Chemo-Immunotherapy for High-Risk Neuroblastoma

Not currently recruiting at 81 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Must not be taking: Corticosteroids, Immunosuppressives, Anticonvulsants, others

Disqualifiers: Progressive disease, MIBG therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 28 days per cycle, up to 5 cycles (6 cycles for isotretinoin)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of chemo-immunotherapy drugs to determine their safety for patients with high-risk neuroblastoma, a type of cancer, after completing initial treatments like stem cell transplants and radiation. The goal is to discover if adding chemotherapy to standard immunotherapy, which uses the body's immune system to fight cancer, improves treatment outcomes. The trial seeks patients with high-risk neuroblastoma who have already received specific treatments and have not experienced cancer progression or recurrence. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot be on certain medications like enzyme-inducing anticonvulsants or strong CYP3A4 inducers/inhibitors within 7 days before joining the study. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of treatments in this trial has been studied for safety in various settings. Dinutuximab, a type of immunotherapy, targets cancer cells while sparing healthy ones. It has helped patients with high-risk neuroblastoma live longer without cancer recurrence. Common side effects include pain and allergic reactions, but these are usually manageable.

Irinotecan, a chemotherapy drug, works effectively but often causes diarrhea, affecting up to 87% of patients. This side effect is well-known and typically treated with supportive care. Temozolomide, another chemotherapy drug, has been studied in children, though it isn't specifically approved for them. However, it is part of the standard treatment for high-risk neuroblastoma and is generally considered safe when monitored closely.

Sargramostim boosts white blood cell production, aiding the body in fighting infections, and is generally well-tolerated by patients. Isotretinoin helps neuroblastoma cells mature and has been studied for safety, though it can cause dryness and other skin-related issues.

Overall, these treatments have been used before, and their side effects are typically manageable. While this trial is in an earlier phase, the inclusion of these drugs in standard care for high-risk neuroblastoma provides some reassurance about their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment approach for high-risk neuroblastoma because it combines chemo-immunotherapy, leveraging the strengths of multiple agents. Dinutuximab is an antibody that specifically targets and helps destroy neuroblastoma cells, a mechanism not typically seen in standard chemotherapy treatments like cyclophosphamide or doxorubicin. Combined with irinotecan and temozolomide, which damage cancer cell DNA, and sargramostim, which boosts the immune response, this regimen represents a novel multi-pronged attack on cancer cells. Additionally, the inclusion of isotretinoin, a vitamin A derivative, helps differentiate residual cancer cells, making them easier targets for the immune system. This comprehensive strategy not only aims to target the cancer more effectively but also to enhance the body’s natural defenses against it.

What evidence suggests that this trial's chemo-immunotherapy treatment could be effective for high-risk neuroblastoma?

In this trial, participants will receive a combination of treatments, including temozolomide, irinotecan, and dinutuximab. Research has shown that dinutuximab can significantly improve outcomes for patients with high-risk neuroblastoma by lowering the risk of death and extending the time patients live without disease progression. Isotretinoin, also included in this trial, has been found to boost survival rates by about 10% in similar patients, making it a crucial part of the treatment regimen. Studies suggest that using sargramostim with anti-GD2 antibodies, such as dinutuximab, can enhance treatment results. Temozolomide has shown promise in extending the time patients live without disease progression. Lastly, irinotecan may help stabilize the disease, although its effectiveness can vary. Together, these treatments offer hope for better long-term outcomes for patients. ^{3 6 7 8 9}

Who Is on the Research Team?

Ami V Desai

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for patients with high-risk neuroblastoma who've completed intensive therapy without disease worsening or recurrence. Eligible participants must have finished 4-6 cycles of chemotherapy, meet specific blood count and organ function criteria, and not have had certain prior treatments like 131I-MIBG therapy or single ASCT. Pregnant women, those on immunosuppressants, or with uncontrolled infections cannot join.

Inclusion Criteria

My cancer is advanced with specific genetic changes.

I have received treatment for my condition before.

I have completed 4-6 cycles of high-risk chemotherapy.

Exclusion Criteria

I've had more cancer treatment after my high-dose chemo and stem cell transplant.

I had one high-dose chemotherapy session with stem cell transplant.

You have had a severe allergic reaction to anti-GD2 antibodies in the past, or had to stop anti-GD2 therapy due to a reaction.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive temozolomide, irinotecan, dinutuximab, sargramostim, and isotretinoin in cycles

28 days per cycle, up to 5 cycles (6 cycles for isotretinoin)

Daily visits during treatment days

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

Follow-up visits at 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months

What Are the Treatments Tested in This Trial?

Interventions

• Dinutuximab
• Irinotecan
• Isotretinoin
• Sargramostim
• Temozolomide

Trial Overview The study tests if a combination of dinutuximab (immunotherapy), GM-CSF (white blood cell booster), isotretinoin (cell maturation aid) along with irinotecan and temozolomide (chemotherapies) is safe after Consolidation therapy in high-risk neuroblastoma patients. This chemo-immunotherapy aims to improve treatment outcomes compared to standard immunotherapy alone.

How Is the Trial Designed?

Group I: Treatment (temozolomide, irinotecan, dinutuximab) Experimental Treatment 13 Interventions

Patients receive temozolomide PO or via enteral tube daily and irinotecan IV over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim SC or IV over 2 hours daily on days 6-12, and isotretinoin PO BID on days 8-21. Patients undergo MUGA during screening. Patients also undergo MRI, or CT, I23I-MIBG, or FDG-PET, BM aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.

Dinutuximab is already approved in United States, European Union for the following indications:

Approved in United States as Unituxin for:

• Neuroblastoma

Approved in European Union as Dinutuximab for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Dinutuximab is a monoclonal antibody that targets GD2, a glycolipid overexpressed in neuroblastoma, and has been approved by the US FDA for treating high-risk neuroblastoma in children when used in combination with other therapies.

The drug works by inducing immune responses that kill cancer cells, and its development has progressed through multiple phases, with ongoing regulatory reviews in the EU and other countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab: first global approval. Dhillon, S.[2019]

In a study of 25 children with relapsed or refractory high-risk neuroblastoma, combining irinotecan/temozolomide chemotherapy with the anti-GD2 antibody dinutuximab beta resulted in a 64% objective response rate, with 32% achieving complete remission.

The treatment was well tolerated, even in patients who had previously received dinutuximab beta, and no patients discontinued due to toxicities, suggesting it is a promising option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma. Wieczorek, A., Zaniewska-Tekieli, A., Ehlert, K., et al.[2023]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

The combination treatment of irinotecan, temozolomide, dintuximab, and GM-CSF (I/T/DIN/GM-CSF) showed significant antitumor activity in patients with relapsed or refractory neuroblastoma, with an overall objective response rate of 41.5% across 53 patients.

The treatment was associated with a one-year progression-free survival rate of 67.9% and an overall survival rate of 84.9%, although it also resulted in notable grade ≥ 3 toxicities, including fever/infection and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. Mody, R., Yu, AL., Naranjo, A., et al.[2021]

In a phase 2 trial involving patients with high-risk neuroblastoma, the combination of irinotecan, temozolomide, and immunotherapy (dinutuximab and GM-CSF) showed a response rate of 53% in the initial cohort, indicating its potential efficacy for treating relapsed or refractory cases.

The study found that specific genotypes related to natural killer (NK) cell activity, particularly KIR and their ligands, were associated with clinical outcomes, highlighting the importance of genetic factors in the effectiveness of the chemoimmunotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group. Erbe, AK., Diccianni, MB., Mody, R., et al.[2023]

In a study involving seven patients with high-risk neuroblastoma, dinutuximab treatment led to complete remission in two patients and partial response in three, highlighting its potential effectiveness in eradicating minimal residual disease.

While dinutuximab shows promise as a first-line treatment for high-risk neuroblastoma, it carries a significant risk of severe adverse reactions, necessitating administration by experienced pediatric oncology centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of immunotherapy into the treatment of neuroblastoma - single center experience with the administration of dinutuximab and management of its adverse effects. Achbergerová, M., Hederová, S., Mikesková, M., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8046731/

Long-term follow-up of a Phase III Study of ch14.18 ... Conclusions: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample ...

2. unituxin.com unituxin.com/hcp/about-unituxin/clinical-trial-data/

Efficacy and Clinical Trial Data 5-year EFS was 57±4.7% for patients randomized to the Unituxin group (n=114) vs 46±5.1% for those randomized to the RA-only group (n=112; P=0.042).4. 5-year EFS ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10729685/

Safety and efficacy of dinutuximab in the treatment of ... High-risk NB responds well to monoclonal antibodies (mAbs) that target GD2. However, different anti-GD2 antibodies have various outcomes and side effects.[7] ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e22000

Efficacy and safety of dinutuximab in the management ... Conclusions: Our findings suggest that dinutuximab is linked to a significant reduction in overall mortality and a noteworthy improvement in the ...

5. link.springer.com link.springer.com/article/10.1007/s11523-025-01155-3

Efficacy and Safety of Anti-GD2 Immunotherapy with ... Where reported, 3-year OS rates for patients receiving dinutuximab beta were 54–86% overall, with better OS rates reported for refractory than ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26917818/

Dinutuximab: An Anti-GD2 Monoclonal Antibody for High- ... Abstract. Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab.

7. aetna.com aetna.com/cpb/medical/data/800_899/0895.html

Dinutuximab (Unituxin) - Medical Clinical Policy Bulletins A nti-GD2-mediated chemo-immunotherapy has a notable anti-tumor activity in patients with r/r high-risk neuroblastoma. In a retrospective, single-center study, ...

8. unituxin.com unituxin.com/hcp/about-unituxin/mechanism-of-action/

Mechanism of Action | Unituxin® (dinutuximab) Injection Unituxin is an anti-GD2 monoclonal antibody that induces tumor cell lysis via multiple mechanisms1. The glycolipid GD2 is an antigen that is expressed on ...

9. journals.lww.com journals.lww.com/jrms/fulltext/2023/09290/safety_and_efficacy_of_dinutuximab_in_the.71.aspx

Safety and efficacy of dinutuximab in the treatment of... Dinutuximab targets high levels of GD2 expression in NB cells, thus increasing event-free survival when used in the maintenance therapy of high-risk patients ...