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A Multi-Arm, Platform Trial For Relapsed Neuroblastoma

ConditionRelapsed Neuroblastoma
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age1+
SponsorUniversity of Birmingham

About this trial

Neuroblastoma is one of the most common solid childhood tumours, and a major cause of cancer-related death in children. More than 1200 children/young adults a year are diagnosed in USA and Europe. Around 600 of these cases are considered high-risk, which means the cancer is more difficult to treat successfully. Despite improvements in survival over recent decades, a significant proportion of patients with high-risk neuroblastoma have disease that does not respond to standard treatments (refractory neuroblastoma) or comes back after completion of standard frontline treatment (relapsed neuroblastoma). Therefore, there is a need to develop new treatment strategies and test new drugs to improve outcomes for children with neuroblastoma.

Aims Of The BEACON2 Trial

* To improve survival for patients with relapsed neuroblastoma by developing new treatment combinations * To evaluate new treatment combinations in relapsed neuroblastoma, within a phase I/II trial that can impact clinical practice, while also allowing dose confirmation for new promising combinations * To evaluate the safety, activity, efficacy and impact on quality of life of these new treatment combinations in relapsed neuroblastoma patients * To improve our understanding of relapsed neuroblastoma biology and advance the development of targeted therapies using biomarkers, by conducting a comprehensive biomarker sample collection.

Trial Design BEACON2 is a randomised phase I/phase II, open label, international trial. The trial will have two tiers: Tier 1 will be the main randomisation for two treatment arms initially. Participants will be randomised at trial entry to receive one of the available regimens, treatment A or treatment B. Tier 2 will include smaller dose expansion/confirmation cohorts for more novel experimental treatment combinations (Arm C and future arms), with the potential for them to be moved to Tier 1.

Current Tier 1 (Randomisation Tier) Treatment Arms in the BEACON2 Trial:

Arm A: dbIT Treatment with dinutuximab beta, irinotecan, and temozolomide, 3 weekly x12 cycles Arm B: BIT Treatment with bevacizumab, irinotecan, and temozolomide, 3 weekly x12 cycles

Current Tier 2 (Registration Only Tier) Treatment Arms in the BEACON2 Trial:

Arm C: dbBIT Treatment with dinutuximab beta, bevacizumab, irinotecan, and temozolomide, 3 weekly x12 cycles

Patient Population and Sample Size Patients aged ≥1 years of age with relapsed neuroblastoma. For each arm in Tier 1, up to 75 patients will be recruited to complete phase 2 investigations. For each arm in Tier 2, 10 patients will be recruited to complete phase I investigations. Approximately 160 participants are initially planned, 75 in each arm of Tier 1 and 10 participants for one dose-confirmation cohort in Tier 2.

The study is expected to recruit patients for 3 years, and then finish patient follow-up after an additional 5 years.

Translational Sub-study / Biological Studies

It is standard of care for patients diagnosed with relapsed neuroblastoma to:

* Have had a tumour sample collected at point of initial diagnosis (either during biopsy or surgery) * Have bloods collected before they start and during treatment for their relapsed neuroblastoma * Have a bone aspirate/trephine procedure in order to help confirm relapse. These samples provide very important opportunities for further research, and the study investigators would like to make full use of these opportunities by collecting the analysis already performed on these samples and collect some additional samples (at the same time as the standard ones) to learn and understand more about neuroblastoma and its treatment. Samples will undergo research analysis at the national SIOPEN reference laboratories.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

Any study drug or component of the formulation

Chinese hamster ovary products or other recombinant human or humanised antibodies.

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

Trial design

Design model

Parallel

Treatments tested in this trial

  • Bevacizumab

    Drug

    Bevacizumab

  • Dinutuximab beta

    Drug

    Dinutuximab beta

  • Irinotecan (drug)

    Drug

    Irinotecan

  • Topotecan

    Drug

    Topotecan

  • Temozolomide (TMZ)

    Drug

    Temozolomide capsule

  • Temozolomide (TMZ)

    Drug

    Temozolomide liquid suspension

Treatment groups

160 Participants
are divided into 3 treatment groups
Group A: Arm A: dinutuximab, irinotecan and temozolomide (dbIT)Active comparator 4 interventions
Group B: Arm B: bevacizumab, irinotecan and temozolomide (BIT)Experimental treatment 4 interventions
Group C: Arm C: dinutuximab, bevacizumab, irinotecan and temozolomide (dbBIT)Experimental treatment 5 interventions

Trial outcomes

Primary outcomes

1

Progression-Free Survival time

• Progression-Free Survival time (as per International Neuroblastoma Response Criteria (PD Progressive disease, SD Stable disease, MR Minor response, PR Partial response, CR Complete response) INRC 2017) - for Tier 1 (randomised comparison)

Time frame
From date of randomization until the date of first documented failure event (progression or death), assessed up to 60 months.
2

Occurrence of dose-limiting toxicities to definition of a safe and tolerable combination regimen

Tier 2 (dose expansion-confirmation cohorts): Definition of a safe and tolerable (i.e. \</= 3 dose-limiting toxicities) combination regimen

Time frame
From date of randomization until the date of first documented failure event (progression or death), assessed up to 60 months.

Secondary outcomes

1

Best objective response

Best objective response (complete and partial response) per the INRC 2017 during trial treatment (12 cycles)

Time frame
At the end of the last treatment cycle, up to 12 cycles (each cycle is 21 days)
2

Clinical benefit

Clinical benefit (complete, partial and minor response and stable disease) per the INRC 2017 (International Neuroblastoma Response Criteria (PD Progressive disease, SD Stable disease, MR Minor response, PR Partial response, CR Complete response))

Time frame
At the end of the last treatment cycle, up to 12 cycles (each cycle is 21 days)
3

Time response to progression

Time between Response to Progression (i.e. Duration of Response) for patients who respond

Time frame
From date of response (Complete Response, Partial Response or Minor Response as per INRC) until the date of first documented failure event (progression or death), assessed up to 60 months.
4

Overall Survival time

Overall Survival time

Time frame
From date of trial entry until the date of first documented failure event (progression or death), assessed up to 60 months.

Other outcomes

1

Quality of life of caregivers measured by Peds-QL questionnaires

Quality of life of caregivers measured by Pediatric Quality of Life Inventory (Peds-QL) questionnaires. 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher PedsQL 3.0 scores indicate better Health Related Quality of Life (HRQOL)

Time frame
At the end of the last treatment cycle, up to 12 cycles (each cycle is 21 days)
2

Correlation between objective response using INRC 2017 and PFS/OS

Correlation between objective response using INRC 2017 and PFS/OS

Time frame
At the end of the last treatment cycle, up to 12 cycles (each cycle is 21 days)
3

Changes in circulating biomarkers and tumour molecular profiles in tumour and blood

Changes molecular and genetic profile of tumour and blood as measured by genetic analysis at baseline and throughout the study.

Time frame
At the end of the last treatment cycle, up to 12 cycles (each cycle is 21 days)

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

University of Birmingham

Lead sponsor

Source ClinicalTrials.gov
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