44 Participants Needed

Nivolumab + Dinutuximab for Neuroblastoma

(MiniVan Trial)

Recruiting at 2 trial locations
DP
Overseen ByDanny Pratt
Age: Any Age
Sex: Any
Trial Phase: Phase 1
Sponsor: University Hospital Southampton NHS Foundation Trust
Stay on Your Current MedsYou can continue your current medications while participating
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are taking systemic corticosteroids or other immunosuppressive agents within 14 days before the study.

What data supports the effectiveness of the drug combination Nivolumab + Dinutuximab for treating neuroblastoma?

Research shows that the drug dinutuximab beta, when used with other treatments, improves survival in patients with high-risk neuroblastoma. Additionally, combining dinutuximab beta with immune checkpoint inhibitors like Nivolumab has shown promising results in preclinical models, suggesting a potential benefit for patients with neuroblastoma.12345

Is the combination of Nivolumab and Dinutuximab safe for treating neuroblastoma?

Dinutuximab, used in treating high-risk neuroblastoma, is generally safe when managed with supportive care, though it can cause pain, allergic reactions, fever, and capillary leak syndrome (fluid leakage from small blood vessels). Safety data for Nivolumab in this specific combination is not provided, but Dinutuximab has been well-tolerated in clinical settings.46789

How is the drug combination of Nivolumab and Dinutuximab Beta unique for treating neuroblastoma?

This drug combination is unique because it combines Nivolumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with Dinutuximab Beta, an antibody that targets neuroblastoma cells, potentially enhancing the immune response against the tumor. This approach is novel as it leverages both immune system activation and direct targeting of cancer cells, which may improve outcomes for patients with high-risk or relapsed neuroblastoma.12345

What is the purpose of this trial?

Neuroblastoma, the most common extra-cranial solid tumour in children, remains one of the major challenges in paediatric oncology. A promising way to further improve outcome in this disease appears to be the development of adjuvant therapeutic strategies. In this research the anti-GD2 antibody, which is a standard treatment, is to be combined with 131-l Metaiodobenzylguanidine (mlBG) and anti-Programmed Cell Death Protein 1 (anti-PD1) antibody Nivolumab - the investigated drugs - with the aim of generating sustained anti-neuroblastoma immunity. In particular it will be determined the safety and tolerability of the novel combination as well as documented any evidence of efficacy in paediatric patients with relapsed and refractory high risk neuroblastoma.This study is sponsored by the University Hospital Southampton and will take place in 4 hospitals in the United Kingdom, Germany and USA. The estimated duration of the study is 2 years, starting in December 2016.This is an "adaptive study". Such design uses accumulating of data from the ongoing trial to modify aspects of the study (e.g. duration, number of treatments) without undermining its validity or integrity. There will be 3 cohorts of patients. As safety of Nivolumab is well established, Cohort 1 will assess its safety and tolerability in combination with 131-l mlBG. Cohort 2 will then add anti-GD2 to the drug combination, assessing safety and tolerability. Cohort 3 will escalate all 3 agents to the full 100% dose level to assure safety for expanded analyses of clinical and laboratory data at that dose level.Patients will initially be recruited into Cohort 1. Patients must have completed at least 12 weeks of trial treatment without reaching a Dose Limiting Toxicity before a patient can be recruited to the next cohort.A minimum of 3 evaluable patients will be treated in cohorts 1-3. Assuming the full dose combination therapy (cohort) is tolerable, 15 evaluable patients will be treated.

Research Team

JG

Juliet Gray

Principal Investigator

Consultant Paediatric Oncologist

Eligibility Criteria

This trial is for children with relapsed/refractory high-risk neuroblastoma. They must have a certain type of active disease visible on imaging, be past specific treatments like myeloablative chemotherapy, and meet health criteria such as adequate organ function and performance status. Children with severe prior reactions to similar therapies or certain medical conditions are excluded.

Inclusion Criteria

MIBG avid disease on imaging within 4 weeks to study entry.
≥ 3 months since any myeloablative chemotherapy / stem cell rescue
≥ 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half lives since last dose of any monoclonal antibody therapy.
See 20 more

Exclusion Criteria

Patients who have previously received ch14.18 (CHO or SP2/0) will not be excluded unless they have had severe or life threatening toxicity necessitating withdrawal of treatment previously or if they have a strong/neutralizing Human Antichimeric Antibody (HACA) (≥ 10 μg/ml)
Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study
You have symptoms of heart failure or an irregular heartbeat that is not under control.
See 12 more

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cohort 1 Treatment

Patients receive 131-I MIBG and Nivolumab to assess safety and tolerability

12 weeks

Cohort 2 Treatment

Patients receive 131-I MIBG, Nivolumab, and anti-GD2 to assess safety and tolerability

12 weeks

Cohort 3 Treatment

Patients receive full dose of 131-I MIBG, Nivolumab, and anti-GD2 for expanded safety analysis

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

  • 131-I mIBG
  • Dinutuximab Beta Antibodies
  • Nivolumab
Trial Overview The study tests the safety and potential effectiveness of combining an anti-GD2 antibody (standard treatment) with two drugs: 131-I mIBG (a radioactive compound) and Nivolumab (an immune system-boosting drug). It's an adaptive trial in three cohorts, gradually increasing doses if safe, across hospitals in the UK, Germany, and USA.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: TreatmentExperimental Treatment2 Interventions
The dose and schedule of 131-I mIBG will be constant, and the doses of ch14.18/ CHO and Nivolumab determined by cohort: * Cohort I: 3 mg/kg Nivolumab (100% adult dose). No ch14.18/CHO. (3-6 patients) * Cohort II: 50mg/m2/cycle ch14.18/CHO (50% established Long Term Intervention (LTI) dose) and 3 mg/kg Nivolumab (100% adult dose) (3-6 patients) * Cohort III: 100mg/m2/cycle ch14.18/CHO (100% established LTI dose) and 3 mg/kg Nivolumab (100% adult dose) (initial 3-6 patients, expanded to 15 patient cohort if tolerated)

Find a Clinic Near You

Who Is Running the Clinical Trial?

University Hospital Southampton NHS Foundation Trust

Lead Sponsor

Trials
221
Recruited
411,000+

University College London Hospitals

Collaborator

Trials
204
Recruited
1,221,000+

University of Wisconsin, Madison

Collaborator

Trials
1,249
Recruited
3,255,000+

University Hospital Greifswald

Collaborator

Trials
5
Recruited
3,900+

Solving Kids' Cancer US/EU

Collaborator

Trials
2
Recruited
110+

Joining Against Cancer in Kids

Collaborator

Trials
1
Recruited
40+

The Band of Parents

Collaborator

Trials
2
Recruited
110+

Findings from Research

In a phase 3 trial involving 406 children and young people with high-risk neuroblastoma, the addition of subcutaneous IL-2 to dinutuximab beta did not improve event-free survival rates compared to dinutuximab beta alone, with 3-year event-free survival rates of 60% and 56% respectively.
The combination treatment with subcutaneous IL-2 resulted in significantly higher toxicity, leading to a lower treatment completion rate (62% vs. 87% for dinutuximab beta alone), indicating that dinutuximab beta with isotretinoin should remain the standard care for these patients.
Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.Ladenstein, R., Pötschger, U., Valteau-Couanet, D., et al.[2022]
Dinutuximab beta (Qarziba®) has been integrated into the standard treatment for high-risk neuroblastoma in Europe, showing positive clinical responses in both first-line and relapsed cases, which has improved patient outcomes.
While effective, dinutuximab beta can cause significant adverse effects such as pain, allergic reactions, and capillary leak syndrome, highlighting the need for optimized management strategies to mitigate these risks.
Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma.Balaguer, J., García Hidalgo, L., Hladun, R., et al.[2023]

References

Combined Blockade of TIGIT and PD-L1 Enhances Anti-Neuroblastoma Efficacy of GD2-Directed Immunotherapy with Dinutuximab Beta. [2023]
Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. [2022]
Dinutuximab Beta Maintenance Therapy in Patients with High-Risk Neuroblastoma in First-Line and Refractory/Relapsed Settings-Real-World Data. [2023]
Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. [2022]
Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. [2021]
Dinutuximab beta in the treatment of high-risk neuroblastoma: A follow-up of a case series in Bratislava. [2023]
Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma. [2023]
Dinutuximab for maintenance therapy in pediatric neuroblastoma. [2019]
Dinutuximab beta plus conventional chemotherapy for relapsed/refractory high-risk neuroblastoma: A single-center experience. [2023]
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