BEACON 2: A Multi-Arm, Multi-Stage Platform Trial For Relapsed Neuroblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The University Of Birmingham

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-08-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Instituto de Salud Carlos III · Princess Máxima Center for Pediatric Oncology · Fight Kids Cancer · Danish Childhood Cancer Foundation · KickCancer · St. Anna Children´s Cancer Research Institute GmbH (CCRI) · Institutional and Pediatric Cancer Foundation · Direction générale de l'offre de soins (DGOS) · Recordati UK Ltd · Kom op tegen kanker

External identifiers

EU CT number

2024-516115-24-00

ClinicalTrials.gov

NCT07334301

ISRCTN

ISRCTN12532102

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacokinetic, Efficacy, Therapy, Safety

1) To determine whether new novel therapy regimens improve progression free survival in relapsed neuroblastoma compared to dbIT - Tier 1 (randomised comparison)
2) To determine a safe and tolerable dose for novel treatment combinations in relapsed neuroblastoma - Tier 2 (dose confirmation cohort)

Secondary objectives 2

1. All secondary outcomes will compare treatment arms to dbIT
2. Clinical o To evaluate the effect of novel therapy regimens on overall survival o To evaluate the effect of novel therapy on objective response and clinical benefit o To evaluate the effect of novel therapy on duration of response o To evaluate the effect of novel therapy on quality of life o To evaluate the effect of novel therapy on safety.

Conditions and MedDRA coding

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), which is histologically proven as per International Neuroblastoma Staging System (INSS) definition.

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001314-PIP01-12

Plan to share IPD

Yes

IPD plan description

The CRCTU is committed to responsible and controlled sharing of anonymised clinical trial data with the wider research community to maximise potential patient 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 the first randomisation within this trial, Arm A vs Arm B, will be shared with Recordati UK Ltd to contribute to approval of dB within the USA. Data on the first 80 patients recruited will be shared for the purposes of obtaining a BLA, this data sharing will be performed as per a data sharing agreement. More information here: https://www.birmingham.ac.uk/research/crctu/Data-sharing-policy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Disease specific: Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition
2. Disease Specific: 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)
3. Disease Specific: Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG or FDG PET/CT/MRI 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
4. General: Age ≥1 year
5. General: Signed informed consent from participant, parent or guardian
6. Performance and organ function: Performance Status - 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)
7. Performance and organ function: Life expectancy of ≥12 weeks
8. Performance and organ function: Bone marrow function (within 72 hours prior to randomisation) - Platelets ≥ 50 x 109/L (unsupported for 72 hours), ANC ≥ 0.50 x 109/L (no G-CSF support for 72 hours) and Haemoglobin > 8 g/dL (transfusions allowed)
9. Performance and organ function: Renal function (within 72 hours prior to randomisation) - 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 and 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
10. Performance and organ function: Liver function (within 72 hours prior to randomisation) - 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
11. Performance and organ function: Coagulation - Participants must not have an active uncontrolled coagulopathy. 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.
12. Performance and organ function: 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.
13. Tier 2 Specific Inclusion Criteria: More than one relapse event or ineligible for Tier 1. 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): bevacizumab, any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’) and previous treatment with temozolomide with irinotecan

Exclusion criteria 19

1. Known contraindication or hypersensitivity to: Any study drug or component of the formulation, Chinese hamster ovary products or other recombinant human or humanised antibodies and 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.
2. 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.
3. Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis) or any ongoing arterial thrombo-embolic events
4. A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis.
5. Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive prophylaxis for PJP.
6. Uncontrolled infection
7. Inadequate recovery from prior surgery with ongoing ≥ Grade 3 surgical complications. Grade ≥ 2 wound dehiscence.
8. 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: Core biopsies within previous 24hr, Open excisional biopsies within previous 48hr, Major surgery within previous 2 weeks, Bone marrow aspirates/trephines, within previous 48hr and Tunnelled central line insertion within previous 48hr
9. Washout from prior treatments (at start of trial treatment): Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens), Any anti-GD2 therapy within previous 2 weeks, Craniospinal radiotherapy or MIBG therapy within previous 6 weeks, Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy), Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within previous 8 weeks, Allogeneic stem cell transplant within previous 12 weeks (with absence of active ≥ G2 acute GVHD) and 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial
10. 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
11. Use of enzyme inducing anticonvulsants within 72hr of start of trial treatment
12. Conditions that increase the risk of bevacizumab-related toxicities: History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation), History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment and Current chronic intestinal inflammatory disease/bowel obstruction
13. Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose
14. 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.
15. Pregnant or lactating participant
16. Live or live-attenuated vaccines given within previous 28 days prior to study enrolment
17. Any uncontrolled medical condition that poses an additional risk to the participant
18. Tier 1 Specific Exclusion Criteria: More than one relapse event after the start of high risk neuroblastoma therapy
19. Tier 1 Specific Exclusion Criteria: Previous treatments that are not allowed - Bevacizumab for relapsed neuroblastoma. Patients who have received BIT for refractory disease are not excluded, providing no progression of disease during this treatment occurred and 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-Free Survival time (as per INRC 2017) – for Tier 1 (randomised comparison)
2. Definition of a safe and tolerable combination regimen – for Tier 2 (dose confirmation cohorts)

Secondary endpoints 18

1. Tier 1 Overarching Secondary Endpoint: Best objective response (complete or partial response) as per INRC 2017 during trial treatment (12 cycles) as per investigator assessment
2. Tier 1 Overarching Secondary Endpoint: Clinical benefit (complete, partial, minor response or stable disease) as per the INRC 2017 as per investigator assessment.
3. Tier 1 Overarching Secondary Endpoint: Duration of response (for responders (CR or PR) only)
4. Tier 1 Overarching Secondary Endpoint: Overall Survival time
5. Tier 1 Overarching Secondary Endpoint: Quality of life measured by Peds-QL questionnaires
6. Tier 1 Overarching Secondary Endpoint: Incidence and Severity of toxicities (AEs & SAEs)
7. Tier 1 BICR Specific Secondary Endpoints (Arms A and B): Confirmed Objective Response (complete or partial response) as per INRC 2017 at any time during 6 and 12 cycles of treatment, responses confirmed by BICR. (N.B. the cycle 6 time point forms the primary outcome for the purposes of BLA submission)
8. Tier 1 BICR Specific Secondary Endpoints (Arms A and B): Duration of Confirmed Objective Response (for BICR confirmed responders (CR or PR))
9. Tier 1 BICR Specific Secondary Endpoints (Arms A and B): Confirmed Objective Response (complete or partial response) as per INRC 2017 at the end of 6 cycles of treatment, responses confirmed by BICR
10. Tier 1 BICR Specific Secondary Endpoints (Arms A and B): Extended Confirmed Objective Response (complete, partial or minor response) as per INRC 2017 at any time during 6 cycles and 12 cycles of treatment, responses confirmed by BICR
11. Tier 1 BICR Specific Secondary Endpoints (Arms A and B): Duration of Extended Confirmed Response (for BICR confirmed responders (CR, PR, MR))
12. Tier 2 Specific Secondary Endpoint: Best Objective Response (complete or partial response) as per INRC 2017 during treatment (12 cycles)
13. Tier 2 Specific Secondary Endpoint: Clinical benefit (complete, partial and minor response and stable disease) as per the INRC 2017
14. Tier 2 Specific Secondary Endpoint: Quality of life measured by Peds-QL questionnaires
15. Tier 2 Specific Secondary Endpoint: Incidence and Severity of toxicity (AEs and SAEs)
16. Tier 1 – Arm A Specific Secondary Endpoints (Laboratory): To measure dinutuximab beta serum concentration immediately pre-Db infusions and immediately post- Db infusions
17. Tier 1 – Arm A Specific Secondary Endpoints (Laboratory): To measure ADA to dinutuximab beta immediately pre-Db infusion
18. Tier 1 – Arm A Specific Secondary Endpoints (Laboratory): To measure CDC immediately pre-Db and immediately post-Db infusion

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 12

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The University Of Birmingham

Sponsor organisation

The University Of Birmingham

Address

Vincent Drive

City

Birmingham

Postcode

B15 2TT

Country

United Kingdom

Scientific contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Public contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Third parties 11

Locations

10 EU/EEA countries · 48 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 246 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications