable reasons for the Investigator to withdraw a patient from the study. 
• 
AE/SAE 
• 
Withdrawal of consent or assent by a parent/guardian or by the patient as applicable 
• 
Serious violation of the study protocol  
• 
Sponsor’s decision to terminate the study 
• 
Failure to meet the Clinical Criteria for [124I]mIBG imaging (section 4.1.3) 
• 
Withdrawal by the Investigator for clinical reasons not related to the study imaging (including 
pregnancy) 


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11 
DEFINING THE END OF TRIAL  
The ‘end of trial’ will be declared when one of the following is fulfilled: 
• 
[124I]mIBG Solution for Injection is considered too toxic to scan any further patients before the 
required number of patients have been recruited. 
• 
Following the interim analysis, it is confirmed the trial is to stop due to futility as per Section 
12.1 (end of trial will be the date of this decision). 
• 
Following the interim analysis, it is confirmed the trial is to stop due to efficacy as per Section 
12.1 (end of trial will be the date of this decision). 
• 
If recruitment continues as allowed under the protocol beyond the interim analysis. Last 
Patient Last Visit is defined as the date when the last patient completes their participation in 
the trial, which will be either completion of the Off-study assessment or early withdrawal from 
the trial. 
It is the responsibility of the CDD to notify the MHRA and the REC of the ‘end of the trial’. 
In cases of early termination of the study (for example, due to toxicity) or a temporary halt by the CDD, 
the CDD will notify the MHRA and the REC within 15 days of the decision and a detailed, written 
explanation for the termination/halt will be given. The entire study will be terminated when: 
• 
[124I]mIBG Solution for Injection is considered too toxic to scan any further patients before the 
required number of patients have been recruited. 
• 
The stated minimum number of evaluable patients has been reached. 
• 
The stated objectives of the study are achieved. 
Regardless of the reason for termination, all data available for patients at the time of termination of the 
study must be recorded in the eCRF.   


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12 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
12.1 
SAMPLE SIZE 
The primary endpoint of the study is the percentage of lesions identified as positive using [123I]mIBG 
planar scintigraphy which are also identified as positive on [124I]mIBG PET/CT.  The definition of a 
positive lesion is described in section 9.1.  The aim is to prove that there is more than 90% agreement 
between the methods, with an expected level of agreement of 97%.  Patients are expected to have a 
median of 3 lesions. Lesions are assumed to be independent within patients for the primary analysis. 
The following two stage design will be used, where the true proportion of agreement is denoted by P:  
In the first stage, a total of at least 9 patients will be recruited, with a combined total of at least 
50 lesions positive on [123I]mIBG.  Initially an exact one-sided binomial test of the null hypothesis: 
P>=97% will be done using alpha=0.05. If this is rejected in favour of the alternative hypothesis 
P<97%, the trial will be stopped early for futility. With a total of exactly 50 lesions this will occur if 45 or 
fewer lesions are also positive on [124I]mIBG PET/CT.  
If the null hypothesis is accepted, a further one-sided binomial test of the null hypothesis: P<=90% will 
be done using alpha=0.025. If this is rejected in favour of the alternative hypothesis P>90% then the 
trial may be stopped early for efficacy. With a total of 50 lesions this will occur only if all 50 lesions are 
also positive in [124I]mIBG PET/CT. If this null hypothesis is not rejected, the trial will continue to the 
second and final stage.  
The second stage will end when an overall total of at least 33 patients with at least 100 lesions have 
been recruited. An exact one-sided binomial test of the null hypothesis: P<=90% will be done using 
alpha=0.025. If this is rejected in favour of the alternative hypothesis P>90% then the trial will be 
declared a success. With a total of 100 lesions this will occur if at least 96 lesions are also positive on 
[124I]mIBG PET/CT.  
Overall this design has 82% power and an alpha of 0.03. If the true percentage of agreement is 97% 
then there is a 22% chance of stopping early for efficacy, and if the true percentage of agreement of 
90% then there is a 57% chance of stopping early for futility. The total sample size of 100 lesions was 
calculated based on a single stage A’hern design with p0=0.9 and p1=0.97, and the overall power and 
alpha has been calculated based on exact binomial probabilities.  
12.2 
INTERIM AND FINAL ANALYSIS 
The interim analysis will be conducted once both of the following conditions are met: 
• 
At least 50 lesions have been identified on [123I]mIBG planar scintigraphy.  These lesions will 
have been identified as positive by a Nuclear Medicine physician at the investigational site. 
• 
A minimum of 9 evaluable patients have completed the study. 
The analysis will be done using all identified lesions from at least 9 patients.  Therefore, the total 
number of lesions is expected to be more than 50.  The number of lesions identified on [123I]mIBG 
planar scintigraphy will be reported to the CSM at the CDD at the time of sponsor authorisation of the 
supply of the [124I]mIBG tracer from the manufacturing organisation to the investigational site.  The 
CSM will communicate to the observers and the statistician when the conditions have been met to 
trigger the interim analysis. 
The interim analysis will assess the primary endpoint by comparison of the number of positive lesions 
detected on [123I]mIBG planar scintigraphy and [124I]mIBG PET/CT in order to compare the two 
modalities.  The imaging data will be analysed and scored separately by an agreed number of 
observers using the same scoring method as described in Section 9.1 in order to prevent subjective 
bias.  Observers may perform their assessment of study imaging data prior to the interim and final 


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analyses in batches but will remain blinded to the scores of the other observers until the interim and 
final analyses are triggered and they meet to perform the consensus reviews.  Assessment of the 
reported safety data will be performed at the interim review and will be considered as part of the 
decision whether to continue recruitment.  The feasibility of recruitment of the required minimum 
number of patients will also be considered in this decision. 
The final analysis will be conducted after one of the following conditions is met: 
• 
The study is terminated early  
• 
The end of trial as defined in Section 11 has been reached. 
Following lesion detection the agreed number of experienced observers will also perform a 
semi-quantitative assessment of [124I]mIBG PET/CT scans and [123I]mIBG imaging employing 
SUVmean and SUVmax.  The level of disease involvement will be assessed using the International 
Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) scoring method and the Curie 
scoring method (see Appendix 5). 
12.2.1 Statistical Analysis of Primary Endpoint  
The proportion of positive lesions detected by routine [123I]mIBG planar scintigraphy which are also 
identified as positive using [124I]mIBG PET/CT will be calculated.  An exact one-sided binomial test of 
the null hypothesis that this proportion is not more than 90% will be performed, using an alpha of 
0.025 to define significance. 
12.2.2 Statistical Analysis of Secondary Endpoint 
The proportion of positive lesions detected by routine [123I]mIBG imaging using 3D SPECT which are 
also identified as positive using [124I]mIBG PET/CT will be calculated.  An exact one-sided binomial 
test of the null hypothesis that this proportion is not more than 90% will be performed, using an alpha 
of 0.05 to define significance. 
12.2.3 Statistical Analyses of Tertiary Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2.4 Safety 
Safety data will be collected from the date of written consent.  Safety variables will be summarised by 
descriptive statistics.  Laboratory variables will be described using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.02. 
AEs will be reported and presented as tables of frequency of AEs by body system and by worse 
severity grade observed.  Tables should indicate related and unrelated events. 
12.3 
PRESENTATION OF DATA 
Data will be presented in a descriptive fashion.  Variables will be analysed to determine whether the 
criteria for the study conduct are met.  This will include a description of patients who did not meet all 
the eligibility criteria, an assessment of protocol violations, IMP accountability and other data that 
impact on the general conduct of the study. 
Baseline characteristics will be summarised for all enrolled patients. 


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13 
ADMINISTRATION 
This study is conducted under a clinical trial authorisation (CTA) from the MHRA.  The favourable 
opinion of the responsible REC will be obtained before the start of this study.  This study is sponsored 
and monitored by the Cancer Research UK CDD.  Applicable regulatory requirements are described in 
this section. 
13.1 
PROTOCOL DEVIATIONS AND AMENDMENTS 
Do not deviate from the protocol unless approval has been obtained prospectively from the CDD.   
Amendments to the protocol may only be made with the approval of the CDD.  A protocol amendment 
may be subject to review by Cancer Research UK’s Protocol Safety and Review Board (PSRB).  
Depending on the type of protocol amendment, the favourable opinion of the responsible Regulatory 
Ethics Committee (REC), Health Research Authority (HRA), and the approval of the Medicines and 
Healthcare products Regulatory Agency (MHRA) may be required.  Where these approvals are 
required, written documentation must be received before the amendment can be implemented. 
13.2 
COMPLETION OF THE ELECTRONIC CASE REPORT FORM (ECRF) 
Electronic CRFs approved by the CDD will be used to collect the data. The Investigator is responsible 
for ensuring the accuracy, completeness, clarity and timeliness of the data reported in the eCRFs with 
reference to the timelines described in the agreement between the CDD and the NHS Trust. 
Only the Investigator and those personnel who have signed the Delegation Log provided by the CDD 
and have been authorised by the Investigator should enter or change data in the eCRFs.  Authorised 
users will be included on a User Management Tool form in order to be provided access to the eCRF.  
All protocol required investigations must be reported in the eCRF. The Investigators must retain all 
original reports, traces and images from these investigations for future reference.   
Data will be entered directly into electronic screens by authorised site personnel.  Amendments to 
eCRF data will be made directly to the system and the system audit trail will retain details of the 
original value(s), who made the change, a date and time, and a reason for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using manual and 
automated checks.  Queries will be issued electronically to the site.  Authorised personnel must 
answer the queries by making relevant amendments to data or providing a response.  Answered 
queries will be closed or reissued as appropriate. 
Once the patient is ‘off study’ and the eCRF has been fully completed, the Investigator must provide 
an electronic signature to authorise the complete subject casebook. 
At the end of the study all eCRFs are retained and archived by the CDD and a PDF copy provided to 
the Investigator who is responsible for archiving at site. 
13.3 
STUDY PERFORMANCE AND MONITORING 
Before the study can be initiated, the prerequisites for conducting the study must be clarified and the 
organisational preparations made with the study centre.  The CDD must be informed immediately of 
any change in the personnel involved in the conduct of the study. 
During the study the CDD Clinical Research Associate (CRA) is responsible for monitoring data quality 
in accordance with CDD’s standard operating procedures (SOPs).  Before the study start, the 
Investigator will be advised of the anticipated frequency of the monitoring visits and plans for remote 
monitoring by the CRA.  The Investigator will receive reasonable notification before a monitoring visit. 


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A strategic monitoring approach, including targeted source data verification, will be implemented 
where appropriate 
It is the responsibility of the CRA to: 
• 
review study records and compare them with source documents 
• 
discuss the conduct of the study and the emerging problems with the Investigator 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate 
• 
verify that the available facilities remain acceptable 
Unused IMP will be safely secured and allowed to decay to acceptable limits (according to the local 
centre) for disposal via normal hospital route.  Following disposal the authorised person will provide 
written confirmation. 
It is the responsibility of the Sponsor to notify the REC of the ‘end of the trial’ (see definition in Section 
11). 
13.4 
SOURCE DOCUMENT VERIFICATION 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data.  
Therefore it is the Investigator’s responsibility to ensure that both he/she and his/her study team 
records all relevant data in the medical records.  The Investigator must allow the CRA direct access to 
relevant source documentation for verification of data entered into the eCRF, taking into account data 
protection regulations.  Entries in the eCRF will be compared with patients’ medical records and the 
verification will be recorded in the eCRF.  
Some source data may exist only electronically and be entered, or loaded directly into the eCRF.   
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the CDD appointed to audit the study, NHS trust staff and by regulatory 
authorities and/or by National Health Service (NHS) Trust staff.  Details will remain confidential and 
patients’ names will not be recorded outside the hospital. 
13.5 
CLINICAL STUDY REPORT 
At the interim analysis, the interim analysis report, and at regular intervals during the study data 
listings, will be prepared to give the Investigators and the CDD the possibility to review the data and 
check the completeness of information collected.  All clinical data will be presented at the end of the 
study on final data listings.  CDD will prepare a clinical study report based on the final data listings, 
formal analysis reports and imaging reports.  The report will be submitted to the Investigators for 
review and confirmation it accurately represents the data collected during the course of the study.  
Summary results of the trial will be provided by the CDD to the MHRA and to the REC. 
13.6 
RECORD RETENTION 
During the clinical study and after study closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical study and the quality of the data produced to be 
evaluated and verified.  These essential documents (as detailed in Chapter V of Volume 10 (Clinical 
Trials) of The Rules Governing Medicinal Products in the EU based upon Section 8 of the ICH GCP 
Guidelines), including source documents such as scans, study related documents and copies of the 
eCRFs, associated audit trail and SAE report forms, shall show whether the Investigator has complied 
with the principles and guidelines of GCP. 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 


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minimum period required by national legislation or for longer if needed by CDD.  Records must not be 
destroyed without prior written approval from CDD. 
The medical files of study subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
13.7 
ETHICAL CONSIDERATIONS 
Before starting the study, the protocol, patient information sheet and consent/assent forms must go 
through the CDD’s external review process, and be approved by the PSRB and the responsible REC. 
It is the Chief/Principal Investigator’s responsibility to update patients and/or the patient’s parent or 
guardian as applicable whenever new information (in nature or severity) becomes available that might 
affect the patient’s, or parent or guardian’s willingness for the patient, to continue in the study.  The 
Chief/Principal Investigator must ensure this is documented in the patient’s medical notes and the 
patient and/or the patient’s parent or guardian as applicable provides informed consent. 
The Sponsor and Chief/Principal Investigator must ensure that the study is carried out in accordance 
with the GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 
2006/1928 as amended), the ICH GCP guidelines and the WMA Declaration of Helsinki (Appendix 1). 
13.8 
INDEMNITY 
This study is sponsored by Cancer Research UK and therefore injury to a patient caused by the 
compounds under study will not carry with it the right to seek compensation from the pharmaceutical 
industry.  Cancer Research UK will provide patients with compensation for adverse side effects, in 
accordance with the principles set out in the Association of the British Pharmaceutical Industry (ABPI) 
guidelines on compensation for medicine-induced injury. 
13.9 
PUBLICATION POLICY AND PRESS RELEASES 
Results of this study must be submitted for publication.  The CDD must be involved in reviewing all 
drafts of the manuscripts, abstracts, press releases and any other publications.  Manuscripts must be 
submitted to CDD at least 60 days in advance of being submitted for publication to allow time for CDD 
to schedule a review and resolve any outstanding issues.  Abstracts and press releases must be 
submitted to CDD at least 30 days in advance of being released.  Authors must acknowledge that the 
study was sponsored by and performed with the support of CDD.  The contribution of the CDD should 
be recognised by at least one member of staff being included as an author on publications.   


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14 
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15 
APPENDICES 
15.1 
APPENDIX 1: DECLARATION OF HELSINKI 
 
Recommendations guiding physicians in biomedical research involving human subjects 
 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, 
amended by the 29th World Medical Assembly Tokyo, Japan, October 1975, 
and the 35th World Medical Assembly, Venice, Italy, October 1983 
and the 41st World Medical Assembly, Hong-Kong, September 1989 
and the 48th General Assembly, Somerset West, Republic of South Africa, October 1996 
 
INTRODUCTION 
 
It is the mission of the physician to safeguard the health of the people.  His or her knowledge and 
conscience are dedicated to the fulfilment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the words, “The 
health of my patient will be my first consideration”, and the International Code of Medical Ethics 
declares that, “A physician shall act only in patient’s interest when providing medical care which might 
have the effect of weakening the physical and mental condition of the patient”. 
 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of 
disease. 
 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards.  
This applies especially to biomedical research. 
 
Medical progress is based on research which ultimately must rest in part on experimentation involving 
human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognised between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, 
the essential object of which is purely scientific and without implying direct diagnostic or therapeutic 
value to the person subjected to the research. 
 
Special caution must be exercised in the conduct of research which may affect the environment, and 
the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human beings to further 
scientific knowledge and to help suffering humanity, the World Medical Association has prepared the 
following recommendations as a guide to every physician in biomedical research involving human 
subjects.  They should be kept under review in the future.  It must be stressed that the standards as 
drafted are only a guide to physicians all over the world.  Physicians are not relieved from criminal, 
civil and ethical responsibilities under the laws of their own countries. 
 
I - BASIC PRINCIPLES 
 
1. Biomedical research involving human subjects must conform to generally accepted scientific 
principles and should be based on adequately performed laboratory and animal experimentation 
and on a thorough knowledge of the scientific literature. 
 
2. The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol which should be transmitted for consideration, 
comment and guidance to a specially appointed committee independent of the investigator and 
the sponsor provided that this independent committee is in conformity with the laws and 


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regulations of the country in which the research experiment is performed. 
 
3. Biomedical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the 
subject of the research, even though the subject has given his or her consent. 
 
4. Biomedical research involving human subjects cannot legitimately be carried out unless the 
importance of the objective is in proportion to the inherent risk to the subject. 
 
5. Every biomedical research project involving human subjects should be preceded by careful 
assessment of predictable risks in comparison with foreseeable benefits to the subject or to 
others.  Concern for the interests of the subject must always prevail over the interests of science 
and society. 
 
6. The right of the research subject to safeguard his or her integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject to minimise the impact of 
the study on the subject’s physical and mental integrity and on the personality of the subject. 
 
7. Physicians should abstain from engaging in research projects involving human subjects unless 
they are satisfied that the hazards involved are believed to be predictable.  Physicians should 
cease any investigation if the hazards are found to outweigh the potential benefits. 
 
8. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results.  Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
 
9. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may 
entail.  He or she should be informed that he or she is at liberty to abstain from participation in the 
study and that he or she is free to withdraw his or her consent to participation at any time.  The 
physician should then obtain the subject’s freely given informed consent, preferably in writing. 
 
10. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship to him or her or may consent under duress.  
In that case the informed consent should be obtained by a physician who is not engaged in the 
investigation and who is completely independent of this official relationship. 
 
11. In case of legal incompetence, informed consent should be obtained from the legal guardian in 
accordance with national legislation.  Where physical or mental incapacity makes it impossible to 
obtain informed consent, or when the subject is a minor, permission from the responsible relative 
replaces that of the subject in accordance with national legislation. 
 
12. The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that the principles enunciated in the present Declaration are complied with. 
 
II - MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
(Clinical research) 
 
1.  In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing health 
or alleviating suffering. 
 
2. The potential benefits, hazards and discomfort of a new method should be weighed against the 
advantages of the best current diagnostic and therapeutic methods. 
 
3. In any medical study, every patient - including those of a control group, if any - should be assured 
of the best proven diagnostic and therapeutic method. This does not exclude the use of inert 
placebo in studies where no proven diagnostic or therapeutic method exists. 


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4. The refusal of the patient to participate in a study must never interfere with the physician-patient 
relationship. 
 
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this 
proposal should be stated in the experimental protocol for transmission to the independent 
Committee (1,2). 
 
6. The physician can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is justified by its 
potential diagnostic or therapeutic value for the patient. 
 
 
III - NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 
(Non-clinical biomedical research) 
 
1. In the purely scientific application of medical research carried out on a human being, it is the duty 
of the physician to remain the protector of the life and health of that person on whom biomedical 
research is being carried out. 
 
2. The subjects should be volunteers - either healthy persons or patients for whom the experimental 
design is not related to the patient’s illness. 
 
3. The investigator or the investigating team should discontinue the research if in his/her or their 
judgement it may, if continued, be harmful to the individual. 
 
4. In research on man, the interest of science and society should never take precedence over 
considerations related to the well-being of the subject. 




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15.3 
APPENDIX 3: LANSKY PLAY SCALE 
 
Recommended for children aged 1 to 12 years as follows: 
Fully active and normal. 
100 
 
Minor restrictions in physically strenuous activity 
90 
 
 Active, but tires more easily 
80 
Both greater restriction of, and less time spent in, active play 
70 
Up and around, but minimal active play; keeps busy with quieter activities 
60 
Gets dressed, but lies around much of the day; no active play; able to participate 
in all quiet play and activities 
50 
Mostly in bed; participates in quiet activities 
40 
In bed; needs assistance even for quiet play 
30 
Often sleeping; play entirely limited to very passive activities 
20 
No play; does not get out of bed 
10 
Unresponsive 
0 
 
 


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15.4 
 APPENDIX 4: DRUG INTERACTIONS WITH mIBG 
(adapted from the Radiopharmacy Protocol of the Nuclear Medicine Department, Queen Elizabeth Hospital, 
Birmingham, UK and taken from the EANM 131I/123I-Metaiodobenzylguanidine (mIBG) Scintigraphy –
Procedures Guidelines For Tumour Imaging) 
 
*Mechanisms of interaction 
1 Inhibition of sodium-dependent uptake system (i.e. uptake-one inhibition) 
2 Transport interference - inhibition of uptake by active transport into vesicles i.e. inhibition of granular 
uptake, and competition for transport into vesicles i.e. competition for granular uptake 
3 Depletion of content from storage vesicles/granules 
4 Calcium mediated 
5 Other, possible, unknown mechanisms 
 
 


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©Cancer Research UK 2013 
 
 
 
 


CONFIDENTIAL 
[124I]mIBG Clinical Protocol Version 13.0 12Nov2019 
 
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©Cancer Research UK 2013 
 
 
 
15.5 
APPENDIX 5: CURIE & SIOPEN SCORING METHODS FOR NEUROBLASTOMA 
Figures 2A & 2B:  
2A
2B
 
Figure 2A; The Curie method. This method divides the skeleton into nine segments to view 
osteomedullary involvement and adds a tenth sector that counts any soft tissue involvement to the 
score. The extension score for this method is graded as: 0. no sites per segment; 1. one site per 
segment; 2. more than one site per segment; and 3. diffuse involvement (>50% of the segment). The 
intensity score is graded as: 0. for no uptake; 1. for doubtful uptake; 2. for definite uptake less than 
liver; and 3. for intense uptake greater than that of liver. Thus, the maximum score for either extension 
or intensity would be 30. The Curie score has been shown to have a good inter-observer concordance 
of 92 and 95% in two independent studies. It has been validated in France and is now widely used in 
North America for the New Approaches to Neuroblastoma Therapy consortium and the Children’s 
Oncology Group (COG). 
Figure 2B: The SIOPEN method: the skeletal distribution of mIBG is recorded in 12 anatomical body 
segments as follows: skull, thoracic cage, proximal right upper limb, distal right upper limb, proximal 
left upper limb, distal left upper limb, spine, pelvis, proximal right lower limb, distal right lower limb, 
proximal left lower limb and distal left lower limb. The extent and pattern of skeletal mIBG involvement 
is scored using a 0–6 scale to discriminate between focal discrete lesions and patterns of more diffuse 
infiltration. Each segment is scored as 0. no involvement; 1. one discrete lesion; 2. two discrete 
lesions; 3. three discrete lesions; 4. > 3 discrete foci or a single diffuse lesion involving < 50% of a 
bone; 5. diffuse involvement of > 50 to 95% of an entire bone; 6, diffuse involvement of the entire 
bone, with a maximum score of 72. The SIOPEN score is the current method being used in Europe for 
a prospective phase 3 neuroblastoma trial. 
 


 
                         
 
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[124I]mIBG Statistical Analysis Plan, Final version 4.0 07Sep2020 
CANCER RESEARCH UK 
Statistical Analysis Plan 
 
 
A Cancer Research UK Phase I/II study to compare 
[124I]mIBG PET/CT to [123I]mIBG imaging in patients with 
metastatic neuroblastoma. 
 
Sponsor protocol number: 
CRUKD/12/002 
 
EudraCT number:  
2012-002029-31 
 
 
Chief Investigator: 
Dr Sue Chua 
Nuclear Medicine and PET 
Department 
Royal Marsden Hospital 
 
  
 
  
 
 
 
 
Sponsor: 
Cancer Research UK 
 
Centre for Drug Development 
 
 
 
 
 
 
 
      
 
     
 
 


 
                         
 
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[124I]mIBG Statistical Analysis Plan, Final version 4.0 07Sep2020 
TABLE OF CONTENTS 
PAGE 
 
TABLE OF CONTENTS ........................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................... 4 
AMENDMENT HISTORY ........................................................................................ 5 
1 
STUDY DETAILS .................................................................................................... 6 
1.1 
Protocol Synopsis and Background .................................................................... 6 
1.2 
Clinical Study Objectives and Endpoints ............................................................ 6 
1.3 
Study Design .......................................................................................................... 8 
1.4 
Number of Subjects .............................................................................................. 9 
2 
ANALYSIS SETS ................................................................................................... 10 
2.1 
Definition of Analysis Sets.................................................................................. 10 
2.2 
Violations and deviations ................................................................................... 10 
3 
PRIMARY AND SECONDARY ENDPOINTS ....................................................... 11 
3.1.1 
Total number of positive lesions recorded ....................................................... 11 
3.1.2 
Confidence scores ................................................................................................ 12 
3.1.3 
SIOPEN scores ..................................................................................................... 12 
3.1.4 
CURIE scores ........................................................................................................ 13 
3.1.5 
Safety and toxicity ............................................................................................... 13 
3.1.6 
 
3.1.7 
 
3.1.8
4 
ANALYSIS METHODS .......................................................................................... 15 
4.1 
General Principles ................................................................................................ 15 
4.2 
Analysis Methods ................................................................................................. 16 
4.2.1 
Primary endpoint ................................................................................................. 16 
4.2.2 
Secondary endpoints ........................................................................................... 17 
4.2.3 
Tertiary endpoints ............................................................................................... 17 
5 
INTERIM ANALYSES ............................................................................................ 19 


 
                         
 
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6 
TIMING OF STATISTICAL ANALYSIS ............................................................... 20 
7 
DATA CHECKING PLAN ....................................................................................... 20 
8 
SIGNATURES ........................................................................................................ 21 
 


 
                         
 
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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
CRUK 
Cancer Research UK 
CT 
computerised tomography 
mIBG 
meta-Iodobenzylguanidine 
MRI 
Magnetic resonance imaging 
PET 
Positron emission tomography 
SPECT 
Single-photon emission computed tomography 
SUV 
Standardised uptake value 
UCLH 
University College London Hospital 
 
 
 
 


 
                         
 
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AMENDMENT HISTORY 
Date 
Brief description of change           
Justification for change 
07Sep2020 
Clarification to tertiary endpoint 
 
 
 
Typography corrections. 
13Mar2020 
Update to study endpoints 
Inclusion of confidence score method as a 
secondary objective. 
To bring the Statistical Analysis Plan in line 
with protocol amendment 10 and 11.
Inclusion of details of the trial populations 
for clarity. 
01Aug2017 
Update to objectives                       
To bring the Statistical Analysis Plan in line 
with protocol amendment 9. 
 
N/A 
 








 
                         
 
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1.4 Number of Subjects 
The primary endpoint of the study is the percentage of lesions identified as positive using 
[123I]mIBG planar scintigraphy which are also identified as positive on [124I]mIBG PET/CT. 
The definition of a positive lesion is described in Section 9.1 of the clinical study protocol. The 
aim is to prove that there is more than 90 % agreement between the methods, with an 
expected level of agreement of 97 %. Patients are anticipated to have a median of 3 lesions. 
Lesions are assumed to be independent within patients for the primary analysis. The 
following two stage design will be used, where the true proportion of agreement is denoted 
by p. 
In the first stage, a total of at least 9 evaluable patients will be recruited, with a combined 
total of at least 50 lesions positive on [123I]mIBG PET/CT. Initially an exact one-sided binomial 
test of the null hypothesis: p>=97 % will be done using alpha (α)=0.05. If this is rejected in 
favour of the alternative hypothesis p<97 %, the study will be stopped early for futility. With 
a total of exactly 50 lesions this will occur if 45 or fewer lesions are also positive on 
[124I]mIBG PET/CT. 
If the null hypothesis is accepted, a further one-sided binomial test of the null hypothesis, 
p<=90%) will be done using α=0.025. If this is rejected in favour of the alternative 
hypothesis p>90% then the study may be stopped early for efficacy. With a total of 50 
lesions this will occur only if all 50 lesions are also positive on [124I]mIBG PET/CT. If this null 
hypothesis is not rejected, the study will continue to the second and final stage. 
Only if following the interim analysis recruitment is to continue, a second stage will be 
required and will end when an overall total of at least 33 evaluable patients with at least 100 
lesions have been recruited. An exact one-sided binomial test of the null hypothesis, 
p<=90%, will be done using alpha=0.025. If this is rejected in favour of the alternative 
hypothesis p>90% then the study will be declared a success. With a total of 100 lesions this 
will occur if at least 96 lesions are also positive on [124I]mIBG PET/CT. 
The overall study design including the second stage has 82 % power and an α of 0.03. If the 
true percentage of agreement is 97 % then there is a 22 % chance of stopping early for 
efficacy; if the true percentage of agreement of 90% then there is a 57 % chance of stopping 
early for futility. The total sample size of 100 lesions was calculated based on a single stage 
A’hern design with p0=0.90 and p1=0.97, and the overall power and α has been calculated 
based on exact binomial probabilities. 


 
                         
 
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2 Analysis Sets 
2.1 Definition of Analysis Sets 
The following trial populations have been defined for reporting purposes: 
• Full Analysis Population: All patients enrolled to the study. 
• Safety [123I]mIBG Population: All patients who receive [123I]mIBG (these patients may 
or may not have received [124I]mIBG). 
• Safety [123I]mIBG and [124I]mIBG Population: All patients who receive both [123I]mIBG 
and [124I]mIBG. 
• Evaluable Population: Patients who received both [123I]mIBG and [124I]mIBG and 
underwent trial scanning with both agents. All lesions from these patients are 
considered independent of one another. 
• 
 
 
• A sensitivity analysis will be informed in those in the evaluable population and have 
less than 10 lesions. 
The primary analysis set will consist of all patients consented to the study, with at least one 
positive lesion recorded on routine [123I]mIBG planar scintigraphy, who have also completed 
[124I]mIBG PET/CT within 3 to 21 days as planned i.e. the Evaluable Population. Patients who 
did not undergo both [123I]mIBG planar scintigraphy and [124I]mIBG PET/CT will be excluded 
from this set, as will any patient where zero positive lesions were found on [123I]mIBG planar 
scintigraphy, and patients with more than 21 days between [123I]mIBG and [124I]mIBG scans.  
The safety analysis set for the secondary objective will consist of all patients consented to the 
study who received any dose of [124I]mIBG at any time whether or not they subsequently 
completed any of the planned imaging procedures i.e. the Safety [123I]mIBG and [124I]mIBG 
Population. Additionally, all AEs occurring post consent and prior to [124I]mIBG will be 
summarised (including those occurring post [123I]mIBG administration). 
2.2 Violations and deviations 
Taking the date of [123I]mIBG scan as Day 0, patients whose [124I]mIBG scans takes place on 
Day 22 or more will be excluded from the primary analysis set, but included in the safety set. 


 
                         
 
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Patients who do not receive the planned injection of [124I]mIBG will not be included in any 
statistical analysis, however their safety data will be summarised as described in Sections 2.1 
and  
3 3.1.5.Primary and Secondary endpoints 
Each evaluable study patient will be assessed for disease using up to five different modalities: 
[124I]mIBG PET/CT (the experimental modality) 
[123I]mIBG planar scintigraphy (the primary comparator) 
[123I]mIBG planar scintigraphy + SPECT (a secondary comparator) 
 
On each modality (unless otherwise stated), each of the following endpoints is recorded.  
[124I]mIBG PET/CT and [123I]mIBG planar scintigraphy results will be assessed by an agreed 
number of observers independently who will record all relevant endpoints as listed below. 
Prior to the interim analysis, the observers will meet to establish a consensus opinion and 
record their agreed consensus endpoints for each patient. The same procedure will take place 
prior to the final analysis, for all scans which had not previously been included in the interim 
analysis. 
 
3.1.1 Total number of positive lesions recorded 
  
The total number of lesions will be provided to the Statistician via validated listings from the 
Sponsor. Data will be recorded in the eCRF by the Trial Manager at the Central Imaging Unit 
and Source Data Verified (SDV’d) by a Sponsor Clinical Research Associate. The Sponsor 
Clinical Study Manager will perform a data review before the eCRF is locked and listings are 
provided to the Statistician. 
In summary, the following data will be provided to the Statistician for each evaluable patient 
for each imaging modality as calculated by each individual Reviewer and as a consensus: 


 
                         
 
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[124I]mIBG Statistical Analysis Plan, Final version 4.0 07Sep2020 
• 
Number of lesions in each skeletal segment and total number of lesions using the 
CURIE method (i.e. all lesions with a score of 4 or 5) and also:  
o Total number of lesions with a confidence score of 1 
o Total number of lesions with a confidence score of 2 
o Total number of lesions with a confidence score of 3 
o Total number of lesions with a confidence score of 4 
o Total number of lesions with a confidence score of 5 
• 
Number of lesions in each skeletal segment and total number of lesions using the 
SIOPEN method (i.e. all lesions with a score of 4 or 5) and also:  
o Total number of lesions with a confidence score of 1 
o
Total number of lesions with a confidence score of 2
o Total number of lesions with a confidence score of 3 
o Total number of lesions with a confidence score of 4 
o Total number of lesions with a confidence score of 5 
 
For example, one Patient’s PET/CT scan will have the data above provided but as three or 
more sets (for detail of the number of reviewers, see the Imaging Review Manual): 
• Reviewer 1’s data set 
• Reviewer 2’s data set 
• Consensus data set 
3.1.2 Confidence scores 
For each lesion (or for each SIOPEN area in which diffuse disease is noted), the observer (or 
group of observers for the consensus opinion) will also note a confidence score to measure 
their certainty of the lesion being malignant, on a 5 point scale from 1 (negative) to 5 
(definitively positive). See section 3.1.1 detailing how this data will be provided to the 
Statistician. 
3.1.3 SIOPEN scores 
SIOPEN scores will be recorded using standard scoring methods for each of the 12 defined 
skeletal areas. The SIOPEN scores will be provided to the Statistician via validated listings 
from the Sponsor. Data will be recorded in the eCRF by the Trial Manager at the Central 
Imaging Unit and Source Data Verified (SDV’d) by a Sponsor Clinical Research Associate. The 
Sponsor Clinical Study Manager will perform a data review before the eCRF is locked and 
listings are provided to the Statistician. 
In summary, the following data will be provided to the Statistician for each patient for each 
imaging modality as calculated by each individual Reviewer and as a consensus: 




 
                         
 
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o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1.7 
 
 
 
 
 
 
   
 
 
 




 
                         
 
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4.2 Analysis Methods 
4.2.1 Primary endpoint 
SIOPEN total numbers of lesions detected on [124I]mIBG vs [123I]mIBG will be compared as 
follows: 
In the first stage, a total of at least 9 evaluable patients will be recruited, with a combined 
total of at least 50 lesions positive on [124I]mIBG PET/CT. Initially an exact one-sided binomial 
test of the null hypothesis: p>=97 % will be done using alpha (α)=0.05. If this is rejected in 
favour of the alternative hypothesis p<97 %, the study will be stopped early for futility.  
If the null hypothesis is accepted, a further one-sided binomial test of the null hypothesis, 
p<=90%) will be done using α=0.025. If this is rejected in favour of the alternative 
hypothesis p>90% then the study may be stopped early for efficacy. If this null hypothesis is 
not rejected, the study will continue to the second and final stage. 
Only if following the interim analysis recruitment is to continue, a second stage will be 
required and will end when an overall total of at least 33 evaluable patients with at least 100 
lesions have been recruited. An exact one-sided binomial test of the null hypothesis, 
p<=90%, will be done using alpha=0.025. If this is rejected in favour of the alternative 
hypothesis p>90% then the study will be declared a success.  
All above tests will be done using the following method: For each patient, the total number of 
lesions assessed as positive by consensus opinion (with confidence score 4 or 5) on 
[123I]mIBG planar scintigraphy is referred to as n123, and the total number of lesions assessed 
as positive by consensus opinion (with confidence score 4 or 5) on [124I]mIBG PET/CT is 
referred to as n124, with the minimum of these two numbers known as nmin. The primary 
endpoint will be reported by the sum of nmin over all patients, divided by the sum of n123 over 
all patients.  
In addition, for each patient the difference and ratios between n123 and n124 will be calculated 
and the distribution of these variables will be summarised using the median, upper and lower 
quartiles. The number and percentage of patients with n124/n123 less than 1, equal to 1 and 
greater than 1 will be reported. 
Population to be used: Evaluable population & sensitivity population 






 
                         
 
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4.2.3.6 
 
 
 
 
 
 
   
  
 
 
 
 
5 Interim Analyses 
The interim analysis should be performed at the first available timepoint after no less than 9 
evaluable patients have completed both their [123I]mIBG and [124I]mIBG scans, and a 
combined total of at least 50 lesions have been found on [123I]mIBG. At this point the 
consensus panel should meet to evaluate and record their opinions as soon as practically 
possible. Once this has been done, the interim analysis can  be performed. 
Initially an exact one-sided binomial test of the null hypothesis: p>=97% will be done using 
alpha=0.05. If this is rejected in favour of the alternative hypothesis p<97%, the study will 
be stopped early for futility. 
If the null hypothesis is accepted, a further one-sided binomial test of the null hypothesis, 
p<=90%, will be done using α=0.025. If this is rejected in favour of the alternative 
hypothesis p>90% then the trial may be stopped early for efficacy. If this null hypothesis is 
not rejected, the trial will continue recruitment to the second and final stage. 
The results of the interim analysis should be reported to the trial sponsor. 


 
                         
 
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6 Timing of Statistical Analysis 
The interim analysis will be performed as detailed in section 5. The final analysis should be 
performed after all patients recruited to the trial have undergone all scheduled on-trial scans,    
7 Data checking plan 
All data checking activities will be carried out by the study sponsor before transferring data 
for analysis. On receipt of data by the study statistician no further formal data checks will be 
made. 


 
                         
 
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8 Signatures 
 
Study Statistician 
 
Date 
 
 
 
Chief Investigator 
Sue Chua 
Date