A Multi-Arm, Multi-Stage Platform Trial For Relapsed Neuroblastoma
Phase: PHASE1
Conditions: Relapsed Neuroblastoma
Sponsor: University of Birmingham



 
 
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AMENDMENTS 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version. 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version number 
Type of amendment       Summary of amendment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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CONTENTS 
Trial Synopsis ...................................................................................................................................................... 11 
Schedule of Events ............................................................................................................................................. 18 
1. 
Background and Rationale ......................................................................................................................... 20 
1.1 
Background ............................................................................................................................................... 20 
1.2 
Trial Rationale ........................................................................................................................................... 23 
2. 
Trial Design .................................................................................................................................................. 30 
2.1 
TIER 1 (Main Randomisation) ................................................................................................................... 30 
2.2 
TIER 2 (Dose Expansion Cohort) .............................................................................................................. 31 
2.3 
Treatment Duration.................................................................................................................................... 32 
3. 
Aims, Objectives and Outcome Measures ................................................................................................ 33 
3.1 
Aims .......................................................................................................................................................... 33 
3.2 
Objectives .................................................................................................................................................. 33 
3.3 
Outcome Measures ................................................................................................................................... 33 
4. 
Eligibilty........................................................................................................................................................ 34 
4.1 
Tier 1 Eligibility .......................................................................................................................................... 34 
4.2 
Tier 2 Eligibility .......................................................................................................................................... 37 
5. 
Screening and Consent............................................................................................................................... 39 
5.1 
Participant Identification ............................................................................................................................ 39 
5.2 
Screening .................................................................................................................................................. 39 
5.3 
Informed Consent ...................................................................................................................................... 40 
6. 
Trial Entry ..................................................................................................................................................... 41 
6.1 
Time Frame for Trial Entry ......................................................................................................................... 41 
6.2 
Trial Entry Process .................................................................................................................................... 41 
7. 
TIER 1 (MAIN RANDOMISATION) ............................................................................................................... 43 
7.1 
Tier 1 Screening ........................................................................................................................................ 43 
7.2 
Tier 1 Screening Assessments (Assessment Timepoint A) ....................................................................... 43 
7.3 
Tier 1 Randomisation ................................................................................................................................ 44 
7.4 
Tier 1 Emergency Randomisation ............................................................................................................. 44 
7.5 
Tier 1 Treatment Details ............................................................................................................................ 45 
7.6 
Tier 1 Treatment Verification ..................................................................................................................... 47 
7.7 
Tier 1 Treatment Breaks and Compensation ............................................................................................. 48 
8. 
TIER 2 (Dose Expansion Cohort) ............................................................................................................... 48 
8.1 
Tier 2 Screening ........................................................................................................................................ 48 
8.2 
Tier 2 Screening Assessments (Assessment Timepoint A) ....................................................................... 48 
8.3 
Tier 2 Registration ..................................................................................................................................... 49 
8.4 
Emergency Registration ............................................................................................................................ 49 
8.5 
Tier 2 Treatment Details ............................................................................................................................ 50 
8.6 
Tier 2 Treatment Verification ..................................................................................................................... 53 
8.7 
Tier 2 Treatment Breaks and Compensation ............................................................................................. 53 
9. 
Assessments ............................................................................................................................................... 53 
9.1 
Tumour Assessment.................................................................................................................................. 53 
9.2 
Urinalysis ................................................................................................................................................... 54 

 
 
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9.3 
GFR ........................................................................................................................................................... 54 
9.4 
Haematology and Blood chemistry ............................................................................................................ 55 
9.5 
Physical examination / symptom assessment ........................................................................................... 55 
10. Sample Collection ....................................................................................................................................... 55 
10.1 
Tumour tissue ............................................................................................................................................ 55 
10.2 
Blood Samples .......................................................................................................................................... 56 
11. Dose modifications ..................................................................................................................................... 57 
11.1 
Dose modifications for dinutuximab beta ................................................................................................... 58 
11.2 
Dose modifications for bevacizumab ......................................................................................................... 60 
11.3 
Chemotherapy dose modifications ............................................................................................................ 62 
12. Supportive Treatment.................................................................................................................................. 65 
12.1 
Supportive Care ........................................................................................................................................ 65 
12.2 
Pain management ..................................................................................................................................... 66 
13. Concomitant Medication ............................................................................................................................. 68 
14. Contraception .............................................................................................................................................. 68 
15. Treatment Compliance ................................................................................................................................ 69 
16. Participant Follow Up .................................................................................................................................. 70 
17. Trial Treatment Discontinuation and Participant Withdrawal .................................................................. 71 
17.1 
Treatment Discontinuation ......................................................................................................................... 71 
17.2 
Participant Withdrawal ............................................................................................................................... 71 
18. Adverse Event Reporting ............................................................................................................................ 72 
18.1 
Reporting Requirements ............................................................................................................................ 72 
18.2 
Reporting period ........................................................................................................................................ 75 
18.3 
Reporting Procedure ................................................................................................................................. 75 
19. Central Review Processes .......................................................................................................................... 78 
20. Quality Of Life Study ................................................................................................................................... 78 
20.1 
Purpose of Quality of Life .......................................................................................................................... 78 
20.2 
Questionnaires .......................................................................................................................................... 78 
20.3 
Target Accrual ........................................................................................................................................... 79 
20.4 
Time Points and Procedure ....................................................................................................................... 80 
21. Translational Sub-Study/ Biological Studies ............................................................................................ 80 
21.1 
Purpose of Translational Sub-study........................................................................................................... 80 
21.2 
Samples to be Collected ............................................................................................................................ 81 
21.3 
End of Trial Arrangements ......................................................................................................................... 82 
22. Data Handling and Record Keeping ........................................................................................................... 83 
22.1 
Data Collection .......................................................................................................................................... 83 
22.2 
Archiving .................................................................................................................................................... 86 
23. Quality Management ................................................................................................................................... 86 
23.1 
Site Set-up and Initiation ........................................................................................................................... 86 
23.2 
On-site Monitoring ..................................................................................................................................... 87 
23.3 
Central Monitoring ..................................................................................................................................... 87 
23.4 
Audit and Inspection .................................................................................................................................. 87 
23.5 
Notification of Serious Breaches ............................................................................................................... 87 

 
 
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24. End of Trial Definition ................................................................................................................................. 88 
25. Statistical Considerations ........................................................................................................................... 88 
25.1 
Definition of Outcome Measures ............................................................................................................... 88 
25.2 
Trial Design ............................................................................................................................................... 89 
25.3 
Analyses .................................................................................................................................................... 91 
25.4 
Analysis of Outcome Measures ................................................................................................................. 93 
26. Trial Organisational Structure .................................................................................................................... 94 
26.1 
Sponsor ..................................................................................................................................................... 94 
26.2 
Coordinating Sponsor ................................................................................................................................ 94 
26.3 
National Coordinating Centres .................................................................................................................. 95 
26.4 
Trial Management Group ........................................................................................................................... 95 
26.5 
Trial Steering Committee ........................................................................................................................... 95 
26.6 
Data Monitoring Committee ....................................................................................................................... 95 
26.7 
Participant and Public Involvement ........................................................................................................... 96 
26.8 
Peer Review .............................................................................................................................................. 96 
27. Finance ......................................................................................................................................................... 96 
28. Ethical And Regulatory Considerations .................................................................................................... 97 
29. Confidentiality and Data Protection ........................................................................................................... 97 
30. Insurance and Indemnity ............................................................................................................................ 98 
31. Publication Policy ........................................................................................................................................ 98 
32. Data And Sample Sharing ........................................................................................................................... 99 
33. Reference List ............................................................................................................................................ 100 
Appendix 1 – Abbreviations ............................................................................................................................. 105 
Appendix 2 - Tumour Staging - INRC Classification [2] ................................................................................. 109 
Appendix 3 - SIOPEN scoring methods for neuroblastoma .......................................................................... 113 
Appendix 4 – Lanksy and Karnofsky ............................................................................................................... 114 
Appendix 5 – Temozolomide Dosing ............................................................................................................... 116 
Appendix 6 - WMA Declaration of Helsinki...................................................................................................... 117 
Appendix 7 - Definition of Adverse Events ..................................................................................................... 120 
Appendix 8 - Common Toxicity Criteria Gradings .......................................................................................... 122 
Appendix 9 – PedsQL™ Administration Guidelines ....................................................................................... 123 
 
 
 
 
 
 

 
 
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TRIAL SYNOPSIS  
Title 
BEACON2: A multi-arm multi-stage platform trial for relapsed neuroblastoma. 
Trial Design 
BEACON2 is a platform multi-arm multi-stage (MAMS) randomised phase I/phase II, open-label, international trial.  
The trial will comprise two tiers: Tier 1 will be the main randomisation, starting with the randomisation of Arms A vs 
B. Participants will be randomised at trial entry to receive one of the regimens. Tier 2 will include a dose 
expansion/confirmation cohort (Arm C and future arms), before the new arm is introduced to Tier 1. Using the rolling 
MAMS design will allow the introduction of novel agents or regimens as new arms, if appropriate. The introduction 
of new arms will take place pending approval of a substantial amendment by each relevant Competent Authority. 
Aims 
• 
To improve survival for patients with relapsed neuroblastoma by developing novel combinations that are 
ready for clinical implementation 
• 
To establish a platform trial to evaluate novel combinations in relapsed neuroblastoma, within a seamless 
phase 1-2 trial that can lead to regulatory approvals and impact clinical practice; allowing dose confirmation 
cohorts for novel combinations 
• 
To evaluate safety, activity, efficacy and quality of life for these novel combinations in relapsed 
neuroblastoma participants  
• 
To improve our understanding of relapsed neuroblastoma biology, tumour clonal evolution, tumour 
microenvironment and develop biomarkers of response and resistance to direct the development targeted 
therapies by conducting a comprehensive biomarker sample collection. 
Objectives 
Primary  
• 
To test novel treatments against current best available treatment in relapsed neuroblastoma 
Secondary  
• 
To evaluate the safety of the regimens, anti-tumour response, longer term outcome and quality of life  
Tertiary  
• 
To evaluate of the role of circulating biomarkers and tumour molecular profiles in blood and tumour as 
prognostic and predictive biomarkers in relapsed neuroblastoma, including neuroblastoma mRNAs, 
circulating DNA, biomarkers of immune response and the tumour microenvironment and analysis of 
genomic aberrations in relapsed tumours 
 
 
 

 
 
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Outcome Measures 
Primary Endpoint 
• 
Progression-Free Survival time (as per INRC 2017) – for Tier 1 (randomised comparison) 
• 
Definition of a safe and tolerable combination regimen – for Tier 2 (dose expansion-confirmation cohorts) 
Secondary Endpoints 
• 
Best objective response (complete and partial response) as per INRC 2017 during trial treatment (12 cycles)  
• 
Clinical benefit (complete, partial and minor response and stable disease) as per INRC 2017. 
• 
Time response to progression (for responders) 
• 
Overall Survival time  
• 
Quality of life measured by Peds-QL questionnaires 
• 
Incidence and Severity of AEs 
Exploratory Endpoints 
• 
Quality of life of caregivers measured by Peds-QL questionnaires 
• 
Correlation between objective response using INRC 2017 and PFS/OS 
• 
Changes in circulating biomarkers and tumour molecular profiles in tumour and blood, including mRNA 
levels, analysis of immune response and tumour microenvironment, analyses of genomic aberrations in 
relapsed neuroblastoma (e.g. MYCN, ALK, RAS/MAPK pathway, ATRX) and development of novel 
biomarkers. 
 
Participant Population 
Participants aged ≥1 with relapsed neuroblastoma. 
 
Sample Size 
This is a multi-arm multi-stage phase 1-2 trial, hence modifications with the addition of new arms during the conduct 
of the trial are expected.  
For each arm in Tier 1, 75 patients will be recruited to complete phase 2 investigation. For each arm in Tier 2, 10 
patients will be recruited to complete phase 1 investigation.  
Approximately 160 participants are initially planned, 75 in each arm of Tier 1 and 10 participants for one dose-
confirmation cohort in Tier 2. Expansion of recruitment may be considered after adding novel arms.  
 
 
 
 

 
 
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Main Inclusion and Exclusion Criteria 
Inclusion Criteria (Common to Tier 1 and Tier 2) 
Disease specific 
• 
Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS)[1] 
definition  
• 
High risk relapsed neuroblastoma (relapsed or progressed after being defined as High Risk at any time 
following diagnosis or progressed/relapsed as high-risk neuroblastoma)  
• 
Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG scan with or without 
bone marrow histology), as per INRC [2, 3]. Participants with only bone marrow detectable disease (bone 
marrow aspirate or trephine) are NOT eligible for the study 
General 
• 
Age ≥1 year 
• 
Signed informed consent from participant, parent or guardian 
Performance and organ function 
• 
Performance Status 
o 
Lansky (for patients ≤12 years of age) or Karnofsky (for those >12) ≥ 50%, (Participants who are 
unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will 
be considered ambulatory for the purpose of assessing performance score) 
• 
Life expectancy of ≥12 weeks 
• 
Bone marrow function (within 72 hours prior to randomisation): 
o 
Platelets ≥ 50 x 109/L (unsupported for 72 hours)  
o 
ANC ≥ 0.50 x 109/L (no G-CSF support for 72 hours) 
o 
Haemoglobin > 8 g/dL (transfusions allowed) 
• 
Renal function (within 72 hours prior to randomisation): 
o 
Absence of clinically significant proteinuria (either early morning urine dipstick ≤ 2+) or if dipstick 
urinalysis shows > 2+ proteinuria, protein: creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein 
excretion must be < 0.5g 
o 
Serum creatinine ≤ 1.5 ULN for age, if higher, a measured GFR (radioisotope or 24 hour urine 
calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2  
• 
Liver function (within 72 hours prior to randomisation):  
o 
Absence of clinically significant signs of liver dysfunction. AST or ALT ≤ 3.0 ULN and total bilirubin ≤ 
1.5 ULN. In patients with liver metastases, AST or ALT ≤ 5 ULN and total bilirubin ≤ 2.5 ULN is 
allowed.  
• 
Coagulation: 
o 
Participants must not have an active uncontrolled coagulopathy. 
o 
Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the 
medical standard of the institution) and the participant has been on a stable dose of anticoagulants 
for at least two weeks at the time of study enrolment.  
• 
Blood pressure below 95th centile for age and sex. Participants ≥18 years of age should have a blood 
pressure ≤150/90 mmHg (within 72 hours prior to randomisation). Use of antihypertensive medication is 
permitted. 
 
Tier 2 Specific Inclusion Criteria 
• 
More than one relapse event or ineligible for Tier 1. 
 

 
 
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NB- The following previous treatments are allowed provided that the principal investigator expects a favourable 
benefit/risk assessment (e.g. patients could derive potential benefit from the Tier 2 combination): 
o 
bevacizumab,  
o 
any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’)  
o 
previous treatment with temozolomide with irinotecan 
Exclusion Criteria (Common to Tier 1 and Tier 2) 
• 
Known contraindication or hypersensitivity to: 
o 
Any study drug or component of the formulation 
o 
Chinese hamster ovary products or other recombinant human or humanised antibodies. 
o 
Participants with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but 
those with severe (or G4) hypersensitivity reactions to anti-GD2 antibodies will be excluded.  
• 
Clinically significant neurological toxicity, uncontrolled seizures or objective peripheral neuropathy (> grade 
2). (Unresolved neurological deficits from previous spinal cord compression or surgeries are acceptable). 
Participants with previous ≥ Grade 3 motor neurotoxicity secondary to anti-GD2 are excluded, even if 
recovered 
• 
Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral 
arterial thrombosis) or any ongoing arterial thrombo-embolic events 
• 
A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis. 
• 
Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive 
prophylaxis for PJP 
• 
Uncontrolled infection 
• 
Inadequate recovery from prior surgery with ongoing ≥ Grade 3 surgical complications. Grade ≥ 2 wound 
dehiscence.  
• 
Recent surgical procedures (at start of trial treatment). Patient can be randomised up to 48hr prior to these 
periods being completed provided that trial treatment only starts after complying with all of them: 
o 
Core biopsies within previous 24hr 
o 
Open excisional biopsies within previous 48hr 
o 
Major surgery within previous 2 weeks 
o 
Bone marrow aspirates/trephines, within previous 48hr 
o 
Tunnelled central line insertion within previous 48hr  
• 
Washout from prior treatments (at start of trial treatment): 
o 
Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens) 
o 
Any anti-GD2 therapy within previous 2 weeks 
o 
Craniospinal radiotherapy or MIBG therapy within previous 6 weeks 
o 
Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy) 
o 
Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within 
previous 8 weeks  
o 
Allogeneic stem cell transplant within previous 12 weeks (with absence of active ≥ G2 acute GVHD) 
o 
14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial 
• 
Bleeding metastases (participants with CNS metastases can be enrolled as long as the metastases are not 
bleeding). At least 6 months from any ≥ G3 haemoptysis or pulmonary haemorrhage  
• 
Use of enzyme inducing anticonvulsants within 72hr of start of trial treatment 
• 
Conditions that increase the risk of bevacizumab-related toxicities:  
o 
History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. 
in the absence of therapeutic anticoagulation) 
o 
History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active 
gastrointestinal bleeding within 6 months prior to study enrolment 
o 
Current chronic intestinal inflammatory disease/bowel obstruction 
• 
Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and 
fructose 

 
 
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• 
Males or females of reproductive potential may not participate unless they agree to use a highly effective 
method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined 
oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the duration of study therapy 
and for up to 6 months after the last dose of trial drugs.  A negative urine or serum pregnancy test must be 
obtained within 72 hours prior to dosing in females who are post-menarche. 
• 
Pregnant or lactating participant 
• 
Live or live-attenuated vaccines given within previous 28 days prior to study enrolment 
• 
Any uncontrolled medical condition that poses an additional risk to the participant  
 
Tier 1 Specific Exclusion Criteria 
• 
More than one relapse/progression event after the start of high risk neuroblastoma therapy 
• 
Previous treatments that are not allowed 
o 
Bevacizumab for relapsed neuroblastoma. Patients who have received BIT for refractory disease are 
not excluded, providing no progression of disease during this treatment occurred  
o 
Treatment with any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’) for 
treatment of relapsed neuroblastoma. Prior treatment with chemo-immunotherapy for refractory 
disease is allowed, provided no disease progression during this therapy.   
 
Trial Treatment 
Tier 1: 
Arm A: dbIT 
Dinutuximab beta 10 mg/m2/day iv days 1-7, Irinotecan 50 mg/m2 iv days 1-5, Temozolomide 100 mg/m2 
po days 1-5 
3 weekly x12 cycles 
Arm B: BIT 
Bevacizumab 15 mg/kg iv day 1, Irinotecan 50 mg/m2 iv days 1-5, Temozolomide 100 mg/m2 po days 1-5 
3 weekly x12 cycles 
Tier 2: 
Arm C: dbBIT 
Bevacizumab 15 mg/kg/day iv day 1, Dinutuximab beta 10 mg/m2/day iv days 1-7, Irinotecan 50 mg/m2 iv 
days 1-5, Temozolomide 100 mg/m2 po days 1-5 
3 weekly x12 cycles 
Sub Studies 
Translational Sub Study 
Primary Tumour Tissue  
Samples of tumour tissue collected at the time of diagnosis, during frontline therapy and/or at the time of 
relapse (where possible) will be collected for genome and expression profile of DNA and RNA. This 

 
 
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sample is mandatory for study entry; if no tumour or subsequent molecular profiling is available 
this will be discussed with the Coordinating Sponsor and the Chief Investigator/clinical 
coordinator before study entry.  
Liquid Biopsy Samples 
Blood samples for the analysis of circulating biomarkers and immunological studies should be collected 
from all patients at the same time points as those required for standard clinical care: 
• 
Baseline  
• 
Pre cycles 2, 4, 6, 9  
• 
Pre Cycle 12 or End of Treatment  
Constitutional DNA taken once at any time will be required for pharmacogenetic studies and is optional. 
Bone marrow aspirate taken at baseline will be required for circulating biomarker analysis and is optional. 
Trial Duration 
Initially, trial duration is 3 years of participant recruitment; which can be extended due to the incorporation of new 
arms through a substantial amendment, plus 5 years of participant follow up. 
 
BEACON2 Trials Office Contact Details 
Children’s Cancer Trials Team CCTT-D 
Cancer Research UK Clinical Trials Unit (CRCTU)  
Institute of Cancer and Genomic Sciences  
College of Medical and Dental Sciences 
University of Birmingham  
Birmingham,  
UK B15 2TT  
 +44 (0) 121 4143799 
 beacon2@trials.bham.ac.uk  
 
Trial Schema 

 
 
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1. 
Performance status will be reported using the Lansky scale for 1-12 year olds and using the Karnofsky scale for older participants. 
Performance status and physical examina ion (including blood pressure, heart rate, temperature, oxygen saturation, weight and height will 
be performed at screening and within 24hr prior to each cycle in all treatment arms. In pa ients where bevacizumab infusions become not 
synchronised with chemotherapy administration, physical examination will also be performed prior to each injection of bevacizumab. 
Menstrual status (regularity of menstruation) in females of childbearing potential should be assessed at screening, end of treatment and 
during follow up. A clinical assessment of pupil responses should be conducted before starting each cycle. If there are any concerns about 
vision or pupil responses during treatment or follow up, a referral to an ophthalmologist should be considered.  
2. 
Patient’s weight will be measured at screening, on day 1 of each cycle prior to dosing and at he end of treatment. Body height will be 
measured at screening, on day 1 of each cycle prior to dosing and at the end of treatment. After end of treatment, weight and height will be 
performed at each follow up visit. 
3. 
HRQoL: HRQoL assessment using PedsQL for patients and parent/guardian, and PedsQL Family Impact Module for parent/guardian will be 
performed at baseline (in 1 week prior to study entry), Post Cycles 2, 4, 6, and at the End of treatment visit. It is highly recommended that all 
questionnaires will be collected on the visits prior to subject’s drug administration or any other interaction with site staff.  
4. 
Haematology, biochemistry and clotting blood tests must be done at screening and within 72hr prior to cycle 1 dosing.  Unless required by 
the investigator, safety tests will not be repeated at cycle 1, day 1 prior to dosing. Beginning in cycle 2 and continuing for all subsequent 
cycles, pre-dose activities can be done within 72hr pre-dose. It is recommended that blood counts are monitored weekly for all patients. 
Additional safety assessments may be done according to institutional standard of care. Laboratory tests and clinical visits as part of standard 
care can be performed at the par icipant’s local hospital, provided they are conducted on time and the local hospital and trial site have a 
procedure to receive and review them timely. Patients should be visited in between cycles as per routine practice. These tests must also be 
performed at end of treatment. Haematology includes - haemoglobin (Hb), white blood cells (WBC) with differential count, neutrophils, 
lymphocytes and platelets.  Biochemistry includes - sodium, potassium, calcium, urea, creatinine, total protein, albumin, bilirubin, ALT or AST. 
If both ALT and AST are not measured at screening, the same measurement must consistently be performed throughout the trial duration. 
Clotting includes INR and APTT and should only be performed at baseline and when clinically indicated. 
5. 
Urinalysis: A Urinalysis test (early morning urine dipstick and/or protein/creatinine ratio) will be performed at screening and within 24hr prior 
to each bevacizumab injection and the start of each cycle of treatment. This will also be repeated at the end of treatment. If there are signs 
of proteinuria, a sample must be sent for determination of albumin/protein and creatinine in urine, and the albumin or protein/creatinine ratio 
must be calculated. 
6. 
For girls who are post-menarchal, a urine (preferred) or serum pregnancy test will be done at screening (within 72hr of dosing), prior to each 
cycle and at end of treatment. Additional tests may be performed as required by institutional policy or local regulations. If the results are 
inconclusive, a repeat test must be performed using a serum sample to definitively determine pregnancy status. In addition, a pregnancy test 
will be done whenever one menstrual cycle is missing during treatment or a potential pregnancy is suspected.  Females who become pregnant 
while on study will be discontinued immediately and the outcome of the pregnancy will be followed.   
7. 
Estimated GFR should be carried out at screening up to 7 days prior to eligibility assessment in patients with a level of serum creatinine > 
1.5 ULN for age. 
8. 
Tumour assessments: The minimum requirement is a cross sectional image of site of measurable disease by MRI (preferred) or CT, 
performed wi hin 6 weeks prior to receiving the first dose of trial treatment. A scan including the brain (either CT or MRI) must also be 
performed at screening to assess participant’s eligibility with regard to the presence of bleeding brain metastases. At baseline, MIBG scans 
(or 18-FDG PET/CT scan for patients with MIBG negative disease) and bilateral bone marrow aspirates and trephine are to be done within 
6 weeks prior to receiving the first dose of trial treatment. Additional investigations of possible metastatic sites should be done upon 
presentation of signs and symptoms. Bone marrow assessments will only be repeated after 2, 4, 6, 9 and 12 courses if positive at screening 
or clinically indicated (until they become negative). To ensure comparability, the same scanner, equipment, method and technique used 
during baseline should be consistently used throughout the study. Tumour lesions previously irradiated will be considered measurable only if 
progressing. Scans should be completed up to 7 days prior to cycles 3, 5, 7, 10 and at end of treatment. Response assessment will be 
performed with the same modalities used at screening. Tumour assessments do not have to be repeated where the following cycle is delayed 
due to toxicity. 
9. 
Please refer to the BEACON2 Laboratory Manual before taking samples. Tumour molecular profiling: Samples of tumour tissue collected 
at the time of diagnosis or during frontline therapy and/or at he time of relapse will be collected. This sample is mandatory for study entry, 
if no tumour or subsequent molecular profiling is available this will be discussed with the Coordinating Sponsor and the Chief 
Investigator before study entry. For patients participating in other sequencing programs, it is acceptable to share DNA or sequencing data 
extracted from the tumour samples. Archival tumour tissue either as paraffin embedded or frozen material will be collected. Blood samples 
will be obtained at baseline, post cycles 2, 4, 6, 9 and 12 for the biomarker analysis. Samples for constitutional DNA analyses are optional 
(samples can be collected the same day as starting he next cycle, but have to be collected before study drug administration). Bone marrow 
aspirate at baseline for circulating biomarkers and circulating tumour cells may be taken at baseline and is optional.  Samples will be taken 
from all patients.   
10. 
Follow up assessments will be scheduled 3 monthly for 2 years after end of treatment, and then annually at 3, 4 and 5 years after the 
registration date, unless the patient withdraws consent. Patients that progress or develop relapse will still have survival, disease status and 
treatment received data collected for them at the time points for follow up visits. Additional follow up visits will be scheduled as needed to 
monitor any sustained unresolved, treatment emergent adverse events. 
11. 
Screening period window: (Assessments performed outside of these windows should be repeated for screening) 
• 
Medical History – Within 4 weeks prior to trial entry 
• 
Physical examination and Performance status – Within 24h prior to trial entry 
• 
Health-related quality of life (HRQoL) – Within 1 week prior to trial entry 
• 
Haematology – Within 72 hours prior to trial entry 
• 
Biochemistry - Within 72 hours prior to trial entry 
• 
Clotting – Wi hin 72 hours prior to trial entry 
• 
Urinalysis – Within 72hours prior to trial entry 
• 
Pregnancy tes ing – Within 72 hours prior to trial entry 
• 
GFR - Within 7 days prior to trial entry 
• 
Tumour Assessment - Within 6 weeks prior to trial entry 
12. 
I123-mIBG scans are highly encouraged during the first 2 years after end of treatment but are not considered mandatory. 
13. 
Assessments performed post cycle 12 or at the end of treatment should be performed 21 days after the last cycle 12 dose or last dose if 
patient discontinued treatment early. However, the assessments can be performed before 21 days if a new treatment is planned to commence 
within that timeframe if the patient has progressed.  

 
 
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participants from 10 European countries from 2013-2021. It evaluated three chemotherapy regimens: 
temozolomide, irinotecan-temozolomide and topotecan-temozolomide, and two novel agents (bevacizumab and 
dinutuximab beta) added to chemotherapy. It is the largest randomised study conducted in patients with relapsed / 
refractory neuroblastoma. The trial used a factorial 3x2 design which grouped participants on different arms 
according to the randomisation (see figure 1 below) e.g. for the bevacizumab randomisation, all participants 
receiving chemotherapy plus bevacizumab were compared to all participants receiving chemotherapy without 
bevacizumab, a design that allows multiple questions in a small sample size when no interactions between the 
different arms are present. 
Figure 1 – BEACON-Neuroblastoma Trial Design 
 
Chemotherapy backbone: 
International cooperative groups have developed several temozolomide based chemotherapy regimens such as 
temozolomide, irinotecan-temozolomide or topotecan-temozolomide [18-20] which have been tested in patients 
with relapsed/refractory neuroblastoma regimens; the BEACON-Neuroblastoma trial compared these, testing the 
addition of irinotecan, and then topotecan, to a temozolomide backbone. The addition of irinotecan or topotecan to 
temozolomide did not achieve higher response rates. However, more patients seem to achieve disease stabilisation 
and hence, PFS is prolonged. Toxicity profiles are consistent with what had been previously reported, confirming 

 
 
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that the addition of irinotecan is associated with more diarrhoea and other gastrointestinal symptoms, which can be 
severe and debilitating in a proportion of patients, whereas the addition of topotecan is associated with increased 
myelotoxicity. On the basis of this it was concluded that there is benefit in adding either irinotecan or topotecan to 
temozolomide, but there is insufficient evidence to choose one of these as superior to the other.  
Addition of bevacizumab to a temozolomide based chemotherapy backbone:   
The testing of the addition of an anti-angiogenetic agent (bevacizumab) to the chemotherapy backbone in BEACON-
Neuroblastoma was based on strong preclinical rationale of therapeutic benefit of antiangiogenic agents in 
neuroblastoma [21-26], particularly in combination with irinotecan-temozolomide-based chemotherapy [27].  
Bevacizumab is among the most established of antiangiogenic drugs and has gained approval in many adult 
indications at the beginning of the era of targeted therapies. In the BEACON-Neuroblastoma trial, objective 
responses were seen in 21/80 patients (Objective Response Rate [ORR]=26%, [95% CI 17% - 37%]) in the 
bevacizumab arms, and in 14/80 patients (ORR=18%, [95% CI 10% - 28%]) in the non-bevacizumab arms; risk 
ratio (RR) was 1.52, [95% CI 0.83 – 2.77], p=0.17. HR for PFS was 0.89 [95% CI 0.63-1.27]. One-year PFS in the 
bevacizumab arms was 0.46 [95% CI 0.34 – 0.56] compared with 0.38 [95% CI 0.27 – 0.49] in the non-bevacizumab 
arms. The pre-defined success criterion for PFS (improvement of 15% in PFS at 1p=0.15) was met.  HR for OS 
was 1.01 [95% CI 0.70-1.45]. One-year OS was 0.69 [95% CI 0.57 – 0.77] for bevacizumab arms compared with 
0.58 [95% CI 0.47 – 0.68] for non-bevacizumab arms.  
Thus the success criteria were met for response and PFS; within the limitations of evidence generated within a 
randomised phase 2 trial. The addition of bevacizumab also increased toxicity, mainly related to increased 
myelotoxicity. Consistently with other large trials in the paediatric population, bevacizumab-specific toxicities seen 
in adults were rare, although proteinuria occurred in 13% of patients, being grade 3-4 in 5% [28, 29] . Hence, within 
the recognised burden of toxicities related to chemotherapy administration in relapsed/refractory neuroblastoma, 
the toxicity profile of the addition of bevacizumab was acceptable.   
Of note, 1 and 2-year PFS estimates for patients in the bevacizumab-irinotecan-temozolomide arm were particularly 
promising 0.67 [95% CI 0.47 – 0.80] and 0.50 [95% CI 0.31 – 0.66] respectively. One and 2-year OS estimates for 
bevacizumab-irinotecan-temozolomide were 0.77 [95% CI 0.57 – 0.88] and 0.73 [95% CI 0.54 – 0.86], respectively. 
While the trial had a factorial design, assuming no interaction between bevacizumab and the different chemotherapy 
regimens, heterogeneity testing for PFS showed some evidence of a potential interaction between irinotecan and 
bevacizumab; showing that the BIT combination could be synergistic in this patient population. Notwithstanding the 
challenges of interpretation of factorial trials in small populations, the promising outcomes from the BIT arm warrant 
further evaluation. 
Addition of dinutuximab beta to the chemotherapy backbone:  
Anti-GD2 antibody, given alone, or with cytokines, has been demonstrated to improve outcome when given as 
maintenance therapy to patients with high-risk neuroblastoma [30, 31]. More recently, a number of studies have 
reported impressive response rates, in both relapse/refractory and upfront settings, when anti-GD2 is given in 
conjunction with chemotherapy [32-34]. The BEACON-Immuno trial investigated the addition of dinutuximab beta 
to chemotherapy (temozolomide or temozolomide/topotecan). Significant improvements were demonstrated in both 
objective response rate (ORR) and progression free survival when the anti-GD2 antibody was given with 
chemotherapy.  ORR was approximately twice as high in patients receiving concurrent dinutuximab beta (34.8% vs 
18.2%), with an adjusted risk ratio for response of 2.19 (80% CI 1.15-4.15) and one-side p-values of significant 
difference of 0.12.  This met the pre-defined success criteria for the trial (one-sided p < 0.23 for response), and 
represented a substantial and clinically significant benefit for patients. This also translated into a significant 
improvement in PFS with chemo-immunotherapy, with 1-year PFS of 53% compared to 27% for patients receiving 
chemotherapy alone (adjusted HR of 0.67 (95% CI 0.35 – 1.328) (p=0.23)).  These results are in line with previously 
reported smaller and/or non-randomised trials in this setting.  The US Children’s Oncology Group (COG) ANBL1221 
study reported ORR 52.9% (9/17) of an initial randomised cohort and 13/36 (36.1%) of a non-randomised expansion 

 
 
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cohort of patients administered dinutuximab with irinotecan, temozolomide and GM-CSF [33]. Importantly, 
dinutuximab beta given with TTo was adequately tolerated by the majority of patients. The incidence of adverse 
events, with the exception of neurological toxicities, was similar to patients receiving chemotherapy alone, with no 
increase in myelosuppression or infection. Neurological toxicities were more common in patients receiving 
dBT/dBTTo. The majority of these were mild (≤ Grade 2) other than one case of Grade 3 myelitis, which improved 
but did not fully resolve within the follow up period. This requires further monitoring in future studies, but the overall 
toxicity burden of this chemoimmunotherapy in this population of heavily pre-treated patients appears acceptable. 
This therefore provides very encouraging phase 2 evidence supporting the efficacy of dinutuximab beta based 
chemoimmunotherapy in patients with relapsed and refractory neuroblastoma. Further clinical trials are required to 
provide definitive evidence of efficacy, and also to evaluate in comparison with other combinational therapies.  
1.1.4 
New targets and novel combinational therapies in relapsed neuroblastoma  
In the current landscape of multimodal therapy for high risk neuroblastoma, chemo-immunotherapy and ALK 
targeted therapy (for participants with ALK aberrations) will be tested in the frontline setting by both the COG and 
SIOPEN regimens. The top priority for the relapsed setting is to develop combinations of chemotherapy with other 
immunotherapeutic or molecularly targeted agents [35]. Several novel immunotherapy combinations have shown 
potent therapeutic effects in pre-clinical neuroblastoma models. Prioritising which of these should be identified for 
inclusion in clinical trial is challenging, given that there is no agreed ‘standard’ immunocompetent murine model 
and models vary considerably in their immunogenicity and aggressiveness, such that it is hard to compare efficacy 
of therapies tested in different models. To overcome this challenge, our group will work with clinicians and scientists 
across the globe to accelerate preclinical testing. Novel arms will be validated by SIOPEN and ITCC collaborators. 
A further challenge is the lack of clinical paediatric safety and preliminary activity data on the specific combinations. 
The ‘Tier 2’ aspect of this trial will facilitate rapid clinical translation of such novel combinations of agents to generate 
initial data in small cohorts that can then be taken forward into the main trial randomisation (named Tier 1).  
Future arms in combination with existing arms will be incorporated after data on ongoing phase 1/1b paediatric trials 
of targeted and immunotherapy agents currently ongoing internationally is available; and could include anti-CD47 
monoclonal antibodies, Aurora kinase inhibitors, GSK3 inhibitors, or even novel CAR-T cell based therapies.  
1.2 
Trial Rationale 
1.2.1 
Justification for participant population  
Despite advances with the introduction of anti-GD2 immunotherapy, there is a major unmet need to develop new 
drugs for treatment of high risk neuroblastoma. Around half of participants relapse despite intensive therapies, and 
outcome following relapse is dismal (<10% long term survival) [9, 36]. Combining chemotherapy with anti-GD2 
therapy has been the most significant advance in relapsed therapy but implementing this into clinical practice faces 
numerous challenges and is still largely unavailable across Europe [37].  
The BEACON trial established a pan-European platform to compare different relapse regimens and identified two 
promising regimens (combining chemotherapy with either anti-GD2 or anti-VEGF) in the phase 2 setting.  Additional 
evidence is required to establish the future first relapse regimen to build on novel combinations, and to obtain 
regulatory and health care provider approval for these novel therapies to become standard of care. Still, further 
innovation is required to cure the majority of children who still die from disease. 
A recent participant advocate-led editorial in the topic highlights key challenges [38]: 1) improve access to innovation 
through clinical trials, 2) ensure appropriate options for participants after trial closure and 3) forward planning for 
positive results. Indeed, the multi-stakeholder platform ACCELERATE recently initiated a working group on 

 
 
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“Innovation after a first paediatric regulatory approval”, a situation where the barriers to implement chemo-
immunotherapy combinations are paradigmatic.  
European neuroblastoma experts from ITCC and SIOPEN and patient advocacy groups strongly support the need 
to develop a new platform trial focused on relapsed neuroblastoma. Building on the results of BEACON, the trial 
will confirm which combination should be taken forward and identify novel combinations that further improve survival 
in this participant group.  
Based on our experience, the BEACON platform will be modified to focus on relapse participants, retaining the 
ability to compare multiple arms, but avoiding factorial design, and will have two tiers (Tier 1, a first relapse 
randomisation and Tier 2, to facilitate smaller dose confirmation expansion cohorts of novel regimens) to be most 
efficient. The network of sites will be significantly enlarged to facilitate rapid recruitment and widen access to novel 
drugs globally.  
Refractory patients will not be included in this trial. The analyses of results from BEACON and BEACON Immuno 
trials and other studies conducted internationally show that relapse and refractory patients represent different 
patient populations that cannot be merged for a common analysis. While both have a major unmet need to develop 
new therapies, patients with refractory disease need therapies that achieve a rapid and robust antitumour response, 
in order to proceed rapidly to consolidation and maintenance strategies (e.g. tandem high dose chemotherapy and 
maintenance anti-GD2 therapy). Hence, the SIOPEN group is currently including refractory patients within the 
frontline high risk neuroblastoma strategy.  
Eligibility criteria in terms of organ function have been adapted to the needs of the population with relapsed 
neuroblastoma, that often suffers from bone marrow metastases or is heavily pretreated. Given the experience of 
the BEACON trial where grade 3-4 haematological and non-haematological events were reversible and 
manageable, the required platelet or neutrophil count, or ALT/AST have been adapted.  
Median age for children recruited in the BEACON trial was 5 (range 1-21 years). Relapsed high risk neuroblastoma 
is exceptional in children younger than 1 year of age, given that 1) infants <18 months of age are mostly considered 
intermediate risk and 2) even some patients diagnosed as infants, by the time a relapse occurs, these have become 
>1 year of age. For these reasons, and given the lack of data on bevacizumab therapy and chemo-immunotherapy 
in this very young population, lower age at trial entry will be one year of age. Neuroblastoma can occur in older 
adolescents and young adults, hence no upper age limit has been included.  
The trial will include patients with first relapsed neuroblastoma with adequate organ function; and be open across 
multiple sites in 15+ countries, thus providing wide access to the trial across all the countries where it opens. The 
trial population will be highly representative of the whole population of children with first relapsed neuroblastoma.   
1.2.2 
Justification for design  
The BEACON2 trial will be a platform trial that will comprise one main randomisation (Tier 1) and a dose confirmation 
element (Tier 2). The main randomisation (Tier 1) will have a multi-arm randomised phase 2 design. Following this 
design, each arm will have two stages for completion of phase 2.. The multi-stage nature of the trial will greatly 
maximise the efficiency of the trial allowing the possible completion of both phase 1, 2 and potentially 3 within the 
same trial depending on the results seen at each interim assessment. Regarding its multi-arm nature, the trial will 
start with two arms, based on the most promising regimens identified from previous trials conducted by SIOPEN 
and others across the globe. However, the design will allow flexibility to incorporate more arms as the trial evolves 
if the evidence supports it. For pragmatic reasons, no more than 3 arms will be open in Tier 1 at a time. The rEECur 
trial for relapsed Ewing sarcoma (NCT02727387) has used a similar multi-arm multi-stage trial proving highly 
efficient addressing multiple treatments over time [39]. Despite multiple novel anticancer drugs becoming 
increasingly available for paediatric use, most of phase 1 data is as single agent and the data on combinations with 
standard of care therapies is still very limited. For this reason, Tier 2 of the trial will allow rapid confirmation of novel 

 
 
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combination schedules. Regimens with no expected overlapping toxicities will be included, and testing within the 
Tier 2 will provide confirmation that the doses and schedules are safe. Patients will only be eligible for Tier 2 when 
not eligible for Tier 1 (e.g. Tier 2 will not compete for recruitment of Tier 1). More than one treatment arm may be 
available in Tier 2 at any given time. 
The majority of tests and procedures performed during screening (see section 7.1 and section 8.1) and the scans 
performed throughout (see section 9.1), are routinely considered as standard of care in relapsed neuroblastoma 
and would likely be performed whether the participant was entered into the trial or not. Furthermore, the 
assessments undertaken during treatment, after treatment and during follow up (see section 9) are also very similar 
to standard of care. Additional biopsies, procedures and surgeries for the collection of tumour or bone marrow, will 
not be required as a consequence of trial participation. This is because samples will be collected from procedures 
performed as part of standard of care, provided informed consent has been obtained. Throughout the participant’s 
treatment additional blood samples, equivalent to around 40 ml of blood, will be collected. The participant will also 
have the option of consenting to the collection, storage, and DNA analysis of an additional blood sample to be 
analysed for use in research associated with this trial. When possible, the blood will be drawn from the long line, 
Hickman or Port-a-cath at the same time as blood being taken for routine blood tests. Therefore, the characteristics 
of the BEACON2 trial intervention are considered as being comparable to normal clinical practice. Combinations of 
chemotherapy with both anti-GD2 therapy and bevacizumab are currently widely used across Europe and North 
America in children with relapsed neuroblastoma.  
1.2.3 
Justification for dosage of IMP’s 
All of the IMPs used within this clinical trial have marketing authorisation issued by the European Medicines Agency 
(EMA) but are being used outside of their licenced indication for the purposes of this trial, with the exception of 
temozolomide oral suspension which is not yet licensed. Further information can be found in the Pharmacy Manual. 
There is a need for temozolomide as an oral suspension as it offers a solution for infants and young children who 
may not be able to swallow capsules, thus not excluding this patient population.  
1.2.4 
Benefit Risk Assessment  
As discussed in section 1.2.1 Justification for participant population and section 1.2.2 Justification for design, there 
are numerous benefits associated with the proposed study regime. Please see the following information relating to 
known and expected risks associated to the proposed study regime, as well as measures taken in accordance to 
the risk profile of the medicinal product.  
1.2.4.1 Trial Treatment 
All IMPs within the trial regimens have been widely used (within trials and/or as part of standard of care) in this 
indication in paediatrics and the safety profiles of the IMPs used in Tier 1 on this trial are well characterised. 
However, new combinations may give increased risk of toxicity, and the combinations are not fully established 
practice.  
The study involves a phase 1 dose finding trial (Tier 2, arm C) in which dinutuximab beta is added to t bevacizumab-
irinotecan-temozolomide (BIT) to create a new regimen, dbBIT. The benefits of adding dinutuximab beta to an 
antiangiogenic and chemotherapy based regimen have not yet been explored in patients with relapsed 
neuroblastoma. The protocol has therefore been designed to first establish a safe dose of dinutuximab beta in 
combination with BIT, and then if established to take this safe dose forward into Phase II testing of activity (Tier 1).  
In the randomised component of this trial (Tier 1), there is a risk that patients may not be assigned to the treatment 
group that they or their parents would prefer. The treatment that participants receive cannot be selected by choice. 

 
 
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If a patient does not wish to have their treatment allocated by chance i.e. by randomisation, then they cannot be 
part of this study and will receive alternative treatment as recommended by their doctor.  
As the efficacy of the BIT, dbIT and dbBIT drug combinations have not been fully established in a paediatric 
population, the patient group includes patients for whom no treatment of greater curative potential is available and 
the alternative management, including best supportive care/palliation will be explained to the patient and/or family, 
to enable an informed decision regarding trial participation.  
As with all clinical trial studies the drug treatments may involve risks that are already known, as well as risks that 
are currently unknown. Patients will be closely monitored for side effects throughout the course of the treatment 
and during follow up. 
1.2.4.2 Pregnancy 
There is a risk that if a patient (or their partner) becomes pregnant while receiving trial treatment or immediately 
after, that the unborn baby could be affected. For this reason, sites will ensure that all females of childbearing 
potential undergo a urine pregnancy test prior to receiving trial medications, prior to each treatment cycle and at 
the end of treatment. We will also educate all patients of childbearing potential regarding the need for adequate 
contraception whilst they are receiving trial drugs and for 6 months afterwards. Should a patient or their partner 
become pregnant between the time of commencing study treatment and up to six months after completion, 
treatment should be discontinued immediately, trial participation will be terminated for safety reasons and the 
pregnancy outcome will be monitored. If a patient's partner becomes pregnant during this period, we would also 
like to collect details of the outcome of the pregnancy with their permission. 
1.2.4.3 Collection and use of Samples 
During the trial, patients will have blood samples taken for trial related purposes. The risks of having blood taken 
from a vein include pain, bruising or infection at the site where the blood was taken, and fainting. Where possible 
blood will be taken from a patient's Hickman line or Portacath rather than directly from a vein, there is a still a small 
risk of infection associated with doing this. Where possible blood samples taken for research purposes will be taken 
at the same time as routine blood sampling to minimise distress to patients. Guidance from the European Medicines 
Agency and Medicines for Children Research Network will be adhered to regarding the maximum volumes of blood 
collected for research purposes. 
During this study, optional samples of bone marrow will be taken so that we can see if any neuroblastoma has 
spread to this area. Risks of bone marrow sampling include pain, bleeding and infection at the sampling site. If a 
patient is allocated to receive bevacizumab there is an additional risk of poor wound healing after having this test. 
For this reason, patients who have no neuroblastoma in their bone marrow at the beginning of the study will not 
have bone marrow samples repeated again during the study. Patients will likely be given either a general 
anaesthetic or sedative to make them drowsy whilst the test is performed. Sedatives are usually well tolerated but 
there is a small chance patients may experience an allergic reaction to this, feel sick or develop an irregular 
heartbeat. 
During the informed consent process, participants or their parents (if aged under 16 years) will be given the option 
of the patient contributing a blood sample for genetic germline DNA analysis. It is possible in rare cases that the 
analysis of this sample could uncover findings that may have direct implications on the patients clinical care (e.g. a 
rare genetic abnormality). Participants/parents are fully informed that should they agree to having this sample taken 
and this   situation arises, their study doctor will be informed and will take the necessary steps to refer the patient 
for the relevant clinical care. 
1.2.4.4 Scans 

 
 
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By participating in this trial patients may have up to 14 CT, MRI or nuclear medicine (MIBG) scans depending on 
the location of their tumour. Radiation may cause cell damage which can, after many years or decades, become 
cancerous.   
In order for some scans to be performed, “contrast agents” are given through the patient’s central line or cannula.  
Whilst these contrast agents allow doctors to gain a clear picture of what is happening inside the body they also 
carry a small risk themselves. A small number of people have an allergic reaction to them which, while usually mild 
and easily treatable, can be life threatening. For this reason, we ask that all patients/parents tell their doctor if they 
have experienced a previous reaction to contrast agents. 
1.2.5 
Choice of treatment arms for BEACON2 – Tier 1 
The BEACON-Neuroblastoma trial has identified two arms which require further evaluation:  
Dinutuximab beta-irinotecan-temozolomide 
The combination of chemotherapy with anti-GD2 immunotherapy has achieved improved results compared to 
chemotherapy alone. ORR was approximately twice as high in patients receiving concurrent dinutuximab beta 
(34.8% vs 18.2%), with an adjusted risk ratio for response of 2.19 (80% CI 1.15-4.15) and one-side p-values of 
0.12. There was also a significant improvement in PFS with the chemo-immunotherapy, with 1-year PFS 53% 
compared to 27% for patients receiving chemotherapy alone (adjusted HR of 0.67 (95% CI 0.35 – 1.328) (p=0.23)).  
This data is in line with that of the ANBL1221 trial conducted by the COG with dinutuximab-GM-CSF-irinotecan-
temozolomide, which showed an ORR of 42% (95% CI, 28.2% to 54.8%) and 1-year PFS of 67.9% (95% CI, 55.4% 
to 80.5%) for children with RR-NB [32, 33] and other studies with chemo-immunotherapy conducted internationally 
using several anti-GD2 antibodies and chemotherapy regimens (see Table 2).  
The BEACON trial has provided sufficient evidence showing that chemotherapy alone (e.g. irinotecan-
temozolomide or topotecan-temozolomide) have inferior outcomes compared to the combinations with 
bevacizumab or dinutuximab beta. Hence, there is strong agreement in the scientific and patient advocacy 
communities that it is not acceptable to include chemotherapy alone arms in the BEACON2 trial.  
Chemo-immunotherapy trials conducted in North America have also included GM-CSF, which is not available in 
Europe. While no comparative data is available, given the promising results shown in BEACON Immuno with 
chemo-immunotherapy without GM-CSF, the BEACON2 trial will also not include GM-CSF. 
The dose of dinutuximab beta-irinotecan-temozolomide has now been aligned with the regimen used by the 
Children’s Oncology Group, with dinutuximab beta (10mg/m2/day) now given for 7 days every 3 weeks coupled 
with irinotecan-temozolomide chemotherapy. This dose is equivalent to the current use of dinutuximab beta 
approved for maintenance of high risk neuroblastoma (10mg/m2/day for 10 days every 5 weeks).  
Bevacizumab-irinotecan-temozolomide 
Bevacizumab-irinotecan-temozolomide (BIT) arm demonstrated very promising 1 year PFS and OS (0.67 and 0.77 
respectively). The toxicity and tolerability of the regimen has been demonstrated to be acceptable.  
To date, there has been no direct comparison between the BIT regimen and anti-GD2 chemoimmunotherapy based. 
The first objective of the BEACON2 study will be therefore to directly compare these regimens to identify the regimen 
with the best efficacy. Irinotecan will be used in both regimens to allow direct comparison of the effects of the 
additional bevacizumab/dinutuximab beta. Although the BEACON Immuno trial used topotecan rather than 
irinotecan, other international trials have shown similar results with irinotecan containing anti-GD2 chemo-
immunotherapy [33, 40]. 

 
 
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1.2.6 
Choice of treatment arms for BEACON2 – Tier 2 (Testing novel combinational arms)  
It is likely that improvements in outcome for patients with relapsed neuroblastoma will only be achieved by 
combinational therapies. Our focus will be on testing regimens which build on current established combinational 
therapies (e.g. BIT, anti-GD2/chemotherapy) based on solid scientific rationale and/or pre-clinical data.  
Dinutuximab beta-Bevacizumab-Irinotecan-Temozolomide 
As discussed above, the addition of each of bevacizumab and dinutuximab beta both met their phase 2 success 
criteria for improving PFS in BEACON. Although the exact mechanism of action accounting for the therapeutic 
benefits of adding these respective agents to a chemotherapy backbone is not clear, it is likely they are different, 
given that bevacizumab is an anti-angiogenic agent, and anti-GD2 is an immunotherapy. Therefore, there is 
potential for there to be additive benefit of giving both agents with the chemotherapy backbone. In addition, as well 
as ‘normalising’  the tumour vasculature, enhancing delivery of chemotherapy + immunotherapy, bevacizumab may 
also favourably modify the immune microenvironment, including promotion of tumour infiltrating lymphocytes and 
suppression in the number and function of inhibitory populations, including myeloid derived suppressor cells, 
regulatory T cells and M2 macrophages [41-43]. In pre-clinical neuroblastoma models, it has been reported to 
augment infiltration and efficacy of anti-GD2 CAR T cells [44] and there are a number of clinical studies in adult 
tumours, indicating benefit in combining bevacizumab with checkpoint blockade [45-47]. There is therefore rationale 
beyond just potential additive effects, for combining bevacizumab with anti-GD2 plus chemotherapy, with the aim 
of favourably modifying the tumour immune and vascular microenvironment to improve the efficacy of chemo-
immunotherapy.  
Given the different mechanisms of action and toxicity profiles of dinutuximab beta and bevacizumab, it is anticipated 
that the addition of both agents together to a chemotherapy backbone would also be acceptable in terms of toxicity 
and tolerability.  
Other novel combinations for testing in Tier 2 
There are a number of potential combinational regimens which show promise, but that are not yet ready for clinical 
testing. Our group has formed a network of international collaborators to accelerate preclinical testing and on-going 
discussions within SIOPEN and ITCC consortia, will prioritise and validate these for inclusion in Tier 2, as new data 
becomes available. 
1.2.7 
Rationale for biological studies and future data sharing 
Biomarkers have been defined as biological characteristics that can be objectively measured and evaluated as an 
indicator of normal biological, pathological processes, or pharmacological responses to a therapeutic intervention 
[48]. 
In regards to anticancer drug development, three main types of biomarkers have been defined [49]:  
• 
Prognostic biomarkers, give information on prognostic features helping to distinguish between cases with 
good or poor outcome, independent of treatment. 
• 
Predictive biomarkers assess the probability that a patient will benefit from a particular treatment. 
• 
Pharmacological/Pharmacodynamic (PD) biomarkers, measure effects of the drug on the tumour. PD 
biomarkers are of major value in making “go-no-go” decisions and assess performance of new drugs. 
The use of biomarkers will accelerate and improve drug development [50-52]. In this study, a comprehensive 
biomarker evaluation has been developed taking into account all considerations for research in the paediatric 
population. Details on when to collect specific samples and how to process them are described in the BEACON2 

 
 
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Laboratory manual. Samples and images will only be collected for research when required as per standard of care 
for the patients, and volumes of blood will comply with local, national and international policies.   
Importantly, the status of molecular genetic alterations known to be clinically decision making should be known 
upon study entry, including tumour MYCN amplification status, and ALK amplification/mutation status. 
1.2.8 
Exploratory biomarker assays performed in blood, blood-derived plasma, bone marrow 
aspirates and tumour samples  
Blood and plasma samples will be taken at study entry, during and at the end of treatment for exploratory biomarker 
studies; see BEACON2 Laboratory manual. Bone marrow aspirates at study entry may be collected for exploratory 
molecular studies of circulating biomarkers, neuroblastoma cells and the bone marrow microenvironment. Biological 
studies include, but are not limited to:  
• 
Tumour molecular profiling. Tumour and blood-derived plasma DNA will be sequenced and tumour gene 
expression profiling performed to explore possible associations between the tumour molecular profile, 
candidate molecular predictors and clinical outcome. This will be performed in tumour samples collected at 
baseline study entry (for clinical purposes) or at the time of diagnosis. Existing genomic and biomarker data 
collected from patients prior to entry into BEACON2 will be sought to provide a complete genomic and 
biomarker profile of patients.  
• 
Circulating tumour DNA and RNA will be assessed at study entry, during and at the end of treatment as 
potential surrogate markers of tumour burden, response of patients to treatment or development of 
resistance mechanisms.  
• 
Biomarker analyses on blood samples will include identifying potential markers of prognosis or response to 
new therapies, and the biology of neuroblastoma. 
• 
Optional exploratory studies in bone marrow aspirates at study entry will investigate the molecular genotype 
and phenotype of neuroblastoma cells in the bone marrow and the bone marrow microenvironment. 

 
 
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2. TRIAL DESIGN  
BEACON2 is a platform multi-arm multi-stage (MAMS) randomised phase 1/phase 2, open-label, international trial. 
The trial will comprise two tiers: Tier 1 will be the main randomisation, starting with the randomisation of Arms A vs 
B. Participants will be randomised at trial entry to receive one of the regimens. Tier 2 will include a dose 
expansion/confirmation cohort (Arm C and future arms), before this is introduced to Tier 1. Using the rolling MAMS 
design will allow the introduction of novel agents or regimens as new arms, if appropriate. The introduction of new 
arms will take place pending approval of a substantial amendment by each relevant Competent Authority. 
Figure 2 – Trial Scheme 
 
2.1 
TIER 1 (Main Randomisation)  
Arm A: dinutuximab beta, irinotecan and temozolomide (dbIT)  
Arm B: bevacizumab, irinotecan and temozolomide (BIT)  
40 participants will be recruited to each arm in the first stage. A further 35 (total n=75 per arm) will be recruited 
following an interim analysis.  
Stratification variables used in this trial include: 
• 
Measurable (disease can be measured in cross-sectional imaging as per RECIST v1.1, e.g. soft tissue 
disease measures >1cm longest diameter) vs evaluable disease (e.g. disease that is non-measurable per 
RECIST 1.1 or only detectable by MIBG or PET/CT scan)[53] 
• 
MYCN amplification / no amplification / unknown 

 
 
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• 
Prior Chemo-Immunotherapy (e.g. chemotherapy with anti-GD2 therapy) 
• 
Prior Bevacizumab, Irinotecan and Temozolomide (BIT) treatment 
2.2 
TIER 2 (Dose Expansion Cohort)  
Arm C:   dinutuximab beta, bevacizumab, irinotecan and temozolomide (dbBIT).   
A safety run-in cohort of 10 participants will be recruited from selected sites. The sites selected to participate in Tier 
2 will be decided by the TMG, whose decision will be based on whether they are ITCC Phase 1 centres, have 
experience in early phase trials, their historical site data return and capacity of their NCC to provide the monitoring 
required. The primary endpoint of this cohort will be the occurrence of dose-limiting toxicities (DLTs) defined using 
standard definitions [54].  
A DLT is defined as a trial IMP-related adverse event occurring during the DLT assessment period (first cycle, i.e. 
3 weeks) that meets 1 of the following criteria: 
• 
Recurrent Grade 3 bronchospasm  
• 
Grade 4 anaphylaxis or allergic reaction 
• 
Grade ≥3 serum sickness 
• 
Grade ≥3 neurological or vision toxicity (as defined in section 11.1) 
• 
Severe, unrelenting neuropathic pain not controlled by maximal analgesia  
• 
Recurrent Grade ≥3 capillary leak syndrome 
• 
Grade 4 hyponatremia (<120 mmol/L) lasting >24 hours despite appropriate fluid management 
• 
Grade 4 skin toxicity 
• 
Grade ≥3 cardiac toxicity 
• 
Any Grade 4 toxicity (laboratory abnormality or non-hematological toxicity) that leads to change of 
management defined as: chemotherapy dose reduction or delay of next cycle more than >14 days 
• 
Any grade ≥4 toxicity leading to any intensive care unit hospitalization for mechanical ventilation/ionotropic 
support/hemofiltration 
• 
Any toxic death (Grade 5 toxicity) 
• 
Persistent (>72h) Grade 3 nausea, vomiting or diarrhea despite optimal therapy  
• 
Grade 3 total bilirubin lasting >72h 
• 
≥ Grade 3 ALT/AST unless resolves in ≤7 days 
• 
Any laboratory abnormality that meets the definition of drug-induced liver injury (DILI) as defined per Hy’s 
law 
• 
Grade 4 anemia 
• 
Grade 4 febrile neutropenia  
• 
Grade 4 thrombocytopenia requiring transfusions for more than 7 days 
• 
Grade 3 thrombocytopenia with Grade ≥3 bleeding 
• 
Specific for treatment with Bevacizumab: 
• 
Grade ≥3 hypertension not controlled by antihypertensive therapy 
• 
Grade >3 proteinuria 
• 
All other haematological toxicities will be not be considered DLTs 
Patients will only be assessable for DLT evaluation provided they have received at least 75% of the planned drug 
dosing a DLT was the reason not to complete dosing and they have not received any other anti-cancer treatment 
that is not allowed in the protocol These patients not contributing to the DLT assessment will be replaced.  
All DLTs will be evaluated by the trial CI/Clinical coordinator as well as by the Trial Management Group (TMG) and 
DMC.   

 
 
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The investigator will fill in the DLT form as soon as a DLT occurs and/or at the end of the DLT period. At the latest, 
the form has to be sent to Sponsor within two working days after end of DLT period. All DLTs require continued 
monitoring and follow-up reporting until they resolve to grade 1 or less, until the patient begins another treatment 
regimen or until the toxicity is determined to be unresolvable or stabilized. 
Recruitment to Tier 2: 
Before a patient can be registered to Tier 2, the local team must contact the Coordinating Sponsor to confirm a slot 
is available.  
For the first 6 patients, no more than 3 patients will be undergoing the 1st cycle of treatment at any one time, i.e: 
• 
First 3 patients are recruited without any time restrictions  
• 
4th patient can only be recruited once one patient has completed 1 full cycle of treatment   
• 
5th patient can only be recruited once 2 patients have completed 1 full cycle of treatment  
• 
6th -10th patients can only be recruited once 3 patients have completed 1 full cycle of treatment   
If 1-2 patients experience ≥1 DLTs, recruit further 3 patients (total 6) to achieve 3 patients completing 1 full cycle. 
If 3 patients experience ≥1 DLTs then reduce dose of any or all of the agents by 25%, dependant on the specific 
DLTs seen and continue recruitment. 
Inclusion of Tier 2 treatment in Tier 1: 
The decision to move an arm from Tier 2 to the main randomisation (Tier 1) will be taken by the TMG based on 
preclinical rationale, mechanism of action, early signs of activity, low proportion of DLTs, lack of overlapping 
toxicities and feasibility of the combination. 
2.3 
Treatment Duration 
Participants will receive treatment for 12 courses, lasting approximately 36 weeks.  
For patients pursuing other consolidation-type therapies, it is acceptable to withdraw from BEACON2 trial treatment 
after 6 cycles. Data about subsequent therapies received before and after subsequent progression/relapse will be 
collected in the Case Report Form (CRF).  
 

 
 
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3. AIMS, OBJECTIVES AND OUTCOME MEASURES  
3.1 
Aims 
• 
To improve survival for patients with relapsed neuroblastoma by developing novel combinations that are 
ready for clinical implementation 
• 
To establish a platform trial to evaluate novel combinations in relapsed neuroblastoma, within a seamless 
phase 1-2 trial that can lead to regulatory approvals and impact clinical practice; allowing dose confirmation 
cohorts for novel combinations 
• 
To evaluate safety, activity, efficacy and quality of life for these novel combinations in relapsed 
neuroblastoma participants  
• 
To improve our understanding of relapsed neuroblastoma biology, tumour clonal evolution, tumour 
microenvironment and develop biomarkers of response and resistance to direct the development targeted 
therapies by conducting a comprehensive biomarker sample collection. 
3.2 
Objectives 
3.2.1 
Primary 
• 
To test novel treatments against current best available treatment in relapsed neuroblastoma 
3.2.2 
Secondary 
• 
To evaluate the safety of the regimens, anti-tumour response, longer term outcome and quality of life 
3.2.3 
Tertiary 
• 
To evaluate the role of circulating biomarkers and tumour molecular profiles in blood and tumour as 
prognostic and predictive biomarkers in relapsed neuroblastoma, including neuroblastoma mRNAs, 
circulating DNA, biomarkers of immune response and the tumour microenvironment and analysis of 
genomic aberrations in relapsed tumours.  
3.3 
Outcome Measures 
3.3.1 
Primary Endpoint 
• 
Progression-Free Survival time (as per INRC 2017 [2]) – for Tier 1 (randomised comparison) 
• 
Definition of a safe and tolerable combination regimen – for Tier 2 (dose expansion-confirmation cohorts) 

 
 
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3.3.2 
Secondary Endpoints 
• 
Best objective response (complete and partial response) as per INRC 2017 during trial treatment (12 cycles)  
• 
Clinical benefit (complete, partial and minor response and stable disease) per the INRC 2017. 
• 
Time response to progression/duration of response (for responders) 
• 
Overall Survival time  
• 
Quality of life measured by Peds-QL questionnaires 
• 
Incidence and Severity of AEs 
3.3.3 
Exploratory/Tertiary Endpoints 
• 
Quality of life of caregivers measured by Peds-QL questionnaires 
• 
Correlation between objective response using INRC 2017 and PFS/OS 
• 
Changes in circulating biomarkers and tumour molecular profiles in blood and tumour, including mRNAs, 
analysis of immune response and tumour microenvironment, analyses of genomic aberrations in relapsed 
neuroblastoma (e.g. MYCN, ALK, RAS/MAPK pathway, ATRX) and development of novel biomarkers. 
4. ELIGIBILTY 
4.1 
Tier 1 Eligibility 
Participants meeting the criteria below are eligible to participate in Tier 1 trial treatment. Eligibility must be confirmed 
by an Investigator (defined as the individual who has the responsibility for the medical care of the participant i.e., 
typically a consultant level doctor), named on the trial delegation log.  
4.1.1 
Tier 1 Inclusion Criteria  
Disease specific 
• 
Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS)[1] 
definition  
• 
High risk relapsed neuroblastoma (relapsed or progressed after being defined as High Risk at any time 
following diagnosis or progressed/relapsed as high-risk neuroblastoma)  
• 
Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG scan with or without 
bone marrow histology), as per INRC [2, 3]. Participants with only bone marrow detectable disease (bone 
marrow aspirate or trephine) are NOT eligible for the study 
General 
• 
Age ≥1 year 
• 
Signed informed consent from participant, parent or guardian 

 
 
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Performance and organ function 
• 
Performance Status: 
o 
Lansky (for patients ≤12 years of age) or Karnofsky (for those >12) ≥ 50%, (Participants who are 
unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will 
be considered ambulatory for the purpose of assessing performance score) 
• 
Life expectancy of ≥ 12 weeks 
• 
Bone marrow function (within 72 hours prior to randomisation): 
o 
Platelets ≥ 50 x 109/L (unsupported for 72 hours)  
o 
ANC ≥ 0.50 x 109/L (no G-CSF support for 72 hours) 
o 
Haemoglobin > 8 g/dL (transfusions allowed) 
• 
Renal function (within 72 hours prior to randomisation): 
o 
Absence of clinically significant proteinuria (either early morning urine dipstick ≤2+) or if dipstick 
urinalysis shows > 2+ proteinuria, protein: creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein 
excretion must be < 0.5g 
o 
Serum creatinine ≤ 1.5 ULN for age, if higher, a measured GFR (radioisotope or 24 hour urine 
calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2  
• 
Liver function (within 72 hours prior to randomisation):  
o 
Absence of clinically significant signs of liver dysfunction. AST or ALT ≤ 3.0 ULN and total bilirubin ≤ 
1.5 ULN. In patients with liver metastases, AST or ALT ≤ 5 ULN and total bilirubin ≤ 2.5 ULN is 
allowed.  
• 
Coagulation: 
o 
Participants must not have an active uncontrolled coagulopathy. 
o 
Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the 
medical standard of the institution) and the participant has been on a stable dose of anticoagulants 
for at least two weeks at the time of study enrolment.  
• 
Blood pressure below 95th centile for age and sex. Participants ≥18 years of age should have a blood 
pressure ≤150/90 mmHg (within 72 hours prior to randomisation). Use of antihypertensive medication is 
permitted. 
4.1.2 
Tier 1 Exclusion Criteria  
• 
Known contraindication or hypersensitivity to: 
o 
Any study drug or component of the formulation 
o 
Chinese hamster ovary products or other recombinant human or humanised antibodies. 
o 
Participants with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but 
those with severe (or G4) hypersensitivity reactions to anti-GD2 antibodies will be excluded.  
• 
Clinically significant neurological toxicity, uncontrolled seizures or objective peripheral neuropathy (> Grade 
2).  (Unresolved neurological deficits from previous spinal cord compression or surgeries are acceptable). 
Participants with previous ≥ Grade 3 motor neurotoxicity secondary to anti-GD2 are excluded, even if 
recovered 
• 
Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral 
arterial thrombosis) or any ongoing arterial thrombo-embolic events 
• 
A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis. 
• 
Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive 
prophylaxis for PJP 
• 
Uncontrolled infection 
• 
Inadequate recovery from prior surgery with ongoing ≥ Grade 3 surgical complications. Grade ≥ 2 wound 
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• 
Recent surgical procedures (at start of trial treatment). Patient can be randomised up to 48hr prior to these 
periods being completed provided that trial treatment only starts after complying with all of them: 
o 
Core biopsies within previous 24hr 
o 
Open excisional biopsies within previous 48hr 
o 
Major surgery within previous 2 weeks. 
o 
Bone marrow aspirates/trephines, within previous 48hr 
o 
Tunnelled central line insertion within previous 48hr  
• 
Washout from prior treatments (at start of trial treatment): 
o 
Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens) 
o 
Any anti-GD2 therapy within previous 2 weeks 
o 
Craniospinal radiotherapy or MIBG therapy within previous 6 weeks 
o 
Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy) 
o 
Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within 
previous 8 weeks  
o 
Allogeneic stem cell transplant within previous 12 weeks (with absence of active ≥G2 acute GVHD) 
o 
14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial 
• 
Bleeding metastases (participants with CNS metastases can be enrolled as long as the metastases are not 
bleeding). At least 6 months from any ≥G3 haemoptysis or pulmonary haemorrhage  
• 
Use of enzyme inducing anticonvulsants within 72hr of randomisation 
• 
Conditions that increase the risk of bevacizumab-related toxicities:  
o 
History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. 
in the absence of therapeutic anticoagulation) 
o 
History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active 
gastrointestinal bleeding within 6 months prior to study enrolment 
o 
Current chronic intestinal inflammatory disease/bowel obstruction 
• 
Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and 
fructose 
• 
Males or females of reproductive potential may not participate unless they agree to use a highly effective 
method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined 
oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the duration of study therapy 
and for up to 6 months after the last dose of trial drugs.  A negative urine or serum pregnancy test must be 
obtained within 72 hours prior to dosing in females who are post-menarche. 
• 
Pregnant or lactating participant 
• 
Live or live-attenuated vaccines given within previous 28 days prior to study enrolment 
• 
Any uncontrolled medical condition that poses an additional risk to the participant  
Tier 1 Specific Exclusion Criteria 
• 
More than one relapse event after the start of high risk neuroblastoma therapy 
• 
Previous treatments that are not allowed 
o 
Bevacizumab for relapsed neuroblastoma (patients who have received BIT for refractory disease are 
not excluded, providing no progression of disease during this treatment occurred 
o 
Treatment with any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’) for 
treatment of relapsed neuroblastoma. Prior treatment with chemo-immunotherapy for refractory 
disease is allowed, provided no disease progression during this therapy.   

 
 
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4.2 
Tier 2 Eligibility  
Participants must have been previously pre-screened or screened for Tier 1 and found to be ineligible, before being 
assessed for Tier 2 eligibility. A reason for the ineligibility for Tier 1 must be provided on the Tier 2 Registration 
form. 
Before offering participation on Tier 2, the local team must confirm with the Coordinating Sponsor that a slot is 
available for treatment in Tier 2.  
Participants meeting the criteria below are eligible to participate in Tier 2 of the trial. Eligibility must be confirmed 
by an Investigator (defined as the individual who has the responsibility for the medical care of the participant i.e., 
typically a consultant level doctor), named on the trial delegation log. 
4.2.1 
Tier 2 Inclusion Criteria 
Disease specific 
• 
Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) [1] 
definition  
• 
High risk relapsed neuroblastoma (relapsed or progressed after being defined as High Risk at any time 
following diagnosis or progressed/relapsed as high-risk neuroblastoma)  
• 
Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG scan with or without 
bone marrow histology), as per INRC [2, 3]. Participants with only bone marrow detectable disease (bone 
marrow aspirate or trephine) are NOT eligible for the study 
General 
• 
Age ≥1 
• 
Signed informed consent from participant, parent or guardian 
Performance and organ function 
• 
Performance Status: 
o 
Lansky (for patients ≤12 years of age) or Karnofsky (for those >12) ≥ 50%, (Participants who are 
unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will 
be considered ambulatory for the purpose of assessing performance score) 
• 
Life expectancy of ≥12 weeks 
• 
Bone marrow function (within 72hr prior to registration): 
o 
Platelets ≥ 50 x 109/L (unsupported for 72hr)  
o 
ANC ≥ 0.50 x 109/L  (no G-CSF support for 72hr) 
o 
Haemoglobin > 8 g/dL (transfusions allowed) 
• 
Renal function (within 72 hours prior to registration): 
o 
Absence of clinically significant proteinuria (either early morning urine dipstick ≤2+) or if dipstick 
urinalysis shows > 2+ proteinuria,  protein: creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein 
excretion must be < 0.5g 
o 
Serum creatinine ≤1.5 ULN for age, if higher, a measured GFR (radioisotope or 24 hour urine 
calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2  
• 
Liver function (within 72 hours prior to registration):  

 
 
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o 
Absence of clinically significant signs of liver dysfunction. AST or ALT ≤ 3.0 ULN and total bilirubin 
≤1.5 ULN. In patients with liver metastases, AST or ALT ≤ 5 ULN and total bilirubin ≤2.5 ULN is 
allowed.  
• 
Coagulation: 
o 
Participants must not have an active uncontrolled coagulopathy  
o 
Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the 
medical standard of the institution) and the participant has been on a stable dose of anticoagulants 
for at least two weeks at the time of study enrolment. 
• 
Blood pressure below 95th centile for age and sex. Participants ≥18 years of age should have a blood 
pressure ≤150/90 mmHg (within 72 hours prior to randomisation). Use of antihypertensive medication is 
permitted. 
Tier 2 Specific Inclusion Criteria 
• 
More than one relapse event 
 
NB- The following previous treatments are allowed provided that the principal investigator expects a 
favourable benefit/risk assessment (e.g. patients could derive potential benefit from the Tier 2 
combination): 
o 
bevacizumab,  
o 
any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’)  
o 
previous treatment with temozolomide with irinotecan 
4.2.2 
Tier 2 Exclusion Criteria 
• 
Known contraindication or hypersensitivity to: 
o 
Any study drug or component of the formulation 
o 
Chinese hamster ovary products or other recombinant human or humanised antibodies. 
o 
Participants with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but 
those with severe (or G4) hypersensitivity reactions to antiGD2 antibodies will be excluded.  
• 
Clinically significant neurological toxicity, uncontrolled seizures or objective peripheral neuropathy (>grade 
2).  (Unresolved neurological deficits from previous spinal cord compression or surgeries are acceptable). 
Participants with previous ≥ Grade 3 motor neurotoxicity secondary to anti-GD2 are excluded, even if 
recovered 
• 
Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral 
arterial thrombosis) or any ongoing arterial thrombo-embolic events 
• 
A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis. 
• 
Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive 
prophylaxis for PJP 
• 
Uncontrolled infection 
• 
Inadequate recovery from prior surgery with ongoing ≥Grade 3 surgical complications. Grade ≥2 wound 
dehiscence. 
• 
Recent surgical procedures (at start of trial treatment). Patient can be registered up to 48h prior to these 
periods being completed provided that trial treatment only starts after complying with all of them: 
o 
Core biopsies within previous 24hr 
o 
Open excisional biopsies within previous 48hr 
o 
Major surgery within previous 2 weeks. 
o 
Bone marrow aspirates/trephines, within previous 48hr 
o 
Tunnelled central line insertion within previous 48hr  

 
 
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• 
Wash out from prior treatment (at start of trial treatment): 
o 
Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens) 
o 
Any anti-GD2 therapy within previous 2 weeks 
o 
Craniospinal radiotherapy or MIBG therapy within previous 6 weeks 
o 
Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy) 
o 
Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within 
previous 8 weeks  
o 
Allogeneic stem cell transplant within previous 12 weeks (with absence of active ≥G2 acute GVHD) 
o 
14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial 
• 
Bleeding metastases (participants with CNS metastases can be enrolled as long as the metastases are not 
bleeding). At least 6 months from any ≥G3 haemoptysis or pulmonary haemorrhage  
• 
Use of enzyme inducing anticonvulsants within 72 hours of start of treatment 
• 
Conditions that increase the risk of bevacizumab-related toxicities:  
o 
History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. 
in the absence of therapeutic anticoagulation) 
o 
History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active 
gastrointestinal bleeding within 6 months prior to study enrolment 
o 
Current chronic intestinal inflammatory disease/bowel obstruction 
• 
Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and 
fructose 
• 
Males or females of reproductive potential may not participate unless they agree to use a highly effective 
method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined 
oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the duration of study therapy 
and for up to 6 months after the last dose of trial drugs.  A negative urine or serum pregnancy test must be 
obtained within 72 hours prior to dosing in females who are post-menarche. 
• 
Pregnant or lactating participant 
• 
Live or live-attenuated vaccines given within previous 28 days prior to study enrolment 
• 
Any uncontrolled medical condition that poses an additional risk to the participant 
5. SCREENING AND CONSENT 
5.1 
Participant Identification  
Participants will be identified by clinicians as per local practice, e.g. in multi-disciplinary teams meetings. 
Participants may be referred to trial participating sites by local hospitals for eligibility assessment by Investigators.  
5.2 
Screening 
The majority of the screening tests defined in this protocol are standard practice and can be commenced prior to 
obtaining consent. However, where tests do not form part of standard medical practice for this group of participants, 
at a specific site, consent (see section 5.3) should be obtained prior to these tests being performed.  
Investigators are expected to maintain a Screening/Enrolment Log of all potential participants considered for the 
trial. This Log will include limited information about the potential participant (e.g. date of diagnosis and gender) and 

 
 
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the date and outcome of the screening process (e.g. enrolled into trial, reason for ineligibility or refused to 
participate). 
For participants who appear to meet the criteria for participation in the trial, the Investigator will provide the potential 
participant with the current approved Participant Information Sheet to allow them to make an informed decision 
regarding their participation. If informed consent is given (see Section 5.3), the Investigator will conduct a full 
screening evaluation to ensure that the participant satisfies all inclusion and exclusion criteria (note, participants 
must meet the all the eligibility criteria at the time they are entered into the trial, see sections 4.1 and 4.2). This 
evaluation should be documented in the medical records. A participant who gives written informed consent and who 
satisfies all the inclusion and exclusion criteria may be entered into the trial (see section 6). Note that assessments 
conducted as standard of care do not require trial specific informed consent and may be provided as screening data 
if conducted within the stipulated time period prior to trial entry. Assessments required at screening are listed in the 
flowchart of assessments and detailed in sections 7.2 and 8.2. 
5.3 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent for each participant prior to performing 
any trial related procedure. A Participant/Parent Information Sheet (PIS) is provided to facilitate this process. 
Investigators must ensure that they adequately explain the aim, trial treatment, anticipated benefits and potential 
hazards of taking part in the trial to the participant. The Investigator should also stress that the participant is 
completely free to refuse to take part or withdraw from the trial at any time. The participant should be given ample 
time (e.g. 24 hours) to read the PIS and to discuss their participation with others outside of the site research team. 
The participant must be given an opportunity to ask questions which should be answered to their satisfaction. The 
right of the participant to refuse to participate in the trial without giving a reason must be respected. 
Specific PIS and Informed Consent Forms (ICF’s) are provided for Tier 1 and Tier 2. Country specific PIS are 
provided. 
If the participant, parent or legal guardian expresses an interest in [their child] participating in the trial they should 
be asked to sign and date one copy of the latest approved version of the ICF. The Investigator must then sign and 
date the form. For children under the age of 16, a parent or legal guardian will sign the ICF. Written assent can also 
be obtained from patients under the age of 16 years where possible, using the relevant section on the ICF.  
A copy of the ICF should be given to the participant, a copy should be filed in the hospital notes, and the original 
placed in the Investigator Site File (ISF). Once the participant is entered into the trial the participant’s trial number 
should be entered on the ICF maintained in the ISF. In addition, if the participant has given explicit consent a copy 
of the signed ICF must be sent in the post to the Trials Office for review. 
Details of the informed consent discussions should be recorded in the participant’s medical notes, this should 
include date of, and information regarding, the initial discussion, the date consent was given, with the name of the 
trial and the version number of the PIS and ICF. Throughout the trial the participant should have the opportunity to 
ask questions about the trial and any new information that may be relevant to the participant’s continued 
participation should be shared with them in a timely manner. On occasion it may be necessary to re-consent the 
participant in which case the process above should be followed and the participant’s right to withdraw from the trial 
respected. 
Electronic copies of the approved country-specific PIS and ICF are available and should be printed or photocopied 
onto the headed paper of the local institution. 

 
 
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Details of all participants approached about the trial should be recorded on the Participant Screening/Enrolment 
Log. Where appropriate and with the participant’s prior consent their General Practitioner (GP) should also be 
informed that they are taking part in the trial. A GP Letter is provided electronically for this purpose. 
6. TRIAL ENTRY   
6.1 
Time Frame for Trial Entry 
Participants should be entered into the trial as soon as possible and within a maximum of 4 weeks from 
commencement of screening assessments. Trial treatment should ideally start within one week of trial entry.  
6.2 
Trial Entry Process 
Participants can be entered into the trial once the applicable National Coordinating Centre (NCC) has confirmed 
that all regulatory requirements have been met by the trial site and the site has been activated by the UK 
Coordinating Centre.  
It will be proposed to the participant and/or participant’s parent/guardian to participate in the BEACON2 trial by 
signing the ICF (for either Tier 1 or Tier 2). Once informed consent has been obtained, participants are assessed 
for either Tier 1 participation using Tier 1 screening assessments (see Tier 1 Screening section 8.1) for further 
details) or Tier 2 participation using Tier 2 screening assessments (see Tier 2 Screening section 8.2) for further 
details), depending on the number of relapses of neuroblastoma. Tier 1 is only for first relapse neuroblastoma 
participants and Tier 2 is only for second (and subsequent) relapsed neuroblastoma participants.   
The eligibility of a participant for Tier 1 may be able to be assessed without screening assessments (i.e. based on 
previous treatment and disease history). If the participant is not eligible for Tier 1 (e.g. prior relapse treated with 
chemo-immunotherapy or BIT, or has had more than one relapse), it may be proposed to the participant and/or 
participant’s parent/guardian to participate in the BEACON2 (Tier 2) trial directly. 
The randomisation to Tier 1 or registration to Tier 2 must be performed prior to the commencement of any trial 
treatment. This procedure is outlined in the diagram ( 
Figure 3 – Trial Entry Process) below. 
Participants that experience progression/relapse on Tier 1 may be considered for participation into Tier 2 arms, if 
they have received at least 3 cycles of Tier 1 treatment.  
In case several arms in Tier 2 become available, study participants might be recruited to one specific arm by 
clinician’s choice with approval of the trial CI or clinical coordinator; based on prior therapies or highest expected 
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Figure 3 – Trial Entry Process 
 
 

 
 
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7. TIER 1 (MAIN RANDOMISATION) 
7.1 
Tier 1 Screening 
No trial specific procedure should be carried out prior to signing the Tier 1 Trial Entry consent form for this study 
(see section 5.3). All participants who have been consented as part of screening must undergo the following 
assessments/procedures within 28 days prior to randomisation and as indicated below. 
7.2 
Tier 1 Screening Assessments (Assessment Timepoint A) 
• 
Imaging of measurable or evaluable disease (MRI (preferred) or CT including the brain, MIBG scan (or 
18FDG PET/CT scans if MIBG negative disease) and bilateral bone marrow aspirates and trephines 
(assessed by local morphology)) must have been performed within 4 weeks prior to trial entry and within 6 
weeks prior to starting trial treatment. Screening tumour assessment should be recorded on the Tumour 
Assessment CRF, recording disease as per INRC 2017 (target and non-target lesions), with cross-sectional 
imaging (primary tumour and metastatic soft tissue) mIBG according to the SIOPEN score and bone marrow 
assessment (report of bilateral aspirates and trephines).  
• 
Complete medical history (including past medical history, concurrent medical events and dates of all 
previous anticancer treatment) within 4 weeks prior to trial entry. 
• 
Health-related quality of life (HRQoL) assessment will be performed within 1 week prior to trial entry. 
• 
Full clinical examination (including physical exam, blood pressure, heart rate, temperature, oxygen 
saturation, weight and height) and performance status at screening and within 24hr prior to trial entry.  
• 
Haematology [includes Haemoglobin (Hb), white blood cells (WBC), neutrophil count, lymphocytes and 
platelets] at screening and within 72hr prior to dosing. If more than 72hr elapse from screening to initiation 
of trial therapy, they should be repeated  
• 
Biochemistry (includes sodium, potassium, calcium, urea, creatinine, total protein, albumin, bilirubin, and 
ALT or AST) must be done at screening and within 72hr prior to dosing 
• 
An estimated GFR must be carried out in participants with serum creatinine > 1.5 ULN for age within 7 days 
of randomisation 
• 
A urine (preferred) or serum pregnancy test will be done on females who are post-menarche within 72hr 
prior to cycle 1 dosing.  Results of the tests are needed to determine participant eligibility and testing may 
need to be repeated so that result from the pregnancy test are available for within 72hr before cycle 1 
dosing  
• 
Sampling: 
o 
A blood sample for the molecular monitoring analysis of mRNA (as per BEACON2 Laboratory 
Manual) 
o 
A whole blood sample taken for DNA constitutional analyses at baseline (optional to 
participant/parent) 
o 
A blood sample for exploratory biomarkers should be collected before study drug administration 
o 
Available tumour sample to be identified prior to starting study medications. If a sample is not 
available, the local physician must agree the potential study entry with the Coordinating Sponsor and 
the CI always before starting trial medication. The tumour sample will be shipped on a regular basis 
as arranged with the Sponsor. It is acceptable to share DNA that has already been extracted or raw 
data for those patients that have already been undergone sequencing studies. Where feasible, 
samples from diagnosis and at the time of relapse will be collected. Please see BEACON2 Laboratory 
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• 
Any ongoing adverse events from previous treatment and concomitant medications must be documented 
and continued to be assessed throughout the study. Records of ongoing concomitant medication will not 
be collected on the CRF, but should be available for reporting when an SAE occurs 
7.3 
Tier 1 Randomisation 
Randomisation for Tier 1 of the trial should be performed by sites using the online electronic remote data capture 
system (eRDC). Informed consent should be obtained prior to any trial-related procedures. Once a paper Tier 1 
Eligibility Checklist has been completed, in order to randomise a participant, the online Tier 1 Randomisation Form 
must be completed. All of the required information, including stratification factors, must be available at the time of 
randomisation. 
The following information about minimisation factors will be necessary to randomise a patient: 
• 
Measurable vs evaluable disease 
• 
MYCN amplification / no amplification / unknown 
• 
Prior Immuno-Chemotherapy 
• 
Prior Bevacizumab, Irinotecan and Temozolomide (BIT) treatment 
Randomisation of participants can be achieved by logging on to:  
https://www.cancertrials.bham.ac.uk/CRCTUPortal 
This program will confirm eligibility and allocate treatment via a computerised minimisation algorithm, developed by 
the CRCTU.  
A copy of the Randomisation Confirmation Report and the participant’s Trial number (TNO) should be printed and 
retained in the Investigator Site File (ISF) and participant’s notes. The TNO should be written on the Informed 
Consent Form filed in the ISF and used on all serious adverse event (SAE) forms and correspondence relating to 
that participant. In addition, where possible a copy of the participant’s Informed Consent Form must be sent in the 
post to the National Coordinating Centre Trial Office. 
7.4 
Tier 1 Emergency Randomisation 
In case of any problems with online randomisation, a paper Eligibility Checklist and paper Randomisation Form 
should be completed. These details can be phoned through to the BEACON2- Trial Office at the Cancer Research 
UK Clinical Trials Unit (CRCTU), University of Birmingham, UK, using the number below: 
STUDY ENTRY/ RANDOMISATION 
(09:00 to 17:00 GMT / BST, Monday to Friday) 
 +44 (0)121 414 3799/ (0)121 414 5345 
 

 
 
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• 
*NB- in extreme cases of toxicity, irinotecan may be replaced with topotecan. Refer to 7.5.3 below. 
After six cycles of treatment, local control including surgery and radiotherapy may be used in parallel to trial 
treatment. Trial treatment can be interrupted temporarily to allow for local control. This information will be collected 
in the CRF. 
For patients pursuing other consolidation-type therapies (such as stem cell transplantation), it is acceptable to 
withdraw from BEACON2 trial treatment after 6 cycles. Data about subsequent therapies received before and after 
subsequent progression/relapse will be collected in the CRF.  
Participants should remain admitted as in-patients during the first course. For subsequent courses, institutional 
practice can be applied, and participants can be discharged on ambulatory pumps if clinically well. 
After 12 cycles of treatment, patients will continue to be followed up as specified in protocol section 16. Treatments 
received after trial treatment (before or after developing progressive disease) can follow SIOPEN guidelines and 
the data will be collected in the CRF.  
7.5.3 
Tier 1 IMP Administration 
Dinutuximab beta 
The dose of dinutuximab beta will be 10 mg/m2/day given through a 24-hour infusion for 7 days (days 1-7). In order 
to administer dinutuximab beta in combination with chemotherapy without interruptions of dinutuximab beta 
infusions, it is necessary to have a double access as per routine practice for the administration of chemo-
immunotherapy. 
Bevacizumab 
If allocated to Arm B (BIT) the dose of bevacizumab will be 15 mg/kg given intravenously.  Bevacizumab should be 
administered prior to chemotherapy as per local practice. The total dose will be rounded to the nearest 5mg.   
• 
Bevacizumab MUST not be administered within 48 hours of any minor surgical procedure (e.g. bone 
marrow exam or insertion of central venous access device [CVAD]) or within 2 weeks of major surgery. In 
all cases, the investigator should verify that there are no wound healing complications before the 
administration of bevacizumab. 
• 
In case of severe toxicity related to bevacizumab, the drug MUST be stopped and not dose reduced. See 
Section 11.2 for criteria. In case of a prolonged dose interruption, the local physician will discuss with the 
Coordinating Sponsor and the medical team the appropriateness of re-starting treatment with bevacizumab, 
given that 4 to 6 weeks will be needed to achieve steady-state concentrations again and there is risk of 
subsequent toxicity related to bevacizumab. For those participants that are near completion of the treatment 
course it will be advisable to stop bevacizumab permanently. In case of chemotherapy-related toxicities 
Arm B: 
BIT 
Bevacizumab 15mg/kg iv 
Irinotecan 50mg/m2 iv* 
Temozolomide 100mg/m2 po 
Irinotecan 50mg/m2 iv* 
Temozolomide 100mg/m2 po 
 
 
Day 1 of 
next cycle 
starts 

 
 
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require that cycles of chemotherapy are delayed, the administration of bevacizumab should be kept to 
schedule (e.g. 3-weekly) even if discoordinated with administration of chemotherapy.  
Irinotecan 
The dose of irinotecan will be 50 mg/m²/day. Irinotecan will be given intravenously over 1 hour on days 1-5, one 
hour following the administration of temozolomide. The total administered dose of chemotherapy may be rounded 
up or down to the nearest dose that can be accurately measured. Irinotecan will be administered as per local 
practice. Topotecan - In instances of severe irinotecan-related toxicity 
The dose of topotecan will be 0.75 mg/m2/day. Topotecan will be given intravenously over 30mins on Days 1-5, at 
least one hour following the administration of temozolomide. The administered dose of chemotherapy may be 
rounded up or down to the nearest dose that can be accurately measured. 
Temozolomide 
The dose of temozolomide will be 100 mg/m2/day orally. Where possible, doses will be rounded to the nearest 5mg 
as per the table in Appendix 5 – Temozolomide Dosing. Temozolomide will be administered as per local practice. 
7.5.4 
Tier 1 – Important Administration Information 
The participant’s height and weight (BW) must be measured prior to each cycle of treatment, and BSA should be 
calculated using local institutional procedures. It is important that the same procedure is used throughout the trial.  
Bevacizumab is prescribed per kg. Temozolomide, irinotecan, topotecan and dinutuximab beta are prescribed per 
body surface area (BSA).  
It is recommended that the same dose is given to the participant every cycle, using the doses calculated using the 
screening or Cycle 1 BW and BSA, UNLESS the calculated dose(s) have changed by ≥10% from the values 
obtained at screening/cycle 1. 
If a participant’s BW exceeds that for the 98th centile for their age: 
• 
Bevacizumab doses should be calculated with the weight for the 98th centile 
• 
Irinotecan, temozolomide and dinutuximab beta doses should be calculated using the BSA, using the BW 
for the 98th centile and the participant’s actual height.   
• 
In all cases, the dosing of overweight participants should be discussed and agreed with the Coordinating 
Sponsor before the administration of any IMP.  
For patients with a body weight of ≤10kg, the temozolomide dose will be reduced to 3.3 mg/kg/day, irinotecan to 
1.7 mg/kg/day and topotecan to 0.025 mg/kg/day. There is no planned dose reduction of dinutuximab beta for 
patients that are ≤10 kg. 
7.6 
Tier 1 Treatment Verification 
Verification of dosing is recorded by local practice, i.e. in pharmacy records and/or in participant’s notes. 

 
 
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7.7 
Tier 1 Treatment Breaks and Compensation 
NOTE: The toxicity profiles of dinutuximab beta, bevacizumab, irinotecan, topotecan and temozolomide are 
different. They should be considered separately and any necessary treatment modification to one element of the 
study treatment should not cause a change or delay to the other element. This is particularly important with respect 
to bevacizumab which takes 4 – 6 weeks to achieve steady state levels. Any treatment delay will require steady 
state levels to be re-established. Bevacizumab infusions should be kept at 3 weekly intervals and do not necessarily 
need to be synchronised with irinotecan and temozolomide. Dinutuximab beta infusions should be aligned with the 
start of irinotecan-temozolomide treatment cycles.  
The maximum delay to the administration of chemotherapy due to adverse events is 36 days. The delay may be 
extended over 36 days only if the participant is showing a good response to the treatment and agreement is obtained 
from the Sponsor. 
Refer to Section 11 Dose Modifications for more details. 
8. TIER 2 (DOSE EXPANSION COHORT) 
8.1 
Tier 2 Screening 
No trial specific procedure should be carried out prior to signing the Tier 2 Trial Entry consent form for this study, 
(see section 5.3). All participants who have been consented as part of screening must undergo the following 
assessments/procedures within 28 days prior to registration and as indicated below. 
8.2 
Tier 2 Screening Assessments (Assessment Timepoint A) 
• 
Imaging of measurable or evaluable disease (MRI (preferred) or CT including the brain, MIBG scan (or 18-
FDG PET/CT scans if MIBG negative disease) and bilateral bone marrow aspirates and trephines 
(assessed by local morphology)) must have been performed within 4 weeks prior to trial entry and within 6 
weeks prior to starting trial treatment. Screening tumour assessment should be recorded on the Tumour 
Assessment CRF, recording disease as per INRC 2017 (target and non-target lesions), with cross-sectional 
imaging (primary tumour and metastatic soft tissue), mIBG (or PET/CT if MIBG scan is negative) according 
to the SIOPEN score and bone marrow assessment (report of bilateral aspirates and trephines).  
• 
Complete medical history (including past medical history, concurrent medical events and dates of all 
previous anticancer treatment) within 4 weeks prior to trial entry. 
• 
Full clinical examination (including physical exam, blood pressure, heart rate, temperature, oxygen 
saturation, weight and height) and performance status at screening and within 24hr prior to trial entry.  
• 
Haematology [includes haemoglobin (Hb), white blood cells (WBC), neutrophil count, lymphocytes and 
platelets] at screening and within 72hr prior to dosing. If more than 72hr elapse from screening to initiation 
of trial therapy, they should be repeated  
• 
Biochemistry (includes sodium, potassium, calcium, urea, creatinine, total protein, albumin, bilirubin, and 
ALT or AST) must be done at screening and within 72 hours prior to dosing 
• 
An estimated GFR must be carried out in participants with serum creatinine > 1.5 ULN for age within 7 days 
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• 
A urine (preferred) or serum pregnancy test will be done on girls who are post-menarche within 72hr prior 
to cycle 1 dosing.  Results of the tests are needed to determine participant eligibility and testing may need 
to be repeated so that result from the pregnancy test are available for within 72hr before cycle 1 dosing  
• 
Sampling: 
o 
A blood sample for the molecular monitoring analysis of mRNA (as per BEACON2 Laboratory 
Manual) 
o 
A whole blood sample taken for DNA constitutional analyses at baseline (optional to 
participant/parent) 
o 
A blood sample for exploratory biomarkers should be collected before study drug administration 
o 
Available tumour sample to be identified prior to starting study medications. If a sample is not 
available, the local physician must agree the potential study entry with the Coordinating Sponsor and 
the CI always before starting trial medication. The tumour sample will be shipped on a regular basis 
as arranged with the Sponsor. It is acceptable to share DNA that has already been extracted or raw 
data for those patients that have already been undergone sequencing studies. Where feasible, 
samples from diagnosis and at the time of relapse will be collected. Please see BEACON2 Laboratory 
Manual for further details. 
• 
Any ongoing adverse events from previous treatment and concomitant medications must be documented 
and continued to be assessed throughout the study. Records of ongoing concomitant medication will not 
be collected on the CRF, but should be available for reporting when an SAE occurs 
8.3 
Tier 2 Registration 
Before offering participation on Tier 2, the local team must confirm with the Coordinating Sponsor that a slot is 
available. Refer to Section 2.2 TIER 2 (Dose Expansion Cohort). 
Registration for Tier 2 treatment should be performed by sites using the online electronic remote data capture 
system (eRDC). Informed consent should be obtained prior to any trial-related procedures. Once a paper Tier 2 
Eligibility Checklist has been completed, in order to register a participant, the online Tier 2 Registration Form must 
be completed. All of the required information, including stratification factors, must be available at the time of 
registration. 
Registration of participants can be achieved by logging on to:  
https://www.cancertrials.bham.ac.uk/CRCTUPortal 
A copy of the Registration Confirmation Report and the participant’s Trial Number (TNO) should be printed and 
retained in the Investigator Site File (ISF) and participant’s notes. The TNO should be written on the Informed 
Consent Form filed in the ISF and used on all serious adverse event (SAE) forms and correspondence relating to 
that participant. In addition, where possible a copy of the participant’s Informed Consent Form must be sent in the 
post to the National Coordinating Centre Trial Office. 
8.4 
Emergency Registration 
In case of any problems with online registration, a paper Eligibility Checklist and paper Registration Form should 
be completed. These details can be phoned through to the BEACON2 Trial Office at the Cancer Research UK 
Clinical Trials Unit (CRCTU), University of Birmingham, UK using the numbers below: 
 

 
 
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• 
*NB- in extreme cases of toxicity, irinotecan may be replaced with topotecan. Refer to 8.5.3 below. 
 
After six cycles of treatment, local control including surgery and radiotherapy may be used in parallel to trial 
treatment. Trial treatment can be interrupted temporarily to allow for local control. This information will be collected 
in the CRF. 
For patients pursuing other consolidation-type therapies, it is acceptable to withdraw from BEACON2 trial treatment 
after 6 cycles (4 months). Data about subsequent therapies received before and after subsequent 
progression/relapse will be collected in the CRF. 
Participants should remain admitted as in-patients during the first course. For subsequent courses, institutional 
practice can be applied, and participants can be discharged on ambulatory pumps if clinically well. 
After 12 cycles of treatment, patients will continue to be followed up as specified in protocol section 16. Treatments 
received after trial treatment (before or after developing progressive disease) can follow SIOPEN guidelines and 
will be collected.  
In order to administer dB in combination with chemotherapy without interruptions of dB infusions, it is necessary to 
have a double central access. This can be achieved through a double lumen central line (Hickman or Port-a-Cath) 
or two single lumen central lines (e.g. one Port-a-cath and a PICC line). 
8.5.3 
Tier 2 Administration 
Dinutuximab beta 
The dose of dinutuximab beta will be 10 mg/m2/day given through a 24-hour infusion for 7 days (days 1-7).  
For administration of dbBIT, on day 1 patients should first receive iv bevacizumab first, then followed by the start of 
infusion of dinutuximab beta, and then irinotecan and temozolomide. On the following days (2-7), patients will 
receive a continuous infusion of dinutuximab beta. Irinotecan will be given through a different line without 
interrupting the dinutuximab beta infusion.  
Bevacizumab:    
The dose of bevacizumab will be 15 mg/kg given intravenously. Bevacizumab should be administered prior to 
chemotherapy and as per local practice. The total dose will be rounded to the nearest 5mg.   
• 
Bevacizumab MUST not be administered within 48hr of any minor surgical procedure (e.g. bone marrow 
exam or insertion of central venous access device [CVAD]) or within 2 weeks of major surgery. In all cases, 
the investigator should verify that there are no wound healing complications before the administration of 
bevacizumab. 
• 
In case of severe toxicity related to bevacizumab, the drug MUST be stopped and not dose reduced. See 
section 11.2 for criteria. In case of a prolonged dose interruption, the local physician will discuss with the 
Coordinating Sponsor and the medical team the appropriateness of re-starting treatment with bevacizumab, 
given that 4 to 6 weeks will be needed to achieve steady-state concentrations again and there is risk of 
subsequent toxicity related to bevacizumab. For those participants that are near completion of the treatment 
Temozolomide 100mg/m2 po 
Temozolomide 
100mg/m2/day po 

 
 
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course it will be advisable to stop bevacizumab permanently. In case of chemotherapy-related toxicities 
require that cycles of chemotherapy are delayed, the administration of bevacizumab should be kept to 
schedule (e.g. 3-weekly) even if discoordinated with administration of chemotherapy. 
Irinotecan 
The dose of irinotecan will be 50 mg/m²/day. Irinotecan will be given intravenously over 1 hour on days 1-5, one 
hour following the administration of temozolomide. The total administered dose of chemotherapy may be rounded 
up or down to the nearest dose that can be accurately measured. Irinotecan will be administered as per local 
practice. 
Topotecan - In instances of severe irinotecan-related toxicity 
The dose of topotecan will be 0.75 mg/m2/day. Topotecan will be given intravenously over 30mins on days 1-5, at 
least one hour following the administration of temozolomide. The administered dose of chemotherapy may be 
rounded up or down to the nearest dose that can be accurately measured. 
Temozolomide 
The dose of temozolomide will be 100 mg/m2/day orally. Where possible, doses will be rounded to the nearest 5mg 
as per the table in Appendix 5 – Temozolomide Dosing. Temozolomide will be administered as per local practice. 
8.5.4 
Tier 2 Important Administration Information 
The participant’s height and weight (BW) must be measured prior to each cycle of treatment, and BSA should be 
calculated using local institutional procedures. It is important that the same procedure is used throughout the trial.  
Bevacizumab is prescribed per kg. Dinutuximab beta, irinotecan, topotecan, and temozolomide are prescribed per 
body surface area (BSA).  
It is recommended that the same dose is given to the participant every cycle, using the doses calculated using the 
screening or Cycle 1 BW and BSA, UNLESS the calculated dose(s) have changed by ≥10% from the values 
obtained at screening/cycle 1. 
If a participant’s BW exceeds that for the 98th centile for their age: 
• 
Bevacizumab doses should be calculated with the weight for the 98th centile 
• 
Irinotecan, temozolomide and dinutuximab beta doses should be calculated using the BSA, using the BW 
for the 98th centile and the participant’s actual height.   
• 
In all cases, the dosing of overweight participants should be discussed and agreed with the Coordinating 
Sponsor before the administration of any IMP.  
For patients with a body weight of ≤10kg, the temozolomide dose will be reduced to 3.3 mg/kg/day, irinotecan to 
1.7 mg/kg/day and topotecan to 0.025 mg/kg/day. There is no planned dose reduction of dinutuximab beta for 
patients that are ≤10 kg. 
 

 
 
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8.6 
Tier 2 Treatment Verification 
Verification of dosing is recorded by local practice, i.e. in pharmacy records and/or in participant’s notes. 
8.7 
Tier 2 Treatment Breaks and Compensation 
NOTE: The toxicity profiles of dinutuximab beta, bevacizumab, irinotecan, topotecan, and temozolomide are 
different. They should be considered separately and any necessary treatment modification to one element of the 
study treatment should not cause a change or delay to the other element. This is particularly important with respect 
to bevacizumab which takes 4 – 6 weeks to achieve steady state levels. Any treatment delay will require steady 
state levels to be re-established. Bevacizumab infusions should be kept at 3 weekly intervals and do not necessarily 
need to be synchronised with dinutuximab beta, irinotecan and temozolomide. Dinutuximab beta infusions should 
be aligned with the start of irinotecan-temozolomide treatment cycles. 
The maximum delay to the administration of chemotherapy due to adverse events is 36 days. The delay may be 
extended over 36 days only if the participant is showing a good response to the treatment and agreement is obtained 
from the Sponsor. 
Refer to section 11 Dose Modifications for more details. 
9. ASSESSMENTS 
All participants receiving a single dose or more of study medications will be considered evaluable for toxicity.  Safety 
endpoints include adverse events, clinical examination (including blood pressure, heart rate, temperature, oxygen 
saturation, weight and height) and laboratory tests (haematology, chemistry).  
All study related procedures must be performed at the study site or at accredited centres/laboratories to which the 
study site refers participants for laboratory tests or imaging if these cannot be routinely performed at the study site. 
Laboratory tests and safety assessments as part of standard care can be performed at the participant’s local 
hospital in between cycles, provided they are conducted on time and the local hospital has a procedure to receive 
and review them in a timely manner.  
In the case of laboratory tests, safety assessments and additional investigations not as part of study related 
procedures being performed at the participant’s local hospital, it is the Investigator’s responsibility to ensure he/she 
receives and reviews the results. The results must be recorded on the CRF as required, and the reports from the 
other hospitals must be available for source data verification. Laboratory reference ranges, including effective dates, 
and evidence of laboratory accreditation must be obtained from all laboratories used. It is the Principal Investigator’s 
responsibility at each site to obtain these. 
9.1 
Tumour Assessment 
As per INRC2017, the minimum requirement is a cross sectional image of site of measurable disease by MRI 
(preferred) or CT, performed within 6 weeks prior to receiving the first dose of trial treatment. A scan including the 
brain (either CT or MRI) must also be performed at screening to assess participant’s eligibility with regard to the 
presence of bleeding brain metastases. At baseline, MIBG scans (or 18-FDG PET/CT scan for patients with MIBG 

 
 
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negative disease) and bilateral bone marrow aspirates and trephines are to be done within 6 weeks prior to receiving 
the first dose of trial treatment. Additional investigations of possible metastatic sites should be done upon 
presentation of signs and symptoms. Tumour lesions previously irradiated will be considered measurable only if 
progressing. Scans should be completed up to 7 days prior to cycles 3, 5, 7 and 10, following cycle 12; and at end 
of treatment if the participant discontinues treatment early. A brain CT/MRI must be repeated following cycles 2, 4, 
6, 9 and 12 only if clinically indicated. Tumour assessments do not have to be repeated where the following cycle 
is delayed due to toxicity. Response assessment will be performed with the same modalities used at screening 
(MRI/CT/MIBG/bone marrow histology as appropriate). To ensure comparability, the same scanner, equipment, 
method and technique used during baseline should be consistently used throughout the study. 
Response after 2, 4, 6, 9 and 12 cycles of treatment will be determined for participants with evaluable disease (only 
MIBG avid disease) using a semi-quantitative score (see Appendix 3 - SIOPEN scoring methods for neuroblastoma) 
and the International Neuroblastoma Response Criteria Appendix 2 - Tumour Staging - INRC Classification [2] 
Participants with MIBG negative scans but lesions on 18FDG-PET/CT scans will be evaluated with 18FDG-PET/CT. 
For these patients the number of FDG-avid bone lesions will be recorded and be used as score to calculate the % 
reduction or increase in comparison with baseline. 
Participants who fail treatment (i.e. develop PD) early, prior to response evaluation, will be considered to be non-
responders.  
Response will be categorised as Complete Response (CR), Partial Response (PR), Minor Response (MR), Stable 
Disease (SD), Progressive Disease (PD – including the appearance of new lesions) or Non Evaluable (NE) as per 
INRC 2017.  
For evaluation of bone marrow involvement, bilateral iliac crest bone marrow aspirates and trephines will be 
performed at screening and only be repeated after 2, 4, 6, 9 and 12 courses if positive at screening or clinically 
indicated (until they become negative).  CR in BM will be defined when 2 aspirates and 2 trephines are negative in 
a previously involved BM. PD will be defined as per [55], as either bone marrow without tumour infiltration that 
becomes >5% tumour infiltration on reassessment, or bone marrow with tumour infiltration that increases by >2-
fold and is >20% tumour infiltration on reassessment. The published international guidelines to evaluate response 
in the bone marrow component will be used at the time of the analysis [55]. 
9.2 
Urinalysis 
A Urinalysis test (early morning urine dipstick and/or protein/creatinine ratio) will be performed at screening. For 
participants receiving bevacizumab, this will be repeated within 24 hours prior to each bevacizumab injection and 
the start of each cycle of treatment. This will also be repeated at the end of treatment. If there are signs of proteinuria, 
a sample must be sent for determination of albumin/protein and creatinine in urine, and the albumin or 
protein/creatinine ratio must be calculated. 
9.3 
GFR 
Estimated GFR should be carried out at screening up to 7 days prior to eligibility assessment in participants with a 
level of serum creatinine > 1.5 ULN for age. 

 
 
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9.4 
Haematology and Blood chemistry  
Haematology, biochemistry and clotting blood tests must be done at screening and within 72hr prior to cycle 1 
dosing. Unless required by the investigator, safety tests will not be repeated at cycle 1, day 1 prior to dosing. 
Beginning in cycle 2 and continuing for all subsequent cycles, pre-dose activities can be done within 72hr pre-dose. 
It is recommended that blood counts are monitored weekly for all participants. Additional safety assessments may 
be done according to institutional standard of care. Laboratory tests and clinical visits as part of standard care can 
be performed at the participant’s local hospital, provided they are conducted on time and the local hospital and trial 
site have a procedure to receive and review them timely. Patients should be visited in between cycles as per routine 
practice. These tests must also be performed at end of treatment.  
Haematology includes - haemoglobin (Hb), white blood cells (WBC) with differential count, neutrophils, lymphocytes 
and platelets. Biochemistry includes - sodium, potassium, calcium, urea, creatinine, total protein, albumin, bilirubin, 
and ALT or AST. Clotting includes INR and APTT and should only be performed at baseline and when clinically 
indicated. 
9.5 
Physical examination / symptom assessment  
Performance status will be reported using the Lansky scale for 1-12 year olds and using the Karnofsky scale for 
older participants. Performance status and physical examination (including blood pressure (BP), heart rate (HR), 
temperature, oxygen saturation, weight and height) will be performed at screening/baseline and within 24 hours 
prior to each cycle in all treatment arms. Both examinations will also be performed at the end of treatment visit, and 
at each follow up visit for 2 years. In patients where bevacizumab infusions become not synchronised with 
chemotherapy administration, physical examination will also be performed prior to each injection of bevacizumab. 
A clinical assessment of pupil responses should be conducted before starting each cycle. If there are any concerns 
about vision or pupil responses during treatment or follow up, a referral to an ophthalmologist should be considered. 
Patient’s weight will be measured at screening, on day 1 of each cycle prior to dosing and at the end of treatment. 
Body height will be measured at screening, on day 1 of each cycle prior to dosing and at the end of treatment. After 
end of treatment, weight, and height will be performed at each follow up visit. 
Menstrual status (regularity of menstruation) in females of childbearing potential should be assessed at screening, 
end of treatment and during follow up. For females who are post-menarchal, a urine (preferred) or serum pregnancy 
test will be done at screening (within 72hr of dosing), prior to each treatment cycle  and at end of treatment. If the 
results are inconclusive, a repeat test must be performed using a urine sample. In addition, a pregnancy test will be 
done whenever one menstrual cycle is missing during treatment or a potential pregnancy is suspected. Females 
who become pregnant while on study will be discontinued immediately and the outcome of the pregnancy will be 
followed.  Pregnancy tests may be repeated during study if required by hospital regulations and/or Research Ethics 
Committees (RECs). 
10. SAMPLE COLLECTION 
10.1 Tumour tissue  
Refer to Section 21 Translational Sub-Study. The evaluation of neuroblastoma related biomarkers will be performed 
on samples of tumour tissue collected at the time of diagnosis or during frontline therapy and/or at the time of 

 
 
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11. DOSE MODIFICATIONS 
Participants should be carefully monitored for toxicity. All toxicities will be graded according to version 5.0 of the 
NCI CTCAE. Doses are to be modified based on the most severe toxicity that the participant experiences, related 
or possibly related to the study treatment between each cycle of treatment. Dose adjustments, delays and 
discontinuation should be managed according to local guidelines and at the clinician’s discretion. 
Participants should be assessed for the development of IMP related adverse events prior to each administration.  
The same criteria used at study entry for haematology renal and liver function should be used to start subsequent 
cycles. Day 1 of the next cycle may be delayed for up to 14 days of toxicity.  
Adverse events should be classified according to whether, in the physician’s judgement, these are likely to be 
related to bevacizumab, dinutuximab beta or chemotherapy (irinotecan/topotecan ± temozolomide) toxicity. These 
should be managed separately. 
NOTE: The toxicity profiles of the IMPs are different. They should be considered separately and any necessary 
treatment modification to one element of the study treatment may not need an adjustment or delay to the other 
element.  
The maximum delay to the administration of chemotherapy due to adverse events is 36 days. The delay may be 
extended over 36 days only if the participant is showing a good response to the treatment and agreement is obtained 
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Grade 2 
Pause dinutuximab beta. Restart at 50% if resolves to Grade 1 or less. If not resolved within 
48 hrs then omit from current cycle. If not resolved to Grade 1 by time next cycle due then 
permanently discontinue  
≥Grade 3 
Permanently discontinue dinutuximab beta Consider high dose systemic steroids / IVIG 
(Discuss with the coordinating sponsor and CI) 
Pain 
≥ Grade 3 despite analgesia 
Pause dinutuximab beta infusion, resume at 50% rate once pain controlled. Increase to 100% 
rate as tolerated 
Visual acuity or ocular 
toxicity 
 
Dilated pupils with sluggish responses 
 
Interrupt infusion. Resume at 50% rate once resolves 
Impaired visual accommodation, correctable with eye glasses does NOT need dose 
modification, provided that these toxicities are judged to be tolerable by the responsible 
clinician, as well as the participant and family 
Accommodation disorders and ophthalmoplegia have been described as common Adverse 
Events and do not require any dose modifications 
≥ Grade 3 
Permanently discontinue dinutuximab beta 
Hyponatraemia  
≤ Grade 2 
Supportive measures. Continue 100% infusion rate 
Grade 3 
Continue dinutuximab beta at 100% rate unless symptomatic hyponatraemia in which sodium 
< 125 mmol/L for more than 48 hours despite corrective measures 
Grade 4 (< 120 mmol/l despite appropriate corrective 
measures) 
Permanently discontinue dinutuximab beta 
Dyspnoea 
≤ Grade 2: Oxygen supplementation needed to 
maintain oxygen saturations > 90% 
Regular salbutamol +/- epinephrine nebulisers if bronchospasm or stridor. If saturations not 
maintained then stop dinutuximab beta infusion; restart at 50% rate if symptoms resolve 
(saturations > 90% in air) and then increased to 100% if tolerated. 
Grade 3  
Stop dinutuximab infusion. If symptoms resolve with supportive measures as above, and 
saturations > 90% in air, then restart dinutuximab beta at 50% and then increase to 100% as 
tolerated 
Grade 4 
Permanently discontinue dinutuximab beta 
Cardiac toxicity 
(including tachycardia, 
cardiac failure, left 
ventricular dysfunction 
≥ Grade 3 
Permanently discontinue dinutuximab beta 

 
 
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Grade 4 
Discontinue bevacizumab 
Wound healing complications 
Any grade 
Delay bevacizumab until the wound has satisfactorily healed 
Proteinuria 
Grade 2-3 
Delay bevacizumab until recovery to grade 1   
Grade 4 
Discontinue bevacizumab 
Venous thrombosis/embolism (including 
vascular access device) 
Grade 3  
Delay bevacizumab 
Bevacizumab may be resumed once the participant has been fully anticoagulated and if the participant has 
not experienced a Grade 3 or 4 haemorrhagic event 
Low-molecular-weight heparin should be prescribed and the treatment monitored in compliance with the 
approved product labelling or according to local clinical practice guidelines 
Similarly, for participants on a coumarin derivative or unfractionated heparin, the INR and APPT, 
respectively, should be within therapeutic range. 
Permanently discontinue bevacizumab if the VTE worsens or recurs after resuming therapy 
Any other clinically significant (CTCAE 
Grade 3/4) AEs that, according to the 
physician’s discretion, are not clearly 
associated with chemotherapy and could 
be related to Bevacizumab 
Grade 3 or 4 
Delay bevacizumab until recovery to grade 1 or resolution 
Permanently discontinue bevacizumab for any of the following toxicities: 
Left ventricular systolic dysfunction 
Grade 3 or 4 
Heart failure 
Any grade 
Gastrointestinal (GI) perforation 
Any grade 
Tracheo-oesophageal fistula 
Any grade 
Any non−tracheo-oesophageal fistula 
Grade 4 
Recto-vaginal fistulae 
Grade 3-5 
Proctalgia 
Grade 3-4 
Haemorrhage: Non-pulmonary or non-CNS 
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Elevated ALT, AST, ALP, Bilirubin 
Grade 3 that recovers to grade ≤2 before day 35 
No dose reduction 
 
No dose modification 
No dose modification 
No dose modification 
Elevated ALT, AST, ALP, Bilirubin 
Grade 3 not recovered to grade ≤2 before day 35 
No dose reduction 
 
No dose modification 
2nd occurrence: 
Discontinue study 
treatment 
1st occurrence: Decrease to dose 
level -1 
2nd occurrence: Discontinue study 
treatment 
Elevated ALT, AST, ALP, GGT, Bilirubin 
Grade 4 
No dose reduction 
 
Reduce to 50% for cycle; 
can be increased to 100% 
for subsequent cycles 
providing improved to 
Grade 2 
2nd occurrence: 
Discontinue study 
treatment 
1st occurrence: Decrease to dose 
level -1 
2nd occurrence: Discontinue study 
treatment 
Diarrhoea > 3 days despite maximum Loperamide 
therapy 
 
Grade 3 or 4 
No dose reduction 
For Grade 3 no reduction; 
For Grade 4, pause 
Dinutuximab beta infusion, 
restart infusion when 
symptoms settle. 
1st occurrence: Decrease 
to dose level -1. 
2nd occurrence: Contact 
Coordinating Sponsor 
and consider switch to 
Topotecan. 
No dose reduction 
 
 

 
 
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12.1.3 Growth Factors 
Prophylactic and therapeutic usage of G-CSF should be at the discretion of the treating physician on an individual 
case basis. For patients in Tier 2, prophylactic use of G-CSF is not allowed during cycle 1.  
12.1.4 Fever and neutropenia 
Antibiotics should be administered on the basis of institutional policy. 
12.1.5 Blood products 
Therapeutic use of blood products will be permitted. A platelet count of 50 is required to start each cycle of 
chemotherapy, therefore platelet infusion can occur where clinically indicated. 
12.1.6 Pneumocystis jirovecii pneumonia (PJP) prophylaxis  
PJP prophylaxis is highly recommended for participants receiving temozolomide. Drugs and schedules for PJP 
prophylaxis should be according to institutional policies. 
12.2 Pain management 
It is anticipated that patients receiving dinutuximab beta by the continuous infusion schedule will be able to be 
managed largely on an outpatient patient basis, with oral opioid or non-opioid medication providing adequate pain 
control. However, since neuropathic pain is an anticipated side effect even in a prolonged continuous infusion 
setting, all patients should receive premedication with gabapentin from at least 3 days prior to the start of the 
dinutuximab beta, as well as intravenous morphine prior to and during antibody infusions as required. 
Concomitant standard pain management should be established with or without IV opioid analgesia and should 
follow standard WHO guidelines including medications as follows: 
12.2.1 Gabapentin 
• 
Prior to receiving dinutuximab beta, the patient should be primed with oral gabapentin, starting 3 days prior 
to the start of the dinutuximab beta infusion.  
• 
The recommended oral dose of gabapentin is 10 mg/kg/dose once daily on day 1, increasing to 10 
mg/kg/dose twice daily on day 2 and 10 mg/kg three times a day thereafter.  
• 
Gabapentin may either be stopped at the end of each continuous antibody infusion (and restarted 3 days 
prior to subsequent cycle) or continued throughout cycles and stopped after the end of the last infusion, 
according to local guidelines. 
• 
Maximum single dose for Gabapentin as per institutional guidelines. 

 
 
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12.2.2 Intravenous morphine 
• 
An intravenous opioid (e.g. morphine infusion 0.03 mg/kg/hr or equivalent) should be commenced 1-2 hour 
prior to starting the first dinutuximab beta infusion (Cycle 1). Thereafter, it is recommended to administer a 
continuous morphine (or alternative intravenous opioid at equivalent dose) infusion rate of up to 0.03 
mg/kg/hour on the first day, with additional boluses as required (in accordance with local guidelines).  
• 
Ideally intravenous morphine can be weaned off on a daily basis over the first 5 days (e.g. to 0.02 
mg/kg/hour to 0.01 mg/kg/h to 0.005 mg/kg/hour).  
• 
Boluses can then be given as required either self-administered or nurse administered at 0.02 mg/kg/dose. 
If continuous opioid is required for more than 5 days then the dose should be weaned at the end of treatment 
by 20% each day. It is expected that the IV opioid can be rapidly tapered off, depending on the individual 
patient’s pain tolerance. 
• 
Subsequent cycles may be started with intravenous morphine as above, depending on the amount of opioid 
required in the previous cycle, until a safe and well tolerated out-patient pain management regime is in 
place for the individual patient. 
12.2.3 Oral and transdermal opioids: e.g. oral morphine 
• 
Can be administered at a dose of 0.2 - 0.4 mg/kg every 4-6 hours. It is not advised to use long acting 
morphine in this situation as it takes 48 hours to stabilise the dose and probably is not useful. Oral tramadol 
may be considered once oral morphine is sufficient at lower doses to control pain satisfactorily. Alternatively 
transdermal application of fentanyl patches may be used in centres where fentanyl patches are regularly 
used for pain control. The equivalent transdermal fentanyl dose rate in µg/hr will be calculated from the 
current use of IV morphine according to the manufacturer’s guidelines. This allows for pain management 
during continuous infusion of dinutuximab beta in an outpatient setting. 
12.2.4 Non-steroidal anti-inflammatory drugs (NSAIDs) 
• 
Used as per local guidelines, dosing and availability as a fixed regimen during antibody treatment. 
• 
Paracetamol 
o 
Recommended dosages as per institutional guidelines. 
• 
Ibuprofen 
o 
This is the most widely used NSAID in paediatrics. It is approved from age 6 months onwards and 
has a longer duration of action (6-8 hours). Recommended dosages as per institutional guidelines. 
Ibuprofen should be used according to local clinical practice. Caution must be taken if platelet count 
< 50 x 109/L due to increased risk of bleeding. 
• 
Metamizole 
o 
Because of its spasmolytic properties metamizole is particularly suitable for visceral pain or colicky 
pain. More useful than repeated short infusions, is a long-term infusion with a dosage of 2.5 to 3.0 
mg/kg/h, always with close monitoring of blood pressure values. Metamizole is approved for use from 
the age of three months onwards. A risk assessment for agranulocytosis in children receiving 
metamizole therapy is not possible at present. 
o 
Recommended dosage of Metamizole: 10 mg/kg PO every 6 hours as needed or long-term infusion 
with a dosage of 2.5 to 3.0 mg/kg/h. However, in some European countries, the use of Metamizole is 
not permitted in paediatric patients and this national guidance needs to be respected. 
• 
Other NSAIDs, e.g. Indomethacin or Ketoralac 
o 
May be used as per institutional guidelines, as an alternative to ibuprofen if fever not controlled. 

 
 
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12.2.5 Hyoscine-butyl-bromide or hyoscyamine 
• 
May be used for children for abdominal pain not responding to morphine, as per institutional guidelines. 
13. CONCOMITANT MEDICATION  
Participants must be instructed not to take any additional medications, including over-the-counter (OTC) products 
and herbal remedies, during the study without prior consultation with their doctor (local PI).   
No chemotherapy, hormonal anticancer therapy, or experimental anticancer medications other than those that are 
study-related will be permitted while the participant is receiving study treatment.  
Caution must be taken for participants receiving bevacizumab if intravenous bisphosphonates are given 
simultaneously or sequentially.  
Due to their immunosuppressive activity, concomitant treatment with corticosteroids is not recommended within 2 
weeks prior to the first treatment course until 1 week after the last treatment course with dinutuximab beta, except 
for life-threatening conditions. 
Concomitant use of intravenous immunoglobulins is not recommended as they may interfere with dinutuximab beta-
dependent cellular cytotoxicity.  
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, 
carbamazepine, phenobarbital, phenytoin, apalutamide) of CYP3A4 may alter the metabolism of irinotecan and 
should be avoided. 
Treatment-related adverse events related to concomitant medication should be treated according to local practice.    
Palliative radiotherapy to non-target lesions present at trial entry, or symptomatic target lesions in participants that 
have other target lesions that allow evaluation of response will be permitted. 
Immunisation with live vaccine will not be permitted. All vaccinations (including influenza and covid-19) should be 
avoided during administration of dinutuximab beta until 10 weeks after the last treatment course, due to immune 
stimulation through dinutuximab beta and possible risk for rare neurological toxicities. Live vaccines, in addition to 
prohibition during conduct of the study, must be prohibited for three months after the last dose of chemotherapy. 
14. CONTRACEPTION 
Females of childbearing potential who are sexually active with a non-sterilised male partner and non-sterilised male 
participants with a partner of childbearing potential must use at least one highly effective method of contraception 
(see Table 13) for 6 months after the last dose of Investigational Medicinal Product plus a barrier method of 
contraception, e.g. condom.  Not engaging in sexual activity for the total duration of the drug treatment is acceptable; 
however, periodic abstinence, the rhythm method and the withdrawal method are not acceptable.  

 
 
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Checklist, to document the discussion between site and patient/caregiver, regarding the safe and effective 
administration of oral Temozolomide at home.  
Participants and/or parents must be instructed to return any unused capsules or oral suspension of temozolomide 
if dispensed for home use and the amount of remaining returned IMP will be recorded. Sites should follow their local 
practice for destruction of unused capsules and oral suspension. For more information regarding accountability 
procedures for the supply and administration of medicinal products to participants, please refer to the Pharmacy 
Manual. Copies of master drug accountability logs will be requested by the Trial Office for central monitoring every 
6 months.  
16. 
PARTICIPANT FOLLOW UP 
Participants will be followed up for a minimum of 5 years from the date of registration/randomisation, or until death 
if sooner.  
Follow up visits until progression or relapse occurs will include:  
Three-monthly visits up to 2 years from the end of treatment will include the following assessments: 
• 
Tumour assessment (a minimum of a cross sectional image of site of measurable disease by MRI 
(preferred) or CT and MIBG scans) 
• 
Vital signs and physical exam 
• 
Survival status (including progression) 
• 
Treatments received (if any) 
• 
Additional assessments as per local practice may be included  
Beyond 2 years from end of treatment, follow-up visits will be carried out annually at 3, 4 and 5 years after the 
registration date and will include the following assessments only: 
• 
Survival status 
• 
Treatments received 
• 
Additional assessments as per local practice 
• 
AEs and late effects 
After progression or relapse occurs: 
Follow up visits will be done annually for at least 5 years from the date of registration and will include the following 
assessments only: 
• 
Survival status   
• 
AEs and late effects (including the occurrence of second malignant neoplasms (SMN)) 
• 
Treatments received  
• 
Additional assessments as per local practice may be included. 
Laboratory tests and safety assessments as part of standard care can be performed at the participant’s local 
hospital at follow up time-points, provided they are conducted on time and the local hospital has a procedure to 

 
 
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receive and review them in a timely manner. It is the Investigator’s responsibility to ensure he/she receives and 
reviews the results. The results must be recorded on the CRF as required, and the reports from the other hospitals 
must be available for source data verification. Laboratory reference ranges, including effective dates, and evidence 
of laboratory accreditation must be obtained from all laboratories used. It is the Principal Investigator’s responsibility 
at each site to obtain these. 
Additional follow up visits will be scheduled as needed, to monitor any sustained unresolved, treatment emergent 
adverse events.     
In the event of progression/relapse, the type of progression/relapse will be recorded (local/metastatic/combined) as 
well as all treatment that is started after trial participation. 
17. TRIAL TREATMENT DISCONTINUATION AND PARTICIPANT WITHDRAWAL   
17.1 Treatment Discontinuation 
Participants should discontinue trial treatment in the following circumstances: 
• 
In the event of progression (as per INRC 2017) 
• 
In the event of unacceptable toxicity (see section 11) 
• 
At the request of the participant (see section 17.2 Participant Withdrawal) 
In the event of a female participant becoming pregnant (see section 1.2.4.2 and section 18.1.6)A Treatment 
Discontinuation Form should be completed to document the reason for treatment discontinuation. Follow up visits 
continue as scheduled, unless the participant withdraws from data collection (see section 17.2). 
17.2 Participant Withdrawal  
Participants may withdraw from study treatment at any time at their own request or at the request of their parents 
(if participant under 16 years of age), or they may stop study treatment at any time at the discretion of the treating 
Investigator or CI for safety, behavioural, or administrative reasons. If a participant does not return for a scheduled 
visit, every effort should be made to contact the participant. In any circumstance, every effort should be made to 
document participant outcome where possible.   
The Investigator should: 
• 
Enquire about the reason for withdrawal 
• 
Request the participant return for a final visit, if applicable 
• 
Follow up with the participant regarding any unresolved adverse events 
• 
Perform a physical exam on the participant (including height, weight, oxygen saturation and blood 
pressure/pulse) 
• 
Arrange for a tumour assessment and all safety labs (full blood count and biochemistry) to be collected  
Participants who withdraw from trial treatment will continue to be followed up as per the protocol for at least 5 years 
after registration. 

 
 
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Participants/parents/legal guardians may withdraw consent at any time during the trial.  The details of the withdrawal 
should be clearly documented and communicated to the BEACON2 Trial Office. 
There are three types of withdrawal as detailed below: 
• 
Participant or their parent(s)/legal guardian would like to withdraw the participant from the trial, but is willing 
for the participant to be followed-up according to the trial schedule (follow-up data can be collected and 
used in the trial analysis) 
• 
Participant or their parent(s)/legal guardian does not wish for the participant to attend trial follow-up visits 
but is willing for the participant to be followed-up at standard clinic visits (follow-up data can be collected at 
standard clinic visits and used in the trial analysis) 
• 
Participant or their parent(s)/legal guardian is not willing for the participant to be followed up for trial 
purposes at any further visits (any data collected prior to the withdrawal of consent will be used in the trial 
analysis) 
The following should be clearly documented in the medical notes:  
• 
The date the participant or their parent(s)/legal guardian withdraw consent  
• 
The reason, if given 
• 
Type of withdrawal 
If a participant withdraws from the trial, please complete and return a Treatment Discontinuation Form and a 
Withdrawal of Consent Form if applicable. 
18. ADVERSE EVENT REPORTING 
The collection and reporting of Adverse Events (AEs) will be in accordance with the Medicines for Human Use 
Clinical Trials Regulations 2004 and its subsequent amendments. Definitions of different types of AE are listed in 
Appendix 7. The Investigator should assess the seriousness and causality (relatedness) of all AEs experienced by 
the participant (this should be documented in the source data) with reference to the Summary of Product 
Characteristics or Investigator Brochure as appropriate.  
18.1 Reporting Requirements 
18.1.1 Tier 1 Adverse Events 
AEs (see Appendix 7 - Definition of Adverse Events for definition) are commonly encountered in participants 
receiving adjuvant chemotherapy. As the safety profiles of the Investigational Medicinal Products used in this trial 
are well characterised, only Grade 3 and Grade 4 (by CTCAE v5.0) AEs experienced during treatment will be 
reported.  
An abnormal laboratory value should only be reported if it: 
• 
Results in participant early discontinuation from the study treatment 

 
 
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• 
Requires treatment, modification or interruption of dose, or any other therapeutic intervention (including 
blood product transfusion), or is judged to be of significant clinical importance 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or syndrome 
should be recorded. 
18.1.2 Tier 2 Adverse Events 
All medical occurrences which meet the definition of an AE (see Appendix 7 - Definition of Adverse Events for 
definition) should be reported. Please note this includes abnormal laboratory findings. 
18.1.3 Serious Adverse Advents 
Investigators should report AEs that meet the definition of an SAE (see Appendix 7 - Definition of Adverse Events 
for definition) and are not excluded from the reporting process as described below. 
18.1.4 Events That Do Not Require Reporting on a Serious Adverse Event Form 
The following events should not be reported on an SAE Form. 
Hospitalisations for: 
• 
Protocol defined treatment 
• 
Pre-planned elective procedures unless the condition worsens 
• 
Treatment for progression of the participant’s cancer 
• 
Progression or death as a result of the participant’s cancer, as this information is captured elsewhere on 
the Case Report Form 
• 
Events that do not require expedited (immediate) reporting which will be reported on an Expected Serious 
Adverse Reaction Form 
18.1.5 Expected Serious Adverse Reactions 
Participants receiving adjuvant chemotherapy may require admission to hospital for appropriate medical 
intervention following development of some of the more severe known side effects of treatment. For this reason the 
following SAEs do not require expedited (immediate) reporting by site and are not regarded as unexpected for the 
purpose of this trial:  
• 
Admissions to control nausea and vomiting unless the condition is life threatening or proves fatal 
• 
Admissions 
for 
supportive 
treatment 
(i.e. 
transfusions 
or 
blood 
products 
for 
anaemia/ 
thrombocytopenia/severe infections, management of diarrhoea, stoma site (line) infections) during an 
episode of myelosuppression, unless this proves fatal or requires admission to a high dependency or 
intensive care facility 
• 
Uncomplicated febrile neutropenia 
• 
Admission for transfusion or allergic reaction that resolves within 24h (unless the condition is life threatening 
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• 
Prolongation of inpatient hospitalisation due to fever related to dinutuximab beta (unless the condition is life 
threatening or proves fatal) 
 
An Expected Serious Adverse Reaction Form can be completed for these specific events instead of a Serious 
Adverse Event Form. However, if there is any doubt over whether an event meets the relevant definition above, a 
Serious Adverse Event Form should be completed.  
18.1.6 Monitoring pregnancies for potential Serious Adverse Events 
It is important to monitor the outcome of pregnancies of participants in order to provide SAE data on congenital 
anomalies or birth defects. 
If a female participant becomes pregnant during the course of the trial, trial treatment should be discontinued 
immediately.  
In the event that a participant or their partner becomes pregnant during the course of the trial and for six months 
after last dose of study drug, please complete a Pregnancy Notification Form (providing the participant’s details) 
and return to the Trials Office as soon as possible. If it is the participant who is pregnant, provide outcome data on 
a follow-up Pregnancy Notification Form. Where the participant’s partner is pregnant consent must first be obtained 
and the participant should be given a pregnancy release of information form to give to their partner. If the partner is 
happy to provide information on the outcome of their pregnancy, they should sign the pregnancy release of 
information form. Once consent has been obtained provide details of the outcome of the pregnancy on a follow-up 
Pregnancy Notification Form. If appropriate also complete an SAE Form as detailed below. 
18.1.7 Post-trial Suspected Unexpected Serious Adverse Reactions  
Serious Adverse Events that are judged to be at least possibly related to the Investigational Medicinal Product and 
are unexpected must still be reported in an expedited manner irrespective of how long after Investigational Medicinal 
Product administration the reaction occurred. 
18.1.8 Overdose 
An overdose is defined as a subject receiving a dose of Investigational Medicinal Product(s) in excess of 20% of 
the planned trial treatment within the current cycle. 
Any overdose with or without associated Adverse Events/Serious Adverse Events, is required to be reported within 
24hours of first knowledge of the event to the Trial Office. 
If the overdose results in an Adverse Event, this must also be recorded on an Adverse Event Form.  
18.1.9 Medication Error 
A medication error is an unintended failure or mistake in the treatment of a participant that either causes harm or 
has the potential to cause harm.  

 
 
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A medication error is a human or process related failure while the drug is under control of the trial site staff or 
participant. 
Examples of events to be reported as medication errors include: 
• 
Dispensing error e.g., medication prepared incorrectly  
• 
Drug not administered or taken as indicated, e.g., wrong site of administration, tablet crushed instead of 
taken whole 
• 
Wrong participant received the medication  
• 
Wrong drug administered to participant  
Examples of events that do not require reporting as medication errors include: 
• 
Participant accidentally missed drug dose(s) e.g., forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
Medication errors are not regarded as an Adverse Event, but an Adverse Event may occur as a consequence of 
the medication error.  
Any medication error with or without associated Adverse Event/Serious Adverse Event is required to be reported 
within 24hours of first knowledge of the event to the Trial Office. 
If the medication error results in an Adverse Event, this must also be recorded on an Adverse Event Form.  
18.2 Reporting period 
Details of all AEs (except those listed above) will be documented and reported from the date of commencement of 
protocol defined treatment until 30 days after the administration of the last trial treatment.  
SAEs that are judged to be at least possibly related to the IMPs must still be reported in an expedited manner 
irrespective of how long after IMP administration the reaction occurred. 
18.3 Reporting Procedure 
18.3.1 Site 
Adverse Events 
For more detailed instructions on Adverse Event reporting refer to the Adverse Event Form Completion Guidelines 
contained in section 6 of the Investigator Site File  
Adverse Events (as defined in Appendix 7) should be reported on an Adverse Event Form and where applicable on 
a Serious Adverse Event Form. Serious adverse events which have been identified in the protocol as not requiring 
immediate reporting (i.e. events listed in section 18.1.4) should be recorded on the Adverse Event Form instead.  
An Adverse Event Form should be completed at each cycle. AEs will be reviewed using the Common Terminology 
Criteria for Adverse Events (CTCAE), version 5.0 (see Appendix 8 - Common Toxicity Criteria Gradings). Any AEs 

 
 
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experienced by the participant but not included in the CTCAE should be graded by an Investigator and recorded on 
the AE Form using a scale of (1) mild, (2) moderate or (3) severe. For each sign/symptom, the highest grade 
observed since the last visit should be recorded. 
Serious Adverse Events 
For more detailed instructions on Serious Adverse Event reporting refer to the Serious Adverse Event Form 
Completion Guidelines contained in section 5 of the Investigator Site File.  
Adverse Events defined as serious and that require reporting as a Serious Adverse Event (excluding events listed 
in section 18.1.4) should be reported on a Serious Adverse Event Form.  When completing the form, the Investigator 
will be asked to define the causality and the severity of the Adverse Event which should be documented using the 
Common Terminology Criteria for Adverse Events version 5.0.  
The form should be emailed to the Trial Office as soon as possible and no later than 24 hours after first becoming 
aware of the event. 
Email Serious Adverse Event Form to: 
Reg@trials.bham.ac.uk   
CC to beacon2@trials.bham.ac.uk  
Include “BEACON2 SAE” in the subject line 
On receipt the Trial Office will allocate each Serious Adverse Event a unique reference number. The site will be 
informed of the Serious Adverse Event reference number in an email acknowledging receipt of the event. If 
confirmation of receipt is not received within 1 working day please contact the Trial Office. The Serious Adverse 
Event reference number should be quoted on all correspondence and follow-up reports regarding the Serious 
Adverse Event. The email from the Trial Office acknowledging receipt should be filed with the Serious Adverse 
Event Form in the Investigator Site File.  
For Serious Adverse Event Forms completed by someone other than the Investigator, the Investigator will be 
required to countersign the original SAE Form to confirm agreement with the causality and severity assessments.  
The form should then be returned to the Trial Office and a copy kept in the Investigator Site File. 
Investigators should also report Serious Adverse Events to their own Trust in accordance with local practice. 
Provision of follow-up information 
Participants should be followed up until resolution or stabilisation of the event. Follow-up information should be 
provided on a new SAE Form (refer to the SAE Form Completion Guidelines for further information).  
18.3.2 BEACON2 Trials Office 
On receipt of an SAE Form seriousness and causality will be determined independently by a Clinical Coordinator. 
An SAE judged by the Investigator or Clinical Coordinator to have a reasonable causal relationship with the trial 
medication will be regarded as a Serious Adverse Reaction (SAR). The Clinical Coordinator will also assess all 
SARs for expectedness. If the event meets the definition of a SAR that is unexpected (i.e. is not defined in the 
Summary of Product Characteristics, or Investigator Brochure as applicable) it will be classified as a Suspected 
Unexpected Serious Adverse Reaction (SUSAR). 

 
 
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18.3.3 Reporting to the Competent Authority and main Research Ethics Committee 
Suspected Unexpected Serious Adverse Reactions 
Individual events categorised as SUSARs will be reported to the EudraVigilance Clinical Trial Module (EVCTM) and 
to each non-EU country as required. Events will be reported in accordance within the regulatory specified time 
frame: 
• 
Fatal or life threatening SUSARs within a maximum of 7 days with a detailed follow-up report within an 
additional 8 days 
• 
All other SUSARs within a maximum of 15 days 
Serious Adverse Reactions 
The UK Coordinating Centre will produce a Development Safety Update Report (including Serious Adverse 
Reactions and Suspected Unexpected Serious Adverse Events) annually from the date of the first Clinical Trial 
Authorisation received for the trial in any country until the submission of the End of Trial Declaration. The National 
Coordinating Centres will be provided with a copy of this report and where contractually required to do so, will report 
to the relevant Competent Authority and Research Ethics Committee. 
Adverse Events 
Details of all Adverse Events will be reported to the Competent Authority on request. 
Other safety issues identified during the course of the trial 
The Competent Authority and Research Ethics Committee(s) will be notified immediately if a significant safety issue 
is identified during the course of the trial.  
18.3.4 Investigators 
Details of all Suspected Unexpected Serious Adverse Events and any other safety issue which arises during the 
course of the trial will be reported to Principal Investigators. A copy of any such correspondence should be filed in 
the Investigator Site File.  
18.3.5 Data Monitoring Committee  
The independent Data Monitoring Committee will review all Serious Adverse Events.  
18.3.6 Manufacturer of Investigational Medicinal Product 
All Serious Adverse Events will be reported to Recordati Rare Diseases Recordati Group as manufacturer of the 
dinutuximab beta by the Coordinating Sponsor within 7 days by email.  

 
 
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19. CENTRAL REVIEW PROCESSES  
As an additional measure of quality control, at least one independent blinded radiologist and at least one nuclear 
medicine physician will review all CT, MRI, MIBG and PET/CT scans at baseline and at tumour assessment time-
points (Post cycle 2, 4, 6, 9 12 and EOT), for all participants. Further details to be provided by the Trial Office. 
 
20. QUALITY OF LIFE STUDY  
20.1 Purpose of Quality of Life  
HRQOL is a multi-dimensional concept commonly used to examine the impact of health status on quality of life. 
There is an increasing recognition in oncology of the importance of improving patients’ QOL throughout the disease 
course [56, 57]. Studies conducted with paediatric population suggest that HRQOL in children during cancer therapy 
is significantly lower than in the healthy population [58, 59]. Also, association between intensity of treatment and 
child-reported HRQOL has been assessed: high-risk children reported poorer QOL than children with a low or 
moderate risk [60]. Therefore, there is a growing acclaim in paediatric cancer research of the importance of 
improving patients' QOL throughout the new therapies [61]. Key aspects of the HRQOL in paediatric oncology 
include the child's physical (physical functioning, symptoms), psychological (body image, self-esteem, distress, 
behavioural problems, cognitive functioning), and social health (interpersonal relationships, social functioning, and 
general health perceptions [62]. Parents and patient’s family members are also affected by the cancer diagnosis 
and treatment and may also be instrumental in the management of the disease [63-65]. Hence, optimal assessment 
of how children’s health affects their families is of both clinical and research importance. 
As most of these aspects are subjective, both the Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) have recommended the use of patient-reported outcome (PRO) measures to support labelling claims 
in oncology [66, 67]. In addition, paediatric HRQOL measurement instruments must be sensitive to cognitive 
development and integrate both child self-report and parent/guardian proxy-report to reflect their potentially unique 
perspectives. With this goal in mind, in this study, HRQOL is evaluated as a secondary objective to determine the 
impact of each treatment arm in patient’s and family’s QOL.  
20.2 Questionnaires 
HRQOL will be assessed with the Pediatric Quality of Life Inventory (PedsQL) 3.0 Cancer Module [68] and with the 
PedsQL Family Impact Module [69].  
The PedsQL 3.0 Cancer Module is a modular instrument designed to measure pediatric cancer specific HRQOL in 
children, adolescents,young people and adults. The PedsQL 3.0 Cancer Module has been translated in over 49 
languages according to a standardized translation procedure.  
The questionnaires comprise parallel child self-report and parent proxy-report formats. Child self-report includes 
ages 5–7 years (young child), ages 8–12 years (child), ages 13–18 years (adolescent), ages 18-25 (young people) 
and 26+ years (adults). Parent proxy-report includes ages 2–4 years (toddler), 5–7 years (young child), 8–12 years 

 
 
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(child), and 13–18 years (adolescent). The parent proxy-report forms are designed to assess the parent's/guardian’s 
perceptions of their child's HRQOL. The items for each of the forms are essentially the same, differing in 
developmentally proper language, and first or third person tense. The 27-item multidimensional PedsQL 3.0 Cancer 
Module encompasses 8 scales: 1) pain and hurt (2 items), 2) nausea (5 items), 3) procedural anxiety (3 items), 4) 
treatment anxiety (3 items), 5) worry (3 items), 6) cognitive problems (5 items), 7) perceived physical appearance 
(3 items), and 8) communication (3 items).   
The instructions ask how much of a problem each item has been during the past 1 month. A 5-point Likert response 
scale is utilized across child self-report for ages 8–18+ years and parent proxy-report (0 = never a problem; 1 = 
almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem). To further 
increase the ease of use for the young child self-report (ages 5–7 years), the Likert scale is reworded and simplified 
to a 3-point scale (0 = not at all a problem; 2 = sometimes a problem; 4 = a lot of a problem), with each response 
choice anchored to a happy to sad faces scale. Parent proxy-report also includes the toddler age range (ages 2–4 
years), which does not include a self-report form given developmental limitations on self-report for children younger 
than 5 years of age and includes only 3 items for the school functioning scale.  
Items are reverse-scored and linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that 
higher PedsQL 3.0 scores indicate better HRQOL. Scale scores are computed as the sum of the items divided by 
the number of items answered. If more than 50% of the items in the scale are missing, the scale score is not 
computed.  
The PedsQL Family Impact Module [69] was designed to measure the impact of pediatric chronic health conditions 
on parents and the family. Despite it is not specific to evaluate QOL in parents of children and AYA with cancer, the 
questionnaire has demonstrated reliability and validity in families with children with complex chronic health 
conditions. Implemented as a complement to the PedsQL Cancer Module, the PedsQL Family Impact Module gives 
a quantitative indicator of the parent’s self-reported HRQOL and family functioning as a result of their child’s cancer 
disease. The PedsQL Family Impact Module has been translated in over 20 languages according to a standardized 
translation procedure. 
The PedsQL Family Impact Module measures parent/guardian self-reported physical, emotional, social, and 
cognitive functioning, communication, and worry. The 36-item PedsQL Family Impact Module Scales encompass 6 
scales measuring parent self-reported functioning: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 
items), 3) Social Functioning (4 items), 4) Cognitive Functioning (5 items), 5) Communication (3 items), 6) Worry (5 
items), and 2 scales measuring parent/guardian reported family functioning; 7) Daily Activities (3 items) and 8) 
Family Relationships (5 items).  
The scale has five response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding 
to scores of 100, 75, 50, 25 and 0). Regarding the interpretation of the scale, higher scores indicate better 
functioning (less negative impact). The PedsQL Family Impact Module Total Scale Score is calculated as the sum 
of the 36 item scores divided by the number of items answered. If more than 50% of the items in the scale are 
missing, the scale score is not computed. 
20.3 Target Accrual 
HRQOL questionnaires will be performed in all trial participants.  

 
 
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20.4 Time Points and Procedure 
Questionnaires will be filled at baseline (within 7 days before treatment initiation), at assessment time-points (cycles 
2, 4, 6) and at EOT visit (21 days after cycle 12 dose or last dose given), according to Table 1 - Schedule of Events. 
HRQOL data must be collected regardless of the participant’s progression status and treatment completion.  
Sites will be provided with a supply of the HRQOL questionnaires at site initiation. Questionnaires must be filled out 
on paper at the hospital when patients come for the scheduled visit according to the “PedsQL™ Administration 
Guidelines” (see Appendix 9 – PedsQL™ Administration Guidelines). The questionnaire will be handed out to the 
patients by the investigator or a study nurse before seeing the doctor for clinical evaluations. Patients should 
complete the questionnaires by themselves in their own language during the visit as completely and accurately as 
possible. It is recommended that a key person at each centre should be responsible for questionnaire data collection 
in order to optimize the compliance of the patient and to ensure the completeness of the data. 
Data will be entered onto the eCRF database.  
21. TRANSLATIONAL SUB-STUDY/ BIOLOGICAL STUDIES  
21.1 Purpose of Translational Sub-study 
In relapsed neuroblastoma, biological studies of the primary tumour, metastatic sites and liquid biopsies for analysis 
of prognostic and especially predictive biomarkers are of utmost importance. These studies require rigorous sample 
collections, according to well-defined standard operating procedures (SOPs).  
• 
Genome and expression profile of DNA and RNA isolated from tumour at relapse whenever possible; 
constitutional DNA will be required for genomic studies.  
21.1.1 Primary tumour tissue 
Samples of tumour tissue collected at the time of diagnosis, during frontline therapy and/or at the time of relapse 
(where possible) will be collected for genome and expression profile of DNA and RNA. This sample is mandatory 
for study entry; if no tumour or subsequent molecular profiling is available this will be discussed with the 
Coordinating Sponsor and the Chief Investigator before study entry. 
Whenever possible, analysis of tumour tissue of the primary tumour, or a metastatic site, obtained at relapse, should 
be performed: following tissue sampling both frozen tumour tissue and formalin fixed paraffin embedded tumour 
tissue are to be collected at diagnosis according to local SOPs and processes. 
In situations where no tumour tissue can be obtained (due to the clinical situation of the patient, or sampling 
difficulties, or because no primary was identified) the following analyses may be done on a representative metastatic 
sample (invaded bone marrow, invaded lymph node), possibly following enrichment techniques. If neither a primary 
tumour nor a metastatic site can be obtained at relapse, a blood sample for analysis of circulating tumour DNA 
should be obtained at study entry and at all protocol-defined timepoints.  
The following investigations will be performed for all patients on tumour tissue:  

 
 
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Genetic analyses: 
• 
MYCN copy number status (clinical decision making at diagnosis) 
The following genetic analyses are highly recommended: 
• 
Whole exome or whole genome sequencing (> 100 x) of paired tumour and germline material should be 
performed for calling of SNVs/mutations, structural variations, and overall copy number profile and indels. 
RNAseq should be performed for expression profiling. Results should be analysed and reviewed by a 
molecular biologist, with a report highlighting clinically relevant biological findings. Alternatively, NGS panel 
sequencing (minimal consensus of 17 genes, including ALK) and Genomic copy number profile (high 
resolution aCGH and/or SNPa and/or lcWGS) can be applied. 
• 
Telomere maintenance mechanism and ALT status.  
• 
The report of the molecular profile should be recorded as in ongoing precision medicine programs [70] 
• 
It is mandatory to analyse the ALK copy number status (amplified yes/no) and mutation status (mutated 
yes/no) on a new sample obtained at relapse/progression (primary tumour and/or metastatic site). If no 
tumour sample can be obtained at relapse/progression, the ALK status may be determined on circulating 
tumour DNA extracted from blood or bone marrow plasma.   
21.1.2 Liquid biopsy samples  
Blood samples for the analysis of circulating biomarkers and immunological studies should be collected from all 
patients at the same time points as those required for standard clinical care: 
• 
Baseline 
• 
Post cycles 2, 4, 6, 9 
• 
Post cycle 12 or End of Treatment 
Core studies include analysis of circulating RNAs [71, 72] and DNAs [73-75]. 
Constitutional DNA taken once at any time will be required for pharmacogenetic studies and is optional. 
Bone marrow aspirate taken at baseline will be required for circulating biomarker analysis and is optional. 
21.2 Samples to be Collected 
Quality control of samples for diagnostic and research procedures and the collaboration within the SIOPEN 
network are of high importance. 
21.2.1 Tumour tissue 
For the Tumour tissue samples, FFPE blocks, unstained slides or frozen samples are required from diagnosis, and 
from relapse if available. Analysis includes, but is not limited to, MYCN, copy number profile or NGS panel 
sequencing, telomere maintenance mechanism and/or ALT status. Samples should be sent to a central accredited 
laboratory identified by the country National Coordinating Centre and Coordinating Sponsor. 

 
 
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As a clinically decision making biomarker, ALK amplification/mutation status on a sample obtained at 
relapse/progression should be determined. 
21.2.2 Blood samples for circulating Biomarker Analysis  
Blood for analysis of circulating biomarkers and circulating tumour cells should be collected at time points: Baseline, 
post cycle 2, 4, 6, 9 and 12, and end of treatment (if not received 12 cycles). Samples should be sent to a central 
accredited laboratory identified by the country National Coordinating Centre and Coordinating Sponsor. Please see 
BEACON2 Laboratory manual. The maximum volume of blood (including the routine blood specimen collected for 
clinical care) will not exceed the maximum according to body weight, as indicated in the Guidelines for Paediatric 
Blood Volume for Research Purposes/HREC [76] and guidance by the European Medicines Agency (EMA 2008). 
The following samples should be collected: 
• 
Blood samples for CTC and circulating biomarker studies 
21.2.3 OPTIONAL - Bone marrow samples for circulating Biomarker Analysis  
Bone marrow aspirates for analysis of circulating biomarkers and characterisation of circulating tumour cells may 
be collected at baseline/entry into the study. 
The following samples should be collected: 
• 
Bone marrow samples for CTC and circulating biomarker studies 
• 
Bone marrow samples for characterisation of neuroblastoma cells and the tumour microenvironment and 
preclinical model development 
21.2.4 OPTIONAL - Blood plasma for constitutional DNA  
Blood plasma should be collected at any time point for constitutional DNA analysis and pharmacogenomics, where 
patient/parent guardian consent is obtained. Samples should be sent to a central accredited laboratory identified 
by the country National Coordinating Centre and Coordinating Sponsor. 
21.2.5 Where to send the samples 
Quality control of samples for diagnostic and research procedures and the collaboration within the SIOPEN network 
are of high importance. Please refer to the BEACON2 Laboratory Manual for details on sample preparation, sample 
conservation, shipping and reference laboratories. 
21.3 End of Trial Arrangements 
Any biological samples remaining at the end of the trial will be transferred to a central tissue bank identified by the 
country National Coordinating Centre and Coordinating Sponsor or made available to another approved ethical 
project. 

 
 
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Arm C dbBIT Treatment 
Form  
Details of dbBIT Treatment  
Within 2 weeks of 
treatment visit  
Adverse Events Form  
Details of  AEs experienced  
To be completed at all 
treatment cycles, within 1 
month of visit   
HRQOL Forms 
(Participant/Parent-Proxy) 
Details of participants quality of life responses 
To be completed at 
baseline, Post cycles 2, 
4, 6, and EOT 
Tumour Assessment 
Form  - Baseline 
Details of tumour assessment measured by 
MRI/CT/MIBG/bone marrow histology  
To be completed at 
baseline within 1 month 
of visit  
Tumour Assessment 
Form - Response 
Details of tumour assessment and response 
measured by MRI/CT/MIBG/bone marrow 
histology 
To be completed Post 
cycles 2, 4, 6, 9, 12 and 
EOT 
Follow up Form – 3m-
24m 
Details follow up visit, disease status, physical 
examination details, performance status, 
laboratory results 
(haematology/biochemistry/clotting if clinically 
indicated), Urinalysis test results. 
To be completed at all 
follow-up visits up until 2 
years post end of 
treatment date, within 1 
month of visit  
Follow up Form – 3y-5y 
Details follow up visit, disease status, laboratory 
results (haematology/biochemistry/clotting if 
clinically indicated), Urinalysis test results. 
To be completed at 
follow-up visits year 3, 4 
and 5, within 1 month of 
visit  
Disease and Medical 
History Form 
Details of first diagnosis, details of disease at time 
of randomisation/registration, details of prior 
neuroblastoma treatment, none-neuroblastoma 
medical history. 
Within 1 month of 
registration/ 
randomisation 
End of Treatment Form 
Treatment details, physical examination details, 
performance status, laboratory results 
(haematology/biochemistry/clotting if clinically 
indicated), urinalysis test results. 
When patient has 
finished course of 
protocol defined 
treatment or as soon as 
possible if patient 
discontinues early 
Pre Cycle Form 
Physical examination details, performance status, 
laboratory results 
(haematology/biochemistry/clotting if clinically 
indicated), urinalysis test results. 
To be completed prior to 
starting cycles 2, 3, 4, 5, 
6, 7, 8, 9, 10, 11, and 12. 

 
 
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A master copy of the paper Case Report Form is available in the Investigator Site File. If the electronic Case Report 
Form system is unavailable for any length of time the Trial Office may instruct sites to complete the paper Case 
Report Form to ensure timely monitoring of participant data. These forms may be entered onto the system by the 
Trial Office.  
For paper SAE and expected SAR Forms, the completed originals should be sent to the Trial Office and a copy 
filed in the Investigator Site File.  
Entries on the paper Case Report Form should be made in ballpoint pen, in blue or black ink, and must be legible. 
Any errors should be crossed out with a single stroke, the correction inserted and the change initialled and dated. 
If it is not obvious why a change has been made, an explanation should be written next to the change.  
Data reported on the Case Report Form should be consistent with the source data or the discrepancies should be 
explained. If information is not known, this must be clearly indicated on the form. All missing and ambiguous data 
will be queried. All sections are to be completed before returning. 
In all cases it remains the responsibility of the Investigator to ensure that the Case Report Form has been completed 
correctly and that the data are accurate.  
The Case Report Form may be amended from time to time by the Trial Office throughout the duration of the trial. 
Whilst this will not constitute a protocol amendment, new versions of the Case Report Form must be implemented 
by participating sites immediately on receipt. 
The following data may not be captured in the source data, e.g., Quality of Life which will be recorded directly onto 
the Case Report Form.  
22.2 Archiving 
It is the responsibility of the Principal Investigator to ensure all essential trial documentation and source records 
(e.g. signed Informed Consent Forms, Investigator Site Files, Pharmacy Files, participants’ hospital notes, copies 
of CRFs etc.) at their site are securely retained for at least 25 years after the end of the trial or following the 
processing of all biological material collected for research, whichever is the later.  Do not destroy any documents 
without prior approval from the CRCTU Document Storage Manager.  
23. QUALITY MANAGEMENT 
23.1 Site Set-up and Initiation 
All sites will be required to sign appropriate contracts with their National Coordinating Centre prior to participation. 
In addition all participating Investigators will be asked to sign the necessary agreements and registration forms and 
supply a current CV with evidence of recent GCP training to the Trials Office.  All members of the site research 
team will also be required to sign the Site Signature and Delegation Log, which should be returned to the Trials 
Office. Prior to commencing recruitment all sites will undergo a process of initiation.  Key members of the site 
research team will be required to attend either a meeting or a teleconference covering aspects of the trial design, 
protocol procedures, Adverse Event reporting, collection and reporting of data and record keeping.  Sites will be 
provided with an Investigator Site File and a Pharmacy File containing essential documentation, instructions, and 

 
 
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other documentation required for the conduct of the trial.  The Trials Office must be informed immediately of any 
change in the site research team. 
23.2 On-site Monitoring  
Monitoring will be carried out as required following a risk assessment and as documented in the BEACON2 Quality 
Management Plan and the National Coordinating Centre Monitoring Plan for each respective country. It is the 
responsibility of the participating National Coordinating Centre to ensure that the level and process of monitoring 
described in the National Coordinating Centre Monitoring Plan for that country is in accordance with their national 
regulations and to inform the Coordinating Sponsor of any issues.  
Additional on-site monitoring visits may be triggered for example by poor CRF return, poor data quality, low SAE 
reporting rates, excessive number of participant withdrawals or deviations.  If a monitoring visit is required the Trials 
Office will contact the site to arrange a date for the proposed visit and will provide the site with written confirmation. 
Investigators will allow the BEACON2 trial staff access to source documents as requested. More information on 
monitoring will be detailed in the UK Quality Management Plan and the International Monitoring Plan.  
23.3 Central Monitoring  
Where a participant has given explicit consent sites are requested to send in copies of signed Informed Consent 
Forms for in-house review. 
Trials staff will be in regular contact with the site research team to check on progress and address any queries that 
they may have.  Trials staff will check incoming Case Report Forms for compliance with the protocol, data 
consistency, missing data and timing. Sites will be sent Data Clarification Forms requesting missing data or 
clarification of inconsistencies or discrepancies.  
Sites may be suspended from further recruitment in the event of serious and persistent non-compliance with the 
protocol and/or GCP, and/or poor recruitment.  Any major problems identified during monitoring may be reported to 
BEACON2 Trial Management Group, and the relevant regulatory bodies.  This includes reporting serious breaches 
of GCP and/or the trial protocol to the main Research Ethics Committee (REC) and the Medicines for Healthcare 
products Regulatory Agency (MHRA). 
23.4 Audit and Inspection 
The Investigators and institutions involved in the clinical trial will permit trial-related monitoring, audits, ethical 
review, and regulatory inspection(s) at their site, providing direct access to source data/documents.  
Sites are requested to notify the applicable NCC of any inspections by the relevant competent authority. NCC’s will 
notify the UK coordinating centre of any significant audit findings. 
23.5 Notification of Serious Breaches 
In accordance with Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 and its 
amendments the Coordinating Sponsor of the trial is responsible for notifying the licensing authority in writing of 
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• 
The conditions and principles of GCP in connection with that trial or; 
• 
The protocol relating to that trial, within 7 days of becoming aware of that breach  
For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a significant degree: 
• 
The safety or physical or mental integrity of the subjects of the trial; or 
• 
The scientific value of the trial 
National Coordinating Centres and sites are therefore requested to notify the Trials Office of a suspected trial-
related serious breach of GCP and/or the trial protocol. Where the Trials Office is investigating whether or not a 
serious breach has occurred sites are also requested to cooperate with the Trials Office in providing sufficient 
information to report the breach to the MHRA where required and in undertaking any corrective and/or preventive 
action.   
24. END OF TRIAL DEFINITION 
The trial ends when (a) decision has been taken that no further arms will be added and (b) the last arm reaches an 
arm-dropping criterion or maximum sample size and (c) on the date of the last patient last follow-up. The National 
Coordinating Centre will notify the Competent Authority and Research Ethics Committee that the trial has ended 
and will provide them with a summary of the clinical trial report within 6 months of the end of trial.  
The trial results will be included on the clinical trial registry (ISRCTN) and on the Clinical Trials Information System. 
A lay summary will be included on the UK Health Research Authority website, the Clinical Trials Information System, 
and the trial website (https://www.birmingham.ac.uk/research/crctu/trials/beacon2/index.aspx) and the Cancer 
Research UK website.   
25. STATISTICAL CONSIDERATIONS  
25.1 Definition of Outcome Measures 
25.1.1 Primary Outcome 
See Section 3.3.1 for details  
• 
Tier 1 (randomised comparison): Progression-Free Survival time (per the INRC 2017 [2])  
• 
Tier 2 (dose expansion-confirmation cohorts): Definition of a safe and tolerable combination regimen 
25.1.2 Secondary Outcome 
See Section 3.3.2 for details  
• 
Best objective response (complete and partial response) per the INRC 2017 during trial treatment (12 
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• 
Clinical benefit (complete, partial and minor response and stable disease) per the INRC 2017 
• 
Time response to progression/Duration of Response (for responders) 
• 
Overall Survival time  
• 
Quality of life of patients measured by Peds-QL questionnaires 
• 
Incidence and Severity of AEs 
25.1.3 Exploratory/Tertiary Outcome 
See Section 3.3.23 for details 
• 
Quality of life of caregivers measured by Peds-QL questionnaires 
• 
Correlation between objective response using INRC 2017 and PFS/OS 
• 
Changes in circulating biomarkers and tumour molecular profiles in tumour and blood, including analysis 
circulating RNAs and CDNAs, immune response and tumour microenvironment, analyses of genomic 
aberrations in relapsed neuroblastoma (e.g. MYCN, ALK, RAS/MAPK, ATRX among others) and 
development of novel biomarkers. 
25.2 Trial Design 
25.2.1 General Principles  
BEACON2 is designed as a two stage, Phase 1/2 multi-arm platform trial, with the possibility of extending 
recruitment into a Phase 3 evaluation, and additional dose expansion/confirmation cohorts (Tier 2) to be conducted 
(where necessary) before introduction of new agents to the main randomisation (Tier 1). The trial will aim to recruit 
a maximum of 75 patients per arm, with an interim analysis at the end of the first stage, when 40 patients have 
completed six cycles of treatment. At the interim analysis, arms that are clearly inferior can be terminated.  When 
stage 2 is completed (75 patients per arm), recruitment will terminate. The DMC will consider whether there is strong 
evidence that randomisation should continue, and if there is, we will seek to re-open randomisation, and recruit up 
to a total of 112 patients per arm.  
The design allows the introduction of novel agents or regimens as new trial arms, following approval of a substantial 
amendment by the relevant Competent Authority (the MHRA in the UK). This trial will use Bayesian statistical 
methods, largely because they are helpful in interpreting trials in limited populations as they can quantify the 
probability of benefit.  
25.2.2 Sample Size 
Because relapsed neuroblastoma is a rare condition, the sample size is necessarily limited. The target sample sizes 
are therefore partly determined by pragmatic considerations, including the need to maintain clinical engagement, 
and for the trial to report results within a reasonably short period.  
The target sample size for stage 2 is 75 patients per arm.  Based on simulations, we expect this sample size to 
have a reasonable probability of giving a positive result if the true hazard ratio between intervention and comparator 
is in the region of 0.7, and a low probability of showing benefit if it is in fact ineffective or harmful (Table 16).Because 
we do not have extensive data on the expected hazard rate in the comparator group, we assumed three plausible 
scenarios of hazard rate (high, medium and low). With the High hazard rate, approximately 30% of participants 

 
 
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Primary comparisons of the trial will be between each intervention arm and concurrent patients recruited to the 
comparator arm, hence for Arm C, the primary comparison will be between patients randomised to Arm C and those 
randomised to Arm A (the comparator) during the period that Arm C was open. 
25.3.2 Tier 2 
For Tier 2, an assessment will be made after recruitment of 10 patients of whether the toxicity is acceptable for the 
intervention to be incorporated into the main Tier 1 randomisation.   
A Tier 2 arm will be considered not tolerable if ≥3/10 DLTs are identified.  This would indicate a greater than 90% 
posterior probability that the true DLT rate was less than 0.5.  
The decision to move an arm from Tier 2 to the main randomisation (Tier 1) will be taken by the TMG based on 
preclinical rationale, mechanism of action, early signs of activity, low proportion of DLTs, lack of overlapping 
toxicities and feasibility of the combination. For more details, see Section 2 Trial Design. 
25.3.3 Stage 1 interim analysis 
In Tier 1, an interim analysis will be conducted for each arm when 40 patients have been recruited and reached six 
cycles after randomisation.  The timing is a compromise between the need for early evaluation, and allowing enough 
time for a reasonable number of events to occur.  At this interim analysis, possible decisions are: 
• 
Termination of randomisation to the experimental arm, if it does not meet the statistical threshold for 
continuation. The criteria will be based on a combination of PFS events, tumour response, and toxicity. 
• 
Continuation of randomisation to both experimental and comparator arms. 
To determine whether an arm should be terminated, we will calculate a utility score based on occurrence of PFS 
events (death or progression), tumour response and toxicity. Arm termination decisions will use a combination of 
these outcomes, so that unacceptable toxicity or evidence than an intervention is inferior to its comparator in events 
or tumour response would lead to closure of the arm. Full details and operating characteristics will be presented in 
the SAP. 
Progression to stage 2 is also dependent on there being no external or operational reasons for terminating 
randomisation to that arm (e.g. unavailability of the drug). Results of the interim analyses will be provided to the 
DMC, who will make recommendations about progression or termination of trial arms. 
25.3.4 Completion of stage 2 
After 75 patients have been recruited to an intervention arm, the trial phase 2 question will be completed and 
recruitment to that arm will be paused. A second interim analysis will be conducted and supplied in confidence to 
the DMC.  Most interventions are expected to be terminated at this point, but the DMC are able to recommend 
continuation of a comparison in exceptional circumstances that require further randomisation. If the DMC 
recommend continuation, randomisation to the arm will be re-opened if this is feasible, and recruitment will continue 
up to a total of 112 patients. The exceptional decision to move to phase 3 will be taken by the TMG, advised by the 
DMC and TSC, considering the following aspects:  
• 
Compelling evidence that further randomisation is necessary 

 
 
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• 
Availability of drug supply for intervention and comparator arms 
• 
Potential competition with other arms  
• 
Feasibility in terms of expected completion of the phase 3 evaluation 
If an arm remains open to recruit up to 112 patients, the relevant comparator arm will also have to remain open.  
25.4 Analysis of Outcome Measures  
The main analytical approaches are summarised here. Full details will be specified in a SAP which will be prepared 
by the trial statisticians and finalised before any analysis is undertaken. 
25.4.1 Statistical Methods 
The main analysis for each intervention arm will be conducted when recruitment to the arm has closed and all 
patients have been followed up for at least 2 years. The final analysis will be conducted when all patients have been 
followed up for at least five years.  All analyses will be undertaken on an intention to treat basis, including all patients 
randomised to each arm, regardless of the intervention actually received. The primary comparisons for each arm 
will be with concurrently-recruited patients from the comparator arm. Further details are included in the SAP. 
The primary comparisons will be with concurrently-recruited patients from the comparator arm, which will be Arm 
A, unless, during the trial, unequivocal emerging evidence suggests the comparator has to be changed. 
Throughout the analyses, we will use a Bayesian statistical approach, so presentation of the results will be based 
around posterior distributions of the parameters of interest derived from the analysis models.  
The primary outcome, progression-free survival time, and overall survival time, are time to event outcomes. They 
are defined as the time from randomisation the first failure event (progression or death). Patients without an event 
at the time of analysis will be censored at their date last seen/last available assessment date. These outcomes will 
be analysed using appropriate survival modelling techniques such as Cox proportional hazards models or 
parametric survival models. We will estimate the hazard ratio between each intervention arm and the comparator 
arm, and estimate the proportion event-free at specific time points.  Models will incorporate prognostically important 
covariates, including factors used for minimisation.  
Time to event outcomes will be illustrated using Kaplan-Meier plots, and results will be presented as plots of the 
posterior distributions of the hazard ratio estimated from the models, and summarised with a point estimate and 
95% interval. 
Analysis of binary response outcomes will use logistic regression models, incorporating relevant covariates, as for 
the primary outcome. Plots of the posterior distributions of parameters will be presented, with point estimates and 
95% intervals. 
Trial research staff will check incoming data for compliance with the protocol, data consistency, missing data and 
timing. Sites will be sent requests for missing data or clarification of inconsistencies or discrepancies. Missing and 
ambiguous data will be queried. If there are extensive missing data, we will consider applying multiple imputation 
methods to adjust for the impact of the missing observations. If there are few missing data, no adjustment will be 
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For analysis of quality of life, we expect no clinically important differences between the treatment arms. We will use 
longitudinal models to analyse the trajectory of quality of life through time in each randomised group.  We will 
estimate the quality of life scores at clinically relevant time points, and the probabilities that differences exceed the 
clinically important threshold of 10 points. 
Change from baseline per timepoint will be reported in a descriptive manner to provide support for the main results. 
An overall effect of the treatment on the QOL scores will be determined. Differences will only be considered as 
clinically relevant if they exceed the 10-point threshold. The proportion of patients experiencing a clinically relevant 
change will be provided as well. For all QOL domains and items, cross-sectional descriptions of the average scores 
will be presented by treatment arm together with confidence intervals and a graphical display of the patterns of 
change over time will be provided. Missing data is a potential major source of bias in HRQOL assessment. In case 
overall compliance is deemed too low (<50%), only a descriptive analysis will be performed instead of the main 
analysis. 
Adverse events will be classified according to CTCAE, and a tabular summary of reported AEs, SAEs and SUSARs 
will be produced. 
25.4.2 Interim Analysis 
Analytical methods for the interim analysis will be the same as for the final analysis (see 25.4.1). 
25.4.3 Subgroup and Other Analyses  
No subgroup analyses of the main outcome variables are planned.  
Analysis of laboratory data will be performed as specified in the analysis plan. 
26. TRIAL ORGANISATIONAL STRUCTURE 
26.1 Sponsor 
The University of Birmingham is the Coordinating Sponsor for this study.  
26.2 Coordinating Sponsor 
The University of Birmingham is the Coordinating Sponsor. The Coordinating Sponsor has delegated the set-up, 
management, and analysis of the trial to the UK Coordinating Centre. The role of the UK Coordinating Centre is 
assumed by the Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham. The trial will be set-
up, managed and analysed in the UK in accordance with CRCTU standard policy and procedures. 

 
 
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26.3 National Coordinating Centres 
National Coordinating Centres are responsible for the conduct of the trial within their own country. The UK 
Coordinating Centre will undertake the responsibilities of National Coordinating Centre in the UK.  
Each National Coordinating Centre (see the introductory pages for the list) will manage the trial in accordance with 
the trial protocol and their standard policy and procedures. 
26.4 Trial Management Group 
A Trial Management Group will be established, and will include the Chief Investigator, University of Birmingham 
Lead Investigator, Pharmacist, Clinical Coordinators, Co-investigators, Patient and Public Involvement and 
Engagement Representatives, the Trial Management Team Leader (or delegate), the Trial Biostatistician, the Trial 
Coordinator, and the Monitor. Other key trial personnel may be invited to join the Trial Management Group as 
appropriate to ensure representation from a range of professional groups.  
26.5 Trial Steering Committee  
An independent Trial Steering Committee will be set up to oversee the conduct of the trial. The Committee will be 
chaired by an independent Chair. Membership will include independent clinicians and at least one participant 
advocate. Selected members of the Trial Management Group including the Chief Investigator and Trial 
Biostatistician will report to the Trial Steering Committee. A secretariat will be provided by the Trial Coordinator.  
The Trial Steering Committee will operate in accordance with a trial specific charter based upon the template 
created by the Damocles Group. 
The Trial Steering Committee will meet shortly before commencement of the trial and then annually thereafter 
(usually be held remotely) after the Data Monitoring Committee meeting.  
The Trial Steering Committee will supervise the conduct of the trial, monitoring progress including recruitment, data 
completeness, losses to follow-up, and deviations from the protocol. They will make recommendations about 
conduct and continuation of the trial to the Coordinating Sponsor. 
26.6 Data Monitoring Committee  
Data analyses will be supplied in confidence to an independent Data Monitoring Committee, which will be asked to 
give advice on whether the accumulated data from the trial, together with the results from other relevant research, 
justifies the continuing recruitment of further participants.  
The Data Monitoring Committee will operate in accordance with a trial specific charter based upon the template 
created by the Damocles Group.  
The Data Monitoring Committee will meet in-person or remotely every 12 months while participants are on 
treatment. Additional meetings may be called if recruitment is much faster than anticipated and the DMC may, at 
their discretion, request to meet more frequently. An emergency meeting may also be convened if a safety issue is 
identified. The Data Monitoring Committee will report to the TMG who will convey the findings of the Data Monitoring 
Committee to the Trial Steering Committee. The Data Monitoring Committee may consider recommending the 

 
 
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discontinuation of the trial if the recruitment rate or data quality are unacceptable or if any issues are identified which 
may compromise participant safety. The trial would also stop early if the interim analyses showed differences 
between treatments that were deemed to be convincing to the clinical community.  
26.7 Participant and Public Involvement  
Members of the public will be mainly represented by patient advocates. They will be involved in all steps of the 
development of the clinical trial: 
• 
Design of the research. A PPI representative will be included on the Trial Management Group and active 
in design discussions. Protocol design will be presented at international conferences, committees and 
cooperative groups with PPI involvement (e.g. ITCC, SIOPEN or NCRI) 
• 
Management and conduct of the research. A PPI Representative will be included in the TMG. The TSC will 
also include PPI representatives.  
• 
Analysis of results: PPI representatives, members of the TMG and TSC will participate to the analysis of 
the results.  
• 
Dissemination of findings: Results will be presented at PPI forum and national/international meetings. 
 
Patient representatives and patient advocacy organisations have been involved in the trial from its inception by 
making substantial contributions to the design of the trial, as well as being on the Trial Management Group, Trial 
Steering Committee and reviewing trial documentation. This will continue throughout the trial. Advocates mainly 
pushed to avoid having chemotherapy-only arms (all current novel arms within the trial include novel promising 
combinations), as chemotherapy alone would not be acceptable for parents; and also for the incorporation of the 
evaluation of QoL for patients and caregivers. Advocates from ITCC and SIOPEN advocate committees have also 
reviewed and supported BEACON2, and will continue to work throughout the trial to disseminate it and promote 
recruitment.  
26.8 Peer Review 
This clinical trial proposal underwent international peer review from the funding organisation (Fight Kids Cancer) as 
well as scientific bodies (SIOPEN, ITCC & NCRI neuroblastoma subgroup). 
27. FINANCE 
This is a clinician-initiated and clinician-led trial funded by Fight Kids Cancer. 
Dinutuximab beta is provided free of charge by Recordati Industria Chimica E Farmaceutica S.P.A, including 
labelling and distribution. Bevacizumab, irinotecan and temozolomide will not be provided free of charge by the 
Coordinating Sponsor and are available commercially.  
No individual per participant payment will be made to Investigators or participants.  
The BEACON2 trial is a National Institute for Health Research (NIHR) Clinical Research Network (CRN) Portfolio 
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28. ETHICAL AND REGULATORY CONSIDERATIONS  
The trial will be performed in accordance with the recommendations guiding physicians in biomedical research 
involving human subjects, adopted by the 18th World Medical Association General Assembly, Helsinki, Finland, 
June 1964, amended at the 48th World Medical Association General Assembly, Somerset West, Republic of South 
Africa, October 1996 (website: http://www.wma.net/en/30publications/10policies/b3/index.html).  
The trial will be conducted in accordance with the protocol, Research Governance Framework for Health and Social 
Care, the applicable UK Statutory Instruments, (which include the Medicines for Human Use Clinical Trials 2004 
and subsequent amendments and the Data Protection Act 2018, Human Tissue Act 2008 and Good Clinical Practice 
(GCP)) and the applicable European regulations (which include the Clinical Trials Regulation (No 536/2014) and 
subsequent amendments) in European Countries. This trial will be carried out under a Clinical Trial Authorisation in 
accordance with the Medicines for Human Use Clinical Trials regulations. The protocol will be submitted to and 
approved by the main Research Ethics Committee (REC) prior to circulation.  
Before any participants are enrolled into the trial, the Principal Investigator at each site is required to obtain local 
R&D approval. Sites will not be permitted to enrol participants until written confirmation of R&D approval is received 
by the Trials Office.  
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments gain the necessary 
local approval. This does not affect the individual clinicians’ responsibility to take immediate action if thought 
necessary to protect the health and interest of individual participants. 
29. CONFIDENTIALITY AND DATA PROTECTION 
Personal data (participants and research staff) recorded on all documents will be regarded as strictly confidential 
and will be handled and stored in accordance with the Data Protection Act 2018 or other relevant data protection 
legislation in each country. The Data Protection Officer will act as the Data Controller for this trial.  
Further information about how data is handled by the University of Birmingham and the CRCTU can be found within 
the CRCTU Privacy Notice (https://www.birmingham.ac.uk/crctu).  
With the participant’s consent, their participant identifiers e.g. National Health Service (NHS) number, or in Scotland 
the Community Health Index (CHI), will be collected at trial entry to allow tracing through the Cancer Registries and 
the NHS Information Centre for Health and Social Care (service formally provided by the Office of National 
Statistics) and to assist with long-term follow-up via other health care professionals (e.g. participant’s GP). 
Participants will be identified using only their unique trial number on the Case Report Form and correspondence 
between an NCC and the participating sites in its country. However, if local regulation/guidance permits, participants 
are asked to give permission for the applicable NCC to be sent a copy of their signed Informed Consent Form which 
will not be anonymised. This will be used to perform in-house monitoring of the consent process and may also be 
forwarded to other health care professionals involved in the treatment of the participant (e.g. participant’s GP) if 
local regulation/guidance permits. 

 
 
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The Investigator must maintain documents not for submission to the applicable NCC (e.g. Participant Identification 
Logs) in strict confidence. In the case of specific issues and/or queries from the regulatory authorities, it will be 
necessary to have access to the complete trial records, provided that participant confidentiality is protected.  
The NCCs will maintain the confidentiality of all participant’s data and will not disclose information by which 
participants may be identified to any third party other than those directly involved in the treatment of the patient and 
organisations for which the patient has given explicit consent for data transfer.  Representatives of the BEACON2 
trial team may be required to have access to participant’s notes for quality assurance purposes but participants 
should be reassured that their confidentiality will be respected at all times. 
30. INSURANCE AND INDEMNITY  
The Coordinating Sponsor will obtain adequate insurance to cover negligent harm arising from the design of the 
protocol and its liabilities in relation to the trial.  
The NCCs are responsible for obtaining insurance to set up and run the trial in their respective countries and for 
ensuring that sites in their country are adequately covered.  
University of Birmingham employees are indemnified by the University insurers for negligent harm caused by the 
design or co-ordination of the clinical trials they undertake whilst in the University’s employment. 
In terms of liability at a site, NHS Trust and non-Trust hospitals have a duty to care for participants treated, whether 
or not the participant is taking part in a clinical trial. Compensation is therefore available via NHS indemnity in the 
event of clinical negligence having been proven. 
The University of Birmingham cannot offer indemnity for non-negligent harm. The University of Birmingham is 
independent of any pharmaceutical company, and as such it is not covered by the Association of the British 
Pharmaceutical Industry (ABPI) guidelines for participant compensation.  
31. PUBLICATION POLICY  
Results of this trial will be submitted for publication in a peer reviewed journal. The manuscript will be prepared by 
the TMG and authorship will be determined by mutual agreement.  
Any secondary publications and presentations prepared by Investigators must be reviewed by the TMG. 
Manuscripts must be submitted to the TMG in a timely fashion and in advance of being submitted for publication, 
to allow time for review and resolution of any outstanding issues.  Authors must acknowledge that the trial was 
performed with the support of the University of Birmingham.  Intellectual property rights will be addressed in the 
corresponding contracts between Coordinating Sponsor and National Coordinating Centres/sites. 
Individual countries will be allowed to publish their efficacy results, however the publication of efficacy results from 
the pooled analysis will take precedence over efficacy result publications of individual countries, unless the TMG 
decides otherwise. 

 
 
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32. DATA AND SAMPLE SHARING 
The CRCTU is committed to responsible and controlled sharing of anonymised clinical trial data with the wider 
research community to maximise potential participant benefit while protecting the privacy and confidentiality of trial 
participants. Data anonymised in compliance with the Information Commissioners Office requirements, using a 
procedure based on guidelines from the Medical Research Council (MRC) Methodology Hubs and Information 
Commissioners Office, will be available for sharing with researchers outside of the trials team within 6 months of 
the primary publication.  
Data resulting from this trial will be shared with the International Neuroblastoma Risk Group (INRG) to contribute to 
the Data Commons database to facilitate international, multi-institutional, interdisciplinary research in childhood 
neuroblastoma. Linked anonymised data (linked using trial, SIOPEN, INRG or another unique identification number) 
may be provided to other 3rd parties (e.g., pharmaceutical companies or other academic institutions) for research 
and safety monitoring. These regulatory authorities or research organisations could be within the UK or abroad. 
This may be to countries outside of Europe where data protection regulations differ. Any such request is carefully 
considered and will only be granted if the necessary procedures and approvals are in place. 
The trial data will participate in the BIOPORTAL study and linkage of data to other SIOPEN studies. 
More detailed information on the CRCTU’s Data Sharing Policy and the mechanism for obtaining data can be found 
on the CRCTU website: https://www.birmingham.ac.uk/research/activity/mds/trials/crctu/index.aspx. 
 
 
 
 
 
 
 

 
 
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33. REFERENCE LIST  
1. 
Brodeur, G.M., et al., Revisions of the international criteria for neuroblastoma diagnosis, staging, 
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79.  
Moreno, L., et al., Bevacizumab, irinotecan or topotecan added to temozolomide for children 
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APPENDIX 1 – ABBREVIATIONS 
AE 
 
ADVERSE EVENT 
AESI 
 
ADVERSE EVENT OF SPECIAL INTEREST 
ALT  
 
ALANINE AMINOTRANSFERASE 
ANC 
 
ABSOLUTE NEUTROPHIL COUNT 
APTT 
 
ACTIVATED PARTIAL THROMBOPLASTIN TIME 
AST 
 
ASPARTATE AMINOTRANSFERASE 
AR 
 
ADVERSE REACTION 
AYA 
 
ADOLESCENT AND YOUNG ADULT 
BIT 
 
BEVACIZUMAB + IRINOTECAN + TEMOZOLOMIDE ARM 
BM 
 
BONE MARROW 
BP 
 
BLOOD PRESSURE 
BSA 
 
BODY SURFACE AREA 
CI  
 
CHIEF INVESTIGATOR  
COG                  CHILDREN’S ONCOLOGY GROUP 
CNS 
 
CENTRAL NERVOUS SYSTEM 
CR 
 
COMPLETE RESPONSE 
CRF  
 
CASE REPORT FORM 
CR UK  
CANCER RESEARCH UK 
CRCTU  
CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) 
CRN 
 
CLINICAL RESEARCH NETWORK 
CSR 
 
CLINICAL STUDY REPORT 
CT 
 
COMPUTERISED TOMOGRAPHY 
CTC 
 
COMMON TERMINOLOGY CRITERIA  
CTCAE  
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 

 
 
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dbIT 
 
DINUTUXIMAB BETA + IRINOTECAN + TEMOZOLOMIDE ARM 
dbBIT 
 
DINUTUXIMAB BETA + BEVACIZUMAB + IRINOTECAN +TEMOZOLOMIDE ARM 
DLT  
 
DOSE LIMITING TOXICITY 
DMC 
 
DATA MONITORING COMMITTEE 
DNA  
 
DEOXYRIBONUCLEIC ACID 
efs 
 
EVENT FREE SURVIVAL 
ema 
 
eUROPEAN MEDICINES AGENCY 
eRDC 
 
ELECTRONIC REMOTE DATA CAPTURE 
EOT 
 
END OF TREATMENT 
FDG-PET  
FLUORODEOXYGLUCOSE - POSITRON EMISSION TOMOGRAPHY 
FFPE 
 
FORMALIN-FIXED PARAFFIN EMBEDDED 
GCP 
 
GOOD CLINICAL PRACTICE 
G-CSF  
GRANULOCYTE COLONY STIMULATING FACTOR 
GD2 
GANGLIOSIDE EXPRESSED ON THE SURFACE OF THE MAJORITY OF NEUROBLASTOMA 
TUMOURS 
GFR 
 
GLOMERULAR FILTRATION RATE 
GM-CSF  
GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR 
GGT 
 
GAMMA-GLUTAMYL TRANSPEPTIDASE 
GP 
 
GENERAL PRACTITIONER 
HR 
 
HEART RATE  
IB 
 
INVESTIGATOR BROCHURE 
ICF 
 
INFORMED CONSENT FORM 
ICH                    INTERNATIONAL CONFERENCE ON HARMONISATION 
IMP 
 
INVESTIGATIONAL MEDICINAL PRODUCT 
INR 
 
INTERNATIONAL NORMALISED RATIO 
INRC                INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA 

 
 
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INRG 
 
INTERNATIONAL NEUROBLASTOMA RISK GROUP 
INSS 
 
INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM 
IRF 
 
INSTITUTIONAL REVIEW BOARD 
ISF 
 
INVESTIGATOR SITE FILE 
ITCC 
 
INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER 
IV 
 
INTRAVENOUS 
MIBG 
 
META-IODO-BENZYL-GUANIDINE 
MHRA  
MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY 
MRI 
 
MAGNETIC RESONANCE IMAGING 
MYCN  
MYELOCYTOMATOSIS VIRAL RELATED ONCOGENE 
NCI 
 
NATIONAL COORDINATING INVESTIGATORS 
NCC 
 
NATIONAL COORDINATOR 
NR 
 
NO RESPONSE 
OS 
 
OVERALL SURVIVAL 
OTC 
 
OVER THE COUNTER 
PD 
 
PROGRESSSIVE DISEASE 
PFS 
 
PROGRESSION FREE SURVIVAL 
PI  
 
PRINCIPAL INVESTIGATOR 
PIS 
 
PARTICIPANT INFORMATION SHEET 
PJP 
 
PNEUMOCYSTIS JIROVECII PNEUMONIA 
PK 
 
PHARMACOKINETICS 
PRES 
 
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME 
PO 
 
ORALLY 
PR 
 
PARTIAL RESPONSE 
REC 
 
RESEARCH ETHICS COMMITTEE 
RNA 
 
RIBONUCLEIC ACID 

 
 
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SAE 
 
SERIOUS ADVERSE EVENT 
SAR 
 
SERIOUS ADVERSE REACTION 
SD 
 
STABLE DISEASE 
SIOPEN               INTERNATIONAL SOCIETY PAEDIATRIC ONCOLOGY EUROPEAN  
      
              NEUROBLASTOMA GROUP  
SNP 
 
SINGLE NUCLEOTIDE POLYMORPHISM 
SPC 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
SUSAR  
SUSPECTED UNEXPECTED SEVERE ADVERSE REACTION 
TH 
 
TYROSINE HYDROXYLASE 
TMG 
 
TRIAL MANAGEMENT GROUP 
TSC 
 
TRIAL STEERING COMMITTEE 
UAR 
 
UNEXPECTED ADVERSE REACTION 
ULN 
 
UPPER LIMIT OF NORMAL 
VTE 
 
VENOUS THROMBO-EMBOLISM 
VEGF 
 
VASCULAR ENDOTHELIAL GROWTH FACTOR 
VGPR 
 
VERY GOOD PARTIAL RESPONSE 
WMA 
 
WORLD MEDICAL ASSOCIATION 
 
 
 

 
 
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APPENDIX 2 - TUMOUR STAGING - INRC CLASSIFICATION [2] 
Primary Tumor 
Response of primary tumor using both RECIST criteria and MIBG (or FDG if tumor is MIBG nonavid) uptake will be 
used. In patients with bilateral adrenal lesions, response will be based on the sum of the longest dimensions of both 
sites unless biopsy proves one to be ganglioneuroma. In patients with multifocal nonadrenal disease, the largest 
tumor will be considered the primary tumor, and additional lesions will be assessed as metastatic sites unless biopsy 
proven to be ganglioneuroma.  
 In some patients, it may be difficult to distinguish postoperative changes in soft tissues in the primary tumor bed 
from true residual neuroblastoma using anatomic imaging alone. This is particularly true when residual soft tissue 
masses are small (1 cm at longest diameter). For this reason, patients with MIBG-nonavid lesions measuring less 
than 1 cm in diameter would be considered to have achieved complete response (CR) in the primary site if the 
tumor was initially MIBG avid. For patients with MIBG-nonavid tumors at the time of diagnosis, small residual tumors 
must not demonstrate increased metabolic activity by FDG-PET imaging and, if biopsied, must not demonstrate 
neuroblastoma or ganglioneuroblastoma . 
Primary (soft tissue) Tumor Response 
 
  
 

 
 
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Metastatic Soft Tissue and Bone Disease 
Tumour Response at Metastatic Soft Tissue 
and Bone Sites 
A 
combination 
of 
anatomic 
imaging 
and 
radionuclide scans will be used to assess 
response in soft tissue (including lymph node and 
non–lymph node) and bone metastases MIBG 
semiquantitative scoring systems have been 
previously used for response assessment with 
international consensus developed for use of 
these scoring systems in disease response. 
Although differences exist in the approach to 
absolute scoring in the various systems, 
comparisons of the relative scores as defined by 
the SIOPEN scoring system and the Curie 
scoring system (used in COG) have yielded 
consistent designations of response and have 
validated MIBG relative scoring as prognostic for 
overall response and patient outcome in patients 
with newly diagnosed neuroblastoma. The 
consensus recommendation is to use the MIBG 
relative score on bone sectors (the absolute score 
of bone lesions at time of response assessment 
divided by the absolute score of bone lesions at 
baseline before therapeutic interventions) for 
response assessment. The same scoring method 
(e.g., Curie, SIOPEN) should be used at each 
time point of response assessment. 
MIBG-SPECT or MIBG-SPECT/CT may be used 
for scoring purposes, but the same imaging 
methodology should be used for all evaluations. 
 
 

 
 
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Bone Marrow Metastases 
Bone Marrow Metastasis Response* 
Exact quantification of bone marrow involvement at 
all sites should be reported; the percentage of 
tumor infiltration of bone marrow space assessed 
by histologic evaluation of trephine or biopsy (with 
immunohistochemical staining encouraged) or 
counting of the number of tumor cells in aspirates 
by cytology or immunocytology (recommended if 
available) divided by the number of hematopoietic 
or mononuclear cells evaluated to obtain a 
percentage of involvement (methodology described 
by Burchill et al). The bone marrow sample with the 
highest percentage of tumor infiltration is used in 
the response algorithm. Neuroblastoma infiltration 
in the marrow can be heterogeneously distributed 
throughout the skeleton. Because the clinical 
impact of this heterogeneity has not yet been fully 
evaluated, detection of more than 0% to # 5% tumor 
infiltration in bone marrow will represent a new 
category of minimal disease. 
Overall Response 
Determination of Overall Response 
Overall response will be defined by combining 
response of the individual components (i.e., soft 
tissue, bone, and bone marrow disease). All 
components must be evaluated and of sufficient 
quality to fully assess overall response. An overall 
CR requires that all involved components have a 
CR. An overall partial response includes a partial 
response of all soft tissue and bone sites or 
noninvolvement in one of these components but 
allows residual minimal disease in the bone 
marrow. The prior category of mixed response has 
been eliminated, and a new category, minor 
response, has been included. Minor response 
requires a partial response or CR in at least one 
component, stable disease for at least one 
component, and no evidence of progressive 
disease in any component. Progressive disease in 
any one component defines overall progressive 
disease. 
 

 
 
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Overall Response Criteria 
 

 
 
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APPENDIX 3 - SIOPEN SCORING METHODS FOR NEUROBLASTOMA  
The SIOPEN Method 
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 the prospective phase 
3 neuroblastoma trial. [77, 78] 
Where the MIBG is negative, FDG-PET/CT is used. The total number 
of discrete metastatic and bone-avid lesions should be recorded. 
 
 
 
 
 
 

 
 
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APPENDIX 4 – LANKSY AND KARNOFSKY 
LANSKY PLAY SCALE 
100 % 
Fully active, normal  
90% 
Minor restrictions in strenuous physical activity  
80%  
Active, but tired more quickly  
70% 
Greater restriction of play and less time spent in play activity  
60% 
Up and around, but active play minimal; keeps busy by being involved in quieter activities  
50% 
Lying around much of the day, but gets dressed; no active playing participates in all quiet play and activities  
40% 
Mainly in bed; participates in quiet activities  
30% 
Bedbound; needing assistance even for quiet play  
20% 
Sleeping often; play entirely limited to very passive activities  
10 % 
Doesn’t play; does not get out of bed  
0% 
Unresponsive  
 
 
 

 
 
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APPENDIX 6 - WMA DECLARATION OF HELSINKI  
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Recommendations guiding physicians 
in biomedical research involving human subjects 
Adopted by the 18th World Medical Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
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 fulfillment of this mission. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, "The Health of my 
participant will be my first consideration," and the International Code of Medical Ethics declares that, "A physician 
shall act only in the participant's interest when providing medical care which might have the effect of weakening the 
physical and mental condition of the participant." 
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 recognized between medical research in which 
the aim is essentially diagnostic or therapeutic for a participant, 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. 

 
 
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I. BASIC PRINCIPLES 
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. 
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 regulations of the country in which the research experiment is 
performed. 
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. 
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. 
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. 
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 and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
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. 
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. 
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. 
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. 
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 

 
 
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national legislation. Whenever the minor child is in fact able to give a consent, the minor's consent must be obtained 
in addition to the consent of the minor's legal guardian. 
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) 
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, reestablishing health or alleviating suffering. 
The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the 
best current diagnostic and therapeutic methods. 
In any medical study, every participant - 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. 
The refusal of the participant to participate in a study must never interfere with the physician-participant relationship. 
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 (I, 2). 
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 participant. 
III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (Non-Clinical 
Biomedical Research) 
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. 
The subject should be volunteers - either healthy persons or participants for whom the experimental design is not 
related to the participant's illness. 
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. 
In research on man, the interest of science and society should never take precedence over considerations related 
to the wellbeing of the subject. 
 
 
 

 
 
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APPENDIX 7 - DEFINITION OF ADVERSE EVENTS  
Adverse Event (AE) 
Any untoward medical occurrence in a participant or clinical trial subject administered a medicinal product and which 
does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including abnormal laboratory findings), symptom 
or disease temporally associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. 
Adverse Reaction (AR) 
All untoward and unintended responses to an IMP related to any dose administered.  
An AE judged by either the reporting Investigator or Sponsor as having causal relationship to the IMP qualifies as 
an AR. The expression reasonable causal relationship means to convey in general that there is evidence or 
argument to suggest a causal relationship. 
Serious Adverse Event (SAE) 
Any untoward medical occurrence or effect that at any dose:  
• 
Results in death (unrelated to original cancer) 
• 
Is life threatening* 
• 
Requires hospitalisation** or prolongation of existing in-participant hospitalisation 
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Or is otherwise considered medically significant by the Investigator*** 
The term severe is often used to describe the intensity (severity) of a specific event. This is not the same as serious, 
which is based on participants/event outcome or action criteria. 
* Life threatening in the definition of a Serious Adverse Event refers to an event in which the participant was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were 
more severe. 
**Hospitalisation is defined as an unplanned, formal in participant admission, even if the hospitalisation is a 
precautionary measure for continued observation. Thus, hospitalisation for protocol treatment (e.g., line insertion), 
elective procedures (unless brought forward because of worsening symptoms) or for social reasons (e.g., respite 
care) are not regarded as an SAE. 
*** Medical judgment should be exercised in deciding whether an Adverse Event is serious in other situations. 
Important Adverse Events that are not immediately life threatening or do not result in death or hospitalisation but 
may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition 
above, should be considered serious. 
Serious Adverse Reaction (SAR) 
An Adverse Reaction which also meets the definition of a Serious Adverse Event. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Serious Adverse Reaction that is unexpected i.e., the nature, or severity of the event is not consistent with the 
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A Suspected Unexpected Serious Adverse Reaction should meet the definition of an Adverse Reaction, 
Unexpected Adverse Reaction and Serious Adverse Reaction. 
Unexpected Adverse Reaction (UAR) 
An Adverse Reaction, the nature or severity of which is not consistent with the Reference Safety Information.  
When the outcome of an Adverse Reaction is not consistent with the Reference Safety Information, the Adverse 
Reaction should be considered unexpected. 
Related Event 
An event which resulted from the administration of any of the research procedures. 
Unexpected and Related Event  
An event which meets the definition of both an Unexpected Event and a Related Event. 
Unexpected Event 
The type of event that is not listed in the protocol as an expected occurrence. 
 
 

 
 
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APPENDIX 8 - COMMON TOXICITY CRITERIA GRADINGS 
Toxicities will be recorded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 
5.0.  The full CTCAE document is available on the National Cancer Institute (NCI) website and is provided in the 
Investigator Site File. 
 
 
 

 
 
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APPENDIX 9 – PEDSQL™ ADMINISTRATION GUIDELINES 
The following guidelines are intended for use by individuals trained in the administration of standardized 
questionnaires.  The PedsQL™ administrator is crucial in developing rapport with the respondents, emphasizing 
the importance of the questionnaire, addressing concerns, and ensuring that the PedsQL™ is completed accurately 
and confidentially.   
General Protocol 
Create a procedure for assigning identification numbers that will allow for parent/child comparisons as well as 
comparisons of baseline/follow-up data. 
If feasible, the PedsQL™ should be completed before the respondents complete any other health data forms and 
before they see their physician or healthcare provider. 
The parent/child should first complete the PedsQL™ Generic Core Scales and then complete any additional 
PedsQL™ Module. 
Parents, Children (8-12) and Teens (13-18) may self-administer the PedsQL™ after introductory instructions from 
the administrator.  If the administrator determines that the child or teen is unable to self-administer the PedsQL 
(e.g., due to illness, fatigue, reading difficulties), the PedsQL should be read aloud to the child or teen.  For the 
Young Child (5-7), the PedsQL™ should be administered by reading the instructions and each item to the young 
child word for word.  At the beginning of each subscale repeat the recall interval instructions (one month or 7 days) 
to remind the young child to respond only for that specific recall interval.  Use the separate page with the three 
faces response choices to help the young child understand how to answer.  When reading items aloud to a child, 
intonation should be kept neutral to avoid suggesting an answer. 
If a child has difficulty understanding the age-appropriate PedsQL, the preceding age group version may be 
administered to the child (e.g., administering the Young Child (5-7) Self-Report version with the three faces 
response choices to an 8 year old).  However, if a child presents with severe cognitive impairments (as determined 
by the administrator), the PedsQL may not be appropriate for that child.  In such cases, only the Parent-Proxy 
Report should be administered to the child’s parent. 
The parent and child must complete the questionnaires independently of one another. Discourage the parent, child, 
or other family members from consulting with one another during the completion of the questionnaire.  Let them 
know that they can feel free to discuss their answers following completion of the questionnaires, but that it is 
important to get both the parent’s and the child’s individual perspectives.  If you are administering the questionnaire 
to the child, the child should be facing away from the parent. 
If the child or parent has a question about what an item means or how they should answer it, do not interpret the 
question for them.  Repeat the item to them verbatim.  Ask them to answer the item according to what they think 
the question means.  If they have trouble deciding on an answer, ask them to choose the response that comes 
closest to how they feel. The child and/or the parent has the option of not answering a question if they truly do not 
understand the question.  
If a parent/child asks you to interpret the responses, tell her/him that you are not trained to interpret or provide a 
score for the answers given.  If the PedsQL™ is being used for a clinical study, let the parent/child know that their 
answers will be combined with other participants’ answers and analyzed as a group rather than as individual 
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Document all reasons for refusals and non-completions of the PedsQL™. 
Administering the PedsQL™ 
The following scripts have been developed as a guide to introduce the PedsQL™ to the child and his/her parent(s).  
Modify the language to a style that is most appropriate for you and the respondent. 
For the child: 
The PedsQL™ asks you questions about how you feel and what you think about your health.  It is not a test, and 
there are no right or wrong answers.  It takes about 5 minutes to complete.   If you have any questions, please let 
me know. 
For the parent: 
The PedsQL™ is a questionnaire that assesses health-related quality of life in children and adolescents.  It contains 
questions about your child’s physical, emotional, social, and school functioning in the past one month (or for the 
Acute version, in the past 7 days).   
The PedsQL™ is brief and typically takes less than 5 minutes to complete.  It is not a test, and there are no right or 
wrong answers.  Please be sure to read the instructions carefully and choose the response that is the closest to 
how you truly feel.  Please do not compare your answers with your child's responses.  We are interested in your 
and your child’s individual perspectives.  However, feel free to discuss the questionnaire with your child after you 
have both completed it and returned it to me.  If you have any questions, please let me know. 
General Protocol 
Provide the respondent with a pen or pencil and a solid writing surface.  If a table is not available, the participant 
should be provided with an item such as a clipboard.  Remain nearby should questions or concerns arise. 
When the parent/child returns the PedsQL™, look it over and check to see that all answers have been completed.  
Verify that no item has more than one response.  If any responses are incomplete, illegible, or there are multiple 
responses for an item, please ask the parent or child to indicate their response.   
Ask the participants if they had any difficulties completing the questionnaire or if they have any other comments 
regarding the questionnaire.  Document any important feedback. 
Thank the parent and child for taking the time to complete the questionnaire.  If the study design involves following 
up with these respondents, let them know that they may be asked to complete the PedsQL™ again at another time.  
Indicate when they can expect to be contacted again if known.